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Mitophagy in tumorigenesis and metastasis

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Abstract

Cells use mitophagy to remove dysfunctional or excess mitochondria, frequently in response to imposed stresses, such as hypoxia and nutrient deprivation. Mitochondrial cargo receptors (MCR) induced by these stresses target mitochondria to autophagosomes through interaction with members of the LC3/GABARAP family. There are a growing number of these MCRs, including BNIP3, BNIP3L, FUNDC1, Bcl2-L-13, FKBP8, Prohibitin-2, and others, in addition to mitochondrial protein targets of PINK1/Parkin phospho-ubiquitination. There is also an emerging link between mitochondrial lipid signaling and mitophagy where ceramide, sphingosine-1-phosphate, and cardiolipin have all been shown to promote mitophagy. Here, we review the upstream signaling mechanisms that regulate mitophagy, including components of the mitochondrial fission machinery, AMPK, ATF4, FoxOs, Sirtuins, and mtDNA release, and address the significance of these pathways for stress responses in tumorigenesis and metastasis. In particular, we focus on how mitophagy modulators intersect with cell cycle control and survival pathways in cancer, including following ECM detachment and during cell migration and metastasis. Finally, we interrogate how mitophagy affects tissue atrophy during cancer cachexia and therapy responses in the clinic.

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Abbreviations

AD:

Alzheimers disease

ADP:

Adenosine diphosphate

ALS:

Amyotrophic lateral sclerosis

AMPK:

5′ AMP-activated protein kinase

ANT:

Adenine nucleotide transporter

ARIH1:

Ariadne RBR E3 ubiquitin protein ligase 1

ASNS:

Asparagine synthetase

ASS1:

Argininosuccinate synthase-1

Atad3a:

ATPase family AAA-domain-containing protein 3 A

ATF4:

Activating transcription factor 4

ATM:

Ataxia telangiectasia mutated

ATP:

Adenosine triphosphate

BCL-2:

Breakpoint cluster locus-2

BCL-XL:

BCL2-like 1 long

BNIP3:

BCL2 interacting protein 3

BNIP3L:

BCL2 interacting protein 3 like

BCL2-L-13:

BCL2-like-13

BRCA1:

Breast cancer 1

CCCP:

Carbonyl cyanide 3-chlorophenylhydrazone

CK2:

Casein kinase-2

CL:

Cardiolipin

DAG:

Diacyl glycerol

DELE1:

DAP3-binding cell death enhancer 1

DTT:

Dithiothreitol

DRP1:

Dynamin-related protein 1

ECM:

Extracellular matrix

ERK:

Extracellular signal-regulated kinase

ETC:

Electron transport chain

FA:

Fanconi anemia

FANC-C:

FA protein C

FIS1:

Mitochondrial fission 1 protein

FoxO3:

Forkhead box protein O3

FKBP8:

FK506-binding protein 8

FUNDC1:

FUN 14 domain-containing 1

GABARAP:

GABA Type A Receptor-Associated Protein

GAP:

GTPase activating protein

cGAS:

Cyclic GMP–AMP synthase

GPX4:

Glutathione peroxidase-4, GTPase activating protein

HIF:

Hypoxia inducible factor

HCC:

Hepatocellular carcinoma

HRI:

Heme-regulated inhibitor

IMM:

Inner mitochondrial membrane

IRF3:

Interferon response factor 3

LC3:

Microtubule-associated protein 1 light chain 3

LIR:

LC3 interacting region

LKB1:

Liver kinase B1

LLC:

Lewis Lung carcinoma

MARCH5:

Membrane-associated ring finger (C3HC4) 5

MCR:

Mitochondrial cargo receptor

MITF:

Melanocyte inducing transcription factor

MFF:

Mitochondrial fission factor

MFN:

Mitofusin

MMP:

Mitochondrial processing peptidase

MPP:

Mitochondrial processing peptidase

mtDNA:

Mitochondrial DNA

MUL1:

Mitochondrial E3 ubiquitin ligase 1

NAC:

N-acetyl cysteine

NAD + :

Nicotinamde adenine dinucleotide

NBR1:

Near BRCA1

NDP52:

Nuclear dot protein 52

NLRP3:

Nucleotide binding domain and leucine rich repeat pyrin domain-containing 3

NR:

Nicotinamide riboside

NRF2:

Nuclear factor, erythroid 2 like

OMM:

Outer mitochondrial membrane

OPTN:

Optineurin

OXPHOS:

Oxidative phosphorylation, p62/SQSTM1

PA:

Phosphatidic acid

PARK2:

Parkin encoding locus

PARK6:

PINK1 encoding locus

PARK8:

LRRK2 encoding locus

PARL:

PINK/PGAM5-associated rhomboid-like proteases

PARP:

Poly-ADP-ribose polymerase

PD:

Parkinson’s disease

PDAC:

Pancreatic ductal adenocarcinoma

PFKFB3:

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 3

PGAM5:

Phosphoglycerate mutase family member 5

PHB-2:

Prohibitin-2

PHGDH:

D-3-phosphoglycerate dehydrogenase

PINK1:

PTEN-induced putative kinase 1

PMI:

P62-mediated mitophagy inducer

PSAT1:

Phosphoserine aminotransferase 1

RAF:

Rapidly accelerated fibrosarcoma oncogene

RHEB:

Ras homolog enriched in brain

ROS:

Reactive oxygen species

S1P:

Sphingosine-1-phosphate

SDS:

Sodium dodecyl sulfide

SPHK1:

Sphingosine kinase 1

SRC:

Rous sarcoma oncogene

STING:

Stimulator of Interferon Genes

TAX1BP1:

Tax1-binding protein 1

TAZ:

Tafazzin

TBK:

TANK-binding kinase 1

TCA:

Tricarboxylic acid cycle

TIM:

Translocase of inner membrane

TFE:

Transcription factor E

TMD:

Transmembrane domain

TNBC:

Triple-negative breast cancer

TOM:

Translocase of outer membrane

ULK1:

Unc-51-like autophagy activating kinase 1

UPRmt :

Mitochondrial unfolded protein response

VPS34:

Vacuolar protein sorting 34

XP:

Xeroderma pigmentosum

ZIP1:

Zinc transporter-1 precursor

References

  1. Palikaras K, Lionaki E, Tavernarakis N (2018) Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol 20(9):1013–1022. https://doi.org/10.1038/s41556-018-0176-2

    Article  CAS  PubMed  Google Scholar 

  2. Macleod KF (2020) Mitophagy and mitochondrial dysfunction in cancer. Ann Rev Cancer Biol 4:41–60

    Google Scholar 

  3. Lazarou M, Sliter DA, Kane LA, Sarraf SA, Wang C, Burman JL, Sideris DP, Fogel AI, Youle RJ (2015) The ubiquitin kinase PINK1 recruits autophagy receptors to induce mitophagy. Nature 524:309–314

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Harper JW, Ordureau A, Heo JM (2018) Building and decoding ubiquitin chains for mitophagy. Nat Rev Mol Cell Biol 19(2):93–108. https://doi.org/10.1038/nrm.2017.129

    Article  CAS  PubMed  Google Scholar 

  5. Geisler S, Holmström KM, Skujat D, Fiesel FC, Rothfuss OC, Kahle PJ, Springer W (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12(2):119–131

    CAS  PubMed  Google Scholar 

  6. Chen Y, Dorn GW (2013) PINK1-phosphorylated Mitofusin-2 is a Parkin receptor for culling damaged mitochondria. Science 340:471–475

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sarraf SA, Raman M, Guarani-Pereira V, Sowa ME, Huttlin EL, Gygi SP, Harper JW (2013) Landscape of the PARKIN-dependent ubiquitylome in response to mitochondrial depolarization. Nature 496:372–376

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Sekine S, Kanamaru Y, Koike M, Nishihara A, Okada M, Kinoshita H, Kamiyama M, Maruyama J, Uchiyama Y, Ishihara N, Takeda K, Ichijo H (2012) Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. J Biol Chem 287(41):34635–34645. https://doi.org/10.1074/jbc.M112.357509

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Sekine S, Wang C, Sideris DP, Bunker E, Zhang Z, Youle RJ (2019) Reciprocal roles of Tom7 and OMA1 during mitochondrial import and activation of PINK1. Mol Cell 73(5):1028-1043.e1025. https://doi.org/10.1016/j.molcel.2019.01.002

    Article  CAS  PubMed  Google Scholar 

  10. Jin G, Xu C, Zhang X, Long J, Rezaeian AH, Liu C, Furth ME, Kridel S, Pasche B, Bian XW, Lin HK (2018) Atad3a suppresses Pink1-dependent mitophagy to maintain homeostasis of hematopoietic progenitor cells. Nat Immunol 19(1):29–40. https://doi.org/10.1038/s41590-017-0002-1

    Article  CAS  PubMed  Google Scholar 

  11. Hoshino A, Wang WJ, Wada S, McDermott-Roe C, Evans CS, Gosis B, Morley MP, Rathi KS, Li J, Li K, Yang S, McManus MJ, Bowman C, Potluri P, Levin M, Damrauer S, Wallace DC, Holzbaur ELF, Arany Z (2019) The ADP/ATP translocase drives mitophagy independent of nucleotide exchange. Nature 575(7782):375–379. https://doi.org/10.1038/s41586-019-1667-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Jin SM, Youle RJ (2013) The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy 9(11):1750–1757. https://doi.org/10.4161/auto.26122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Fiesel FC, James ED, Hudec R, Springer W (2017) Mitochondrial targeted HSP90 inhibitor Gamitrinib-TPP (G-TPP) induces PINK1/Parkin-dependent mitophagy. Oncotarget 8(63):106233–106248. https://doi.org/10.18632/oncotarget.22287

    Article  PubMed  PubMed Central  Google Scholar 

  14. Yun J, Puri R, Yang H, Lizzio MA, Wu C, Sheng ZH, Guo M (2014) MUL1 acts in parallel to the PINK1/parkin pathway in regulating mitofusin and compensates for loss of PINK1/parkin. eLife 3:e01958. https://doi.org/10.7554/eLife.01958

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Rojansky R, Cha MY, Chan DC (2016) Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. eLife. https://doi.org/10.7554/eLife.17896

    Article  PubMed  PubMed Central  Google Scholar 

  16. Villa E, Proics E, Rubio-Patino C, Obba S, Zunino B, Bossowski JP, Rozier RM, Chiche J, Mondragon L, Riley JS, Marchetti S, Verhoeyen E, Tait SWG, Ricci JE (2017) Parkin-independent mitophagy controls chemotherapeutic response in cancer cells. Cell Rep 20(12):2846–2859. https://doi.org/10.1016/j.celrep.2017.08.087

    Article  CAS  PubMed  Google Scholar 

  17. Chen Z, Liu L, Cheng Q, Li Y, Wu H, Zhang W, Wang Y, Sehgal SA, Siraj S, Wang X, Wang J, Zhu Y, Chen Q (2017) Mitochondrial E3 ligase MARCH5 regulates FUNDC1 to fine-tune hypoxic mitophagy. EMBO Rep 18(3):495–509. https://doi.org/10.15252/embr.201643309

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schwarten M, Mohrluder J, Ma P, Stoldt M, Thielman Y, Stangler T, Hersch N, Hoffman B, Merkel R, Wilbold D (2009) Nix binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy 5(5):690–698

    CAS  PubMed  Google Scholar 

  19. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, Rozenknop A, Rogov V, Löhr F, Popovic D, Occhipinti A, Reichert AS, Terzic J, Dötsch V, Ney PA, Dikic I (2010) Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep 11(1):45–51

    CAS  PubMed  Google Scholar 

  20. Hanna RA, Quinsay MN, Orogo AM, Giang K, Rikka S, Gustafsson AB (2012) Microtubule-associated protein 1 light chain 3 (LC3) interacts with BNip3 protein to selectively remove endoplasmic reticulum and mitochondria via autophagy. J Biol Chem 287:19094–19104

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Ney PA (2015) Mitochondrial autophagy: origins, significance, and role of BNIP3 and NIX. Biochim Biophy Acta 1853:2775–2783

    CAS  Google Scholar 

  22. Springer MZ, Poole LP, Drake LE, Bock-Hughes A, Boland ML, Smith AG, Hart J, Chourasia AH, Liu I, Bozek G, Macleod KF (2021) BNIP3-dependent mitophagy promotes cytosolic localization of LC3B and metabolic homeostasis in the liver. Autophagy Jan 17. https://doi.org/10.1080/15548627.2021.1877469

  23. Zhu Y, Massen S, Terenzio M, Lang V, Chen-Lindner S, Eils R, Novak I, Dikic I, Hamacher-Brady A, Brady NR (2012) Modulation of serines 17 and 24 in the LC3-interacting region of BNIP3 determines pro-survival mitophagy VS apoptosis. J Biol Chem 288(2):1099–1113

    PubMed  PubMed Central  Google Scholar 

  24. Sulistijo ES, MacKenzie KR (2009) Structural basis for dimerization of the BNIP3 transmembrane domain. Biochem 48:5106–5120

    CAS  Google Scholar 

  25. Vande Velde C, Cizeau J, Dubik D, Alimonti J, Brown T, Israels S, Hakem R, Greenberg AH (2000) BNIP3 and genetic control of necrosis-like cell death through the mitochondrial permeability transition pore. Mol Cell Biol 20(15):5454–5468

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Marinković M, Šprung M, Novak I (2020) Dimerization of mitophagy receptor BNIP3L/NIX is essential for recruitment of autophagic machinery. Autophagy. https://doi.org/10.1080/15548627.2020.1755120

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ohi N, Tokunaga A, Tsunoda H, Nakano K, Haraguchi K, Oda K, Motoyama N, Nakajima T (1999) A novel adenovirus E1B19K-binding protein B5 inhibits apoptosis induced by Nip3 by forming a heterodimer through the C-terminal hydrophobic region. Cell Death Differ 6(4):314–325. https://doi.org/10.1038/sj.cdd.4400493

    Article  CAS  PubMed  Google Scholar 

  28. Guo K, Searfoss G, Krolikowski D, Pagnoni M, Franks C, Clark K, Yu KT, Jaye M, Ivashchenko Y (2001) Hypoxia induces the expression of the pro-apoptotic gene BNIP3. Cell Death Diff 8:367–376

    CAS  Google Scholar 

  29. Dayan F, Roux D, Brahimi-Horn C, Pouyssegur J, Mazure NM (2006) The oxygen sensing factor-inhibiting hypoxia-inducible factor-1 controls expression of distinct genes through the bi-functional transcriptional character of hypoxia-inducible factor-1a. Cancer Res 66:3688–3698

    CAS  PubMed  Google Scholar 

  30. Bruick RK (2000) Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc Natl Acad Sci USA 97(6):9082–9087

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Kasper LH, Boussouar F, Boyd K, Xu W, Biesen M, Rehg J, Baudino T, Cleveland JL, Brindle PK (2005) Two transcriptional mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J 24:3846–3858

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Pouyssegur J, Dayan F, Mazure NM (2006) Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 441:437–443

    CAS  PubMed  Google Scholar 

  33. Glick D, Zhang W, Beaton M, Marsboom G, Gruber M, Simon MC, Hart J, Dorn GW II, Brady MJ, Macleod KF (2012) BNip3 regulates mitochondrial function and lipid metabolism in the liver. Mol Cell Biol 32(13):2570–2584

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Lee JM, Wagner M, Xiao R, Kim KH, Lazar MA, Moore DD (2014) Nutrient-sensing nuclear receptors coordinate autophagy. Nature 516:112–115

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, Burden SJ, Di Lisi R, Sandri C, Zhao J, Goldberg AL, Schiaffino S, Sandri M (2007) FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 6:458–471

    CAS  PubMed  Google Scholar 

  36. Reed SA, Sandesara PB, Senf SM, Judge AR (2012) Inhibition of FoxO transcriptional activity prevents muscle fiber atrophy during cachexia and induces hypertrophy. FASEB J 26(3):987–1000. https://doi.org/10.1096/fj.11-189977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Brown JL, Rosa-Caldwell ME, Lee DE, Blackwell TA, Brown LA, Perry RA, Haynie WS, Hardee JP, Carson JA, Wiggs MP, Washington TA, Greene NP (2017) Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice. J Cachexia Sarcopenia Muscle 8(6):926–938. https://doi.org/10.1002/jcsm.12232

    Article  PubMed  PubMed Central  Google Scholar 

  38. Fei P, Wang W, Kim SH, Wang S, Burns TF, Sax JK, Buzzai M, Dicker DT, McKenna WG, Bernhard EJ, El-Deiry WS (2005) Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. Cancer Cell 6:597–609

    Google Scholar 

  39. Feng X, Liu X, Zhang W, Xiao W (2011) p53 directly suppresses BNIP3 expression to protect against hypoxia-induced cell death. EMBO J 30:3397–3415

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Rogov VV, Suzuki H, Marinkovic M, Lang V, Kato R, Kawasaki M, Buljubasic M, Sprung M, Rogova N, Wakatsuki S, Hamacher-Brady A, Dotsch V, Dikic I, Brady NR, Novak I (2017) Phosphorylation of the mitochondrial autophagy receptor Nix enhances its interaction with LC3 proteins. Sci Rep 7(1):1131. https://doi.org/10.1038/s41598-017-01258-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ding WX, Ni HM, Li M, Liao Y, Chen X, Stolz DB, Dorn GW 2nd, Yin XM (2010) Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming. J Biol Chem 285(36):27879–27890. https://doi.org/10.1074/jbc.M110.119537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gao F, Chen D, Si J, Hu Q, Qin Z, Fang M, Wang G (2015) The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Hum Mol Genet 24(9):2528–2538. https://doi.org/10.1093/hmg/ddv017

    Article  CAS  PubMed  Google Scholar 

  43. Zhang T, Xue L, Li L, Tang C, Wan Z, Wang R, Tan J, Tan Y, Han H, Tian R, Billiar TR, Tao WA, Zhang Z (2016) BNIP3 protein suppresses PINK1 kinase proteolytic cleavage to promote mitophagy. J Biol Chem 291(41):21616–21629. https://doi.org/10.1074/jbc.M116.733410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Liu J, Zhang C, Zhao Y, Yue X, Wu H, Huang S, Chen J, Tomsky K, Xie H, Khella CA, Gatza ML, Xia D, Gao J, White E, Haffty BG, Hu W, Feng Z (2017) Parkin targets HIF-1alpha for ubiquitination and degradation to inhibit breast tumor progression. Nat Commun 8(1):1823. https://doi.org/10.1038/s41467-017-01947-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Li C, Zhang Y, Cheng X, Yuan H, Zhu S, Liu J, Wen Q, Xie Y, Liu J, Kroemer G, Klionsky DJ, Lotze MT, Zeh HJ, Kang R, Tang D (2018) PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev Cell 46(4):441-455.e448. https://doi.org/10.1016/j.devcel.2018.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kietzmann T (2017) Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol 11:622–630. https://doi.org/10.1016/j.redox.2017.01.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ben-Moshe S, Itzkovitz S (2019) Spatial heterogeneity in the mammalian liver. Nat Rev Gastroenterol Hepatol 16(7):395–410. https://doi.org/10.1038/s41575-019-0134-x

    Article  PubMed  Google Scholar 

  48. Diwan A, Koesters AG, Odley AM, Pushkaran S, Baines CP, Spike BT, Daria D, Jegga AG, Geiger H, Aronow BJ, Molkentin JD, Macleod KF, Kalfa TA, Dorn GW (2007) Unrestrained erythroblast development in Nix-/- mice reveals a mechanism for apoptotic modulation of erythropoiesis. Proc Natl Acad Sci USA 104:6794–6799

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, Dorsey FC, Kundu M, Opferman JT, Cleveland JL, Miller JL, Ney PA (2007) NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc Natl Acad Sci USA 104:19500–19505

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Sandoval H, Thiagarajan P, Dasgupta SK, Scumacker A, Prchal JT, Chen M, Wang J (2008) Essential role for Nix in autophagic maturation of red cells. Nature 454:232–235

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Yang C, Hashimoto M, Lin QXX, Tan DQ, Suda T (2019) Sphingosine-1-phosphate signaling modulates terminal erythroid differentiation through the regulation of mitophagy. Exp Hematol 72:47-59.e41. https://doi.org/10.1016/j.exphem.2019.01.004

    Article  CAS  PubMed  Google Scholar 

  52. Quiros PM, Langer T, Lopez-Otin C (2015) New roles for mitochondrial proteases in health, ageing and disease. Nat Rev Mol Cell Biol 16(6):345–359. https://doi.org/10.1038/nrm3984

    Article  CAS  PubMed  Google Scholar 

  53. Mottis A, Herzig S, Auwerx J (2019) Mitocellular communication: shaping health and disease. Science 366(6467):827–832. https://doi.org/10.1126/science.aax3768

    Article  CAS  PubMed  Google Scholar 

  54. Esteban-Martinez L, Sierra-Filardi E, McGreal RS, Salazar-Roa M, Marino G, Seco E, Durand S, Enot D, Grana O, Malumbres M, Cvekl A, Cuervo AM, Kroemer G, Boya P (2017) Programmed mitophagy is essential for the glycolytic switch during cell differentiation. Embo J 36(12):1688–1706. https://doi.org/10.15252/embj.201695916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. O’Sullivan TE, Johnson LR, Kang HH, Sun JC (2015) BNIP3 and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity 43:331–342

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Li Y, Wang Y, Kim E, Beemiller P, Wang CY, Swanson J, You M, Guan KL (2007) Bnip3 mediates the hypoxia-induced inhibition on mTOR by interacting with Rheb. J Biol Chem 282:35803–35813

    CAS  PubMed  Google Scholar 

  57. Melser S, Chatelain EH, Lavie J, Mahfouf W, Jose C, Obre E, Goorden S, Priault M, Elgersma Y, Rezvani HR, Rossignol R, Bénard G (2013) Rheb regulates mitophagy induced by mitochondrial energetic status. Cell Metab 17(5):719–730

    CAS  PubMed  Google Scholar 

  58. Saxton RA, Sabatini DM (2017) mTOR signaling in growth, metabolism, and disease. Cell 168(6):960–976. https://doi.org/10.1016/j.cell.2017.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu L, Feng D, Chen G, Chen M, Zheng Q, Song P, Ma Q, Zhu C, Wang R, Qi W, Huang L, Xue P, Li B, Wang X, Jin H, Wang J, Yang F, Liu P, Zhu Y, Sui S, Chen Q (2012) Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells. Nat Cell Biol 14(2):177–185

    PubMed  Google Scholar 

  60. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor RC, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461

    CAS  PubMed  Google Scholar 

  61. Russell RC, Tian Y, Yuan H, Park HW, Chang YY, Kim J, Kim H, Neufeld TP, Dillin A, Guan KL (2013) ULK1 induces autophagy by phosphorylating Beclin-1 and activating VPS34 lipid kinase. Nat Cell Biol 15(7):741–750. https://doi.org/10.1038/ncb2757

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Wu WK, Tian W, Hu Z, Chen G, Huang L, Li W, Zhang X, Xue P, Zhou C, Liu L, Zhu Y, Zhang X, Li L, Zhang L, Sui S, Zhao B, Feng D (2014) ULK1 translocates to mitochondria and phosphorylates FUNDC1 to regulate mitophagy. EMBO Rep 15(5):566–575

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Chen G, Han Z, Feng D, Chen Y, Chen L, Wu H, Huang L, Zhou C, Cai X, Fu C, Duan L, Wang X, Liu L, Liu X, Shen Y, Zhu Y, Chen Q (2014) A regulatory signaling loop comprising the PGAM5 phosphatase and CK2 controls receptor-mediated mitophagy. Mol Cell 54(3):362–377. https://doi.org/10.1016/j.molcel.2014.02.034

    Article  CAS  PubMed  Google Scholar 

  64. Lu W, Karuppagounder SS, Springer DA, Allen MD, Zheng L, Chao B, Zhang Y, Dawson VL, Dawson TM, Lenardo M (2014) Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder. Nat Commun 5:4930. https://doi.org/10.1038/ncomms5930

    Article  CAS  PubMed  Google Scholar 

  65. Wu W, Lin C, Wu K, Jiang L, Wang X, Li W, Zhuang H, Zhang X, Chen H, Li S, Yang Y, Lu Y, Wang J, Zhu R, Zhang L, Sui S, Tan N, Zhao B, Zhang J, Li L, Feng D (2016) FUNDC1 regulates mitochondrial dynamics at the ER-mitochondrial contact site under hypoxic conditions. Embo J 35(13):1368–1384. https://doi.org/10.15252/embj.201593102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Li Y, Xue Y, Xu X, Wang G, Liu Y, Wu H, Li W, Wang Y, Chen Z, Zhang W, Zhu Y, Ji W, Xu T, Liu L, Chen Q (2019) A mitochondrial FUNDC1/HSC70 interaction organizes the proteostatic stress response at the risk of cell morbidity. Embo J. https://doi.org/10.15252/embj.201798786

    Article  PubMed  PubMed Central  Google Scholar 

  67. Li W, Zhang X, Zhuang H, Chen HG, Chen Y, Tian W, Wu WK, Li Y, Wang S, Zhang L, Chen Y, Li L, Zhao B, Sui S, Feng D (2014) MicroRNA-137 is a novel hypoxia-responsive microRNA that inhibits mitophagy via regulation of two mitophagy receptors FUNDC1 and NIX. J Biol Chem 289:10691–10701

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Murakawa T, Yamaguchi O, Hashimoto A, Hikoso S, Takeda T, Oka T, Yasui H, Ueda H, Akazawa Y, Nakayama H, Taneike M, Misaka T, Omiya S, Shah AM, Yamamoto A, Nishida K, Ohsumi Y, Okamoto K, Sakata Y, Otsu K (2015) Bcl-2-like protein 13 is a mammalian Atg32 homologue that mediates mitophagy and mitochondrial fragmentation. Nat Commun 6:7527. https://doi.org/10.1038/ncomms8527

    Article  PubMed  Google Scholar 

  69. Murakawa T, Okamoto K, Omiya S, Taneike M, Yamaguchi O, Otsu K (2019) A mammalian mitophagy receptor, Bcl2-L-13, recruits the ULK1 complex to induce mitophagy. Cell Rep 26(2):338-345.e336. https://doi.org/10.1016/j.celrep.2018.12.050

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Merkwirth C, Dargazanli S, Tatsuta T, Geimer S, Löwer B, Wunderlich FT, von Kleist-Retzow JC, Waisman A, Westermann B, Langer T (2008) Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev 22(4):476–488

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Wei Y, Chiang WC, Sumpter R Jr, Mishra P, Levine B (2016) Prohibitin 2 is an inner mitochondrial membrane mitophagy receptor. Cell. https://doi.org/10.1016/j.cell.2016.11.042

    Article  PubMed  PubMed Central  Google Scholar 

  72. Yoshii SR, Kishi C, Ishihara N, Mizushima N (2011) Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem 286(22):19630–19640. https://doi.org/10.1074/jbc.M110.209338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Dumas JF, Peyta L, Couet C, Servais S (2013) Implication of liver cardiolipins in mitochondrial energy metabolism disorder in cancer cachexia. Biochimie 95(1):27–32. https://doi.org/10.1016/j.biochi.2012.07.009

    Article  CAS  PubMed  Google Scholar 

  74. Chu CT, Ji J, Dagda RK, Jiang JF, Tyurina YY, Kapralov AA, Tyurin VA, Yanamala N, Shrivastava IH, Mohammadyani D, Qiang Wang KZ, Zhu J, Klein-Seetharaman J, Balasubramanian K, Amoscato AA, Borisenko G, Huang Z, Gusdon AM, Cheikhi A, Steer EK, Wang R, Baty C, Watkins S, Bahar I, Bayir H, Kagan VE (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nat Cell Biol 15(10):1197–1205. https://doi.org/10.1038/ncb2837

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Hsu P, Liu X, Zhang J, Wang HG, Ye JM, Shi Y (2015) Cardiolipin remodeling by TAZ/tafazzin is selectively required for the initiation of mitophagy. Autophagy 11(4):643–652. https://doi.org/10.1080/15548627.2015.1023984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Sentelle RD, Senkal CE, Jiang W, Ponnusamy S, Gencer S, Selvam SP, Ramshesh VK, Peterson YK, Lemasters JJ, Szulc ZM, Bielawski J, Ogretmen B (2012) Ceramide targets autophagosomes to mitochondria and induces lethal mitophagy. Nat Chem Biol 8(10):831–838. https://doi.org/10.1038/nchembio.1059

    Article  PubMed  PubMed Central  Google Scholar 

  77. Gao X, Lee K, Reid MA, Sanderson SM, Qiu C, Li S, Liu J, Locasale JW (2018) Serine availability influences mitochondrial dynamics and function through lipid metabolism. Cell Rep 22(13):3507–3520. https://doi.org/10.1016/j.celrep.2018.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Csaki LS, Reue K (2010) Lipins: multifunctional lipid metabolism proteins. Annu Rev Nutr 30:257–272. https://doi.org/10.1146/annurev.nutr.012809.104729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Harris TE, Finck BN (2011) Dual function lipin proteins and glycerolipid metabolism. Trends Endocrinol Metab TEM 22(6):226–233. https://doi.org/10.1016/j.tem.2011.02.006

    Article  CAS  PubMed  Google Scholar 

  80. Zhang P, Verity MA, Reue K (2014) Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle. Cell Metab 20(2):267–279. https://doi.org/10.1016/j.cmet.2014.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Alshudukhi AA, Zhu J, Huang D, Jama A, Smith JD, Wang QJ, Esser KA, Ren H (2018) Lipin-1 regulates Bnip3-mediated mitophagy in glycolytic muscle. FASEB J. https://doi.org/10.1096/fj.201800374

    Article  PubMed  PubMed Central  Google Scholar 

  82. Leong WI, Saba JD (2010) S1P metabolism in cancer and other pathological conditions. Biochimie 92(6):716–723. https://doi.org/10.1016/j.biochi.2010.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hart PC, Chiyoda T, Liu X, Weigert M, Curtis M, Chiang CY, Loth R, Lastra R, McGregor SM, Locasale JW, Lengyel E, Romero IL (2019) SPHK1 is a novel target of metformin in ovarian cancer. Mol Cancer Res MCR 17(4):870–881. https://doi.org/10.1158/1541-7786.mcr-18-0409

    Article  CAS  PubMed  Google Scholar 

  84. Ader I, Malavaud B, Cuvillier O (2009) When the sphingosine kinase 1/sphingosine 1-phosphate pathway meets hypoxia signaling: new targets for cancer therapy. Can Res 69(9):3723–3726. https://doi.org/10.1158/0008-5472.can-09-0389

    Article  CAS  Google Scholar 

  85. Kim S, Sieburth D (2018) Sphingosine kinase activates the mitochondrial unfolded protein response and is targeted to mitochondria by stress. Cell Rep 24(11):2932-2945.e2934. https://doi.org/10.1016/j.celrep.2018.08.037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Martinez-Reyes I, Diebold LP, Kong H, Schieber M, Huang H, Hensley CT, Mehta MM, Wang T, Santos JH, Woychik R, Dufour E, Spelbrink JN, Weinberg SE, Zhao Y, DeBerardinis RJ, Chandel NS (2016) TCA cycle and mitochondrial membrane potential are necessary for diverse biological functions. Mol Cell 61(2):199–209. https://doi.org/10.1016/j.molcel.2015.12.002

    Article  CAS  PubMed  Google Scholar 

  87. Herzig S, Shaw RJ (2018) AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 19(2):121–135. https://doi.org/10.1038/nrm.2017.95

    Article  CAS  PubMed  Google Scholar 

  88. Toyama EQ, Herzig S, Courchet J, Lewis TL Jr, Loson OC, Hellberg K, Young NP, Chen H, Polleux F, Chan DC, Shaw RJ (2016) Metabolism. AMP-activated protein kinase mediates mitochondrial fission in response to energy stress. Science 351(6270):275–281. https://doi.org/10.1126/science.aab4138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Pei S, Minhajuddin M, Adane B, Khan N, Stevens BM, Mack SC, Lai S, Rich JN, Inguva A, Shannon KM, Kim H, Tan AC, Myers JR, Ashton JM, Neff T, Pollyea DA, Smith CA, Jordan CT (2018) AMPK/FIS1-mediated mitophagy is required for self-renewal of human AML stem cells. Cell Stem Cell 23(1):86-100.e106. https://doi.org/10.1016/j.stem.2018.05.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Domenech E, Maestre C, Esteban-Martinez L, Partida D, Pascual R, Fernandez-Miranda G, Seco E, Campos-Olivas R, Perez M, Megias D, Allen K, Lopez M, Saha AK, Velasco G, Rial E, Mendez R, Boya P, Salazar-Roa M, Malumbres M (2015) AMPK and PFKFB3 mediate glycolysis and survival in response to mitophagy during mitotic arrest. Nat Cell Biol 17(10):1304–1316. https://doi.org/10.1038/ncb3231

    Article  CAS  PubMed  Google Scholar 

  91. Eichner LJ, Brun SN, Herzig S, Young NP, Curtis SD, Shackelford DB, Shokhirev MN, Leblanc M, Vera LI, Hutchins A, Ross DS, Shaw RJ, Svensson RU (2019) Genetic analysis reveals AMPK is required to support tumor growth in murine kras-dependent lung cancer models. Cell Metab 29(2):285-302.e287. https://doi.org/10.1016/j.cmet.2018.10.005

    Article  CAS  PubMed  Google Scholar 

  92. Nakada D, Saunders TL, Morrison SJ (2010) Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature 468(7324):653–658. https://doi.org/10.1038/nature09571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, Tzatsos A, Ozsolak F, Milos P, Ferrari F, Park PJ, Shirihai OS, Scadden DT, Bardeesy N (2010) The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature 468(7324):659–663. https://doi.org/10.1038/nature09572

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Masand R, Paulo E, Wu D, Wang Y, Swaney DL, Jimenez-Morales D, Krogan NJ, Wang B (2018) Proteome imbalance of mitochondrial electron transport chain in brown adipocytes leads to metabolic benefits. Cell Metab 27(3):616-629.e614. https://doi.org/10.1016/j.cmet.2018.01.018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Kottakis F, Nicolay BN, Roumane A, Karnik R, Gu H, Nagle JM, Boukhali M, Hayward MC, Li YY, Chen T, Liesa M, Hammerman PS, Wong KK, Hayes DN, Shirihai OS, Dyson NJ, Haas W, Meissner A, Bardeesy N (2016) LKB1 loss links serine metabolism to DNA methylation and tumorigenesis. Nature 539(7629):390–395. https://doi.org/10.1038/nature20132

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Yang K, Blanco DB, Neale G, Vogel P, Avila J, Clish CB, Wu C, Shrestha S, Rankin S, Long L, Kc A, Chi H (2017) Homeostatic control of metabolic and functional fitness of Treg cells by LKB1 signalling. Nature 548(7669):602–606. https://doi.org/10.1038/nature23665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. He N, Fan W, Henriquez B, Yu RT, Atkins AR, Liddle C, Zheng Y, Downes M, Evans RM (2017) Metabolic control of regulatory T cell (Treg) survival and function by Lkb1. Proc Natl Acad Sci USA 114(47):12542–12547. https://doi.org/10.1073/pnas.1715363114

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Quiros PM, Prado MA, Zamboni N, D’Amico D, Williams RW, Finley D, Gygi SP, Auwerx J (2017) Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J Cell Biol 216(7):2027–2045. https://doi.org/10.1083/jcb.201702058

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Bao XR, Ong SE, Goldberger O, Peng J, Sharma R, Thompson DA, Vafai SB, Cox AG, Marutani E, Ichinose F, Goessling W, Regev A, Carr SA, Clish CB, Mootha VK (2016) Mitochondrial dysfunction remodels one-carbon metabolism in human cells. eLife. https://doi.org/10.7554/eLife.10575

    Article  PubMed  PubMed Central  Google Scholar 

  100. Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, Ciciliot S, Soriano ME, Morbidoni V, Cerqua C, Loefler S, Kern H, Franceschi C, Salvioli S, Conte M, Blaauw B, Zampieri S, Salviati L, Scorrano L, Sandri M (2017) Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab 25(6):1374-1389.e1376. https://doi.org/10.1016/j.cmet.2017.04.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Khan NA, Nikkanen J, Yatsuga S, Jackson C, Wang L, Pradhan S, Kivela R, Pessia A, Velagapudi V, Suomalainen A (2017) mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression. Cell Metab 26(2):419-428.e415. https://doi.org/10.1016/j.cmet.2017.07.007

    Article  CAS  PubMed  Google Scholar 

  102. Forsstrom S, Jackson CB, Carroll CJ, Kuronen M, Pirinen E, Pradhan S, Marmyleva A, Auranen M, Kleine IM, Khan NA, Roivainen A, Marjamaki P, Liljenback H, Wang L, Battersby BJ, Richter U, Velagapudi V, Nikkanen J, Euro L, Suomalainen A (2019) Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions. Cell Metab 30(6):1040-1054.e1047. https://doi.org/10.1016/j.cmet.2019.08.019

    Article  CAS  PubMed  Google Scholar 

  103. Ebert SM, Dyle MC, Kunkel SD, Bullard SA, Bongers KS, Fox DK, Dierdorff JM, Foster ED, Adams CM (2012) Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. J Biol Chem 287(33):27290–27301. https://doi.org/10.1074/jbc.M112.374777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Guo X, Aviles G, Liu Y, Tian R, Unger BA, Lin YT, Wiita AP, Xu K, Correia MA, Kampmann M (2020) Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway. Nature 579(7799):427–432. https://doi.org/10.1038/s41586-020-2078-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Fessler E, Eckl EM, Schmitt S, Mancilla IA, Meyer-Bender MF, Hanf M, Philippou-Massier J, Krebs S, Zischka H, Jae LT (2020) A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol. Nature 579(7799):433–437. https://doi.org/10.1038/s41586-020-2076-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Harada T, Iwai A, Miyazaki T (2010) Identification of DELE, a novel DAP3-binding protein which is crucial for death receptor-mediated apoptosis induction. Apoptosis 15(10):1247–1255. https://doi.org/10.1007/s10495-010-0519-3

    Article  CAS  PubMed  Google Scholar 

  107. Fiorese CJ, Schulz AM, Lin YF, Rosin N, Pellegrino MW, Haynes CM (2016) The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr Biol CB 26(15):2037–2043. https://doi.org/10.1016/j.cub.2016.06.002

    Article  CAS  PubMed  Google Scholar 

  108. Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, D’Amico D, Moullan N, Potenza F, Schmid AW, Rietsch S, Counts SE, Auwerx J (2017) Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. Nature 552(7684):187–193. https://doi.org/10.1038/nature25143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Molenaars M, Janssens GE, Williams EG, Jongejan A, Lan J, Rabot S, Joly F, Moerland PD, Schomakers BV, Lezzerini M, Liu YJ, McCormick MA, Kennedy BK, van Weeghel M, van Kampen AHC, Aebersold R, MacInnes AW, Houtkooper RH (2020) A conserved mito-cytosolic translational balance links two longevity pathways. Cell Metab 31(3):549-563.e547. https://doi.org/10.1016/j.cmet.2020.01.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337(6094):587–590. https://doi.org/10.1126/science.1223560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Nargund AM, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell 58(1):123–133. https://doi.org/10.1016/j.molcel.2015.02.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Palikaras K, Lionaki E, Tavernarakis N (2015) Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521:525–528

    CAS  PubMed  Google Scholar 

  113. Gupte R, Liu Z, Kraus WL (2017) PARPs and ADP-ribosylation: recent advances linking molecular functions to biological outcomes. Genes Dev 31(2):101–126. https://doi.org/10.1101/gad.291518.116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Kerr JS, Lu Q, Waltz TB, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA (2016) NAD+ replenishment improves lifespan and healthspan in ataxia telangiectasia models via mitophagy and DNA repair. Cell Metab 24(4):566–581. https://doi.org/10.1016/j.cmet.2016.09.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, Mitchell JR, Croteau DL, Bohr VA (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction. Cell 157(4):882–896. https://doi.org/10.1016/j.cell.2014.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gerhart-Hines Z, Dominy JE Jr, Blattler SM, Jedrychowski MP, Banks AS, Lim JH, Chim H, Gygi SP, Puigserver P (2011) The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+). Mol Cell 44(6):851–863. https://doi.org/10.1016/j.molcel.2011.12.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rzymski T, Milani M, Pike L, Buffa F, Mellor HR, Winchester L, Pires I, Hammond E, Ragoussis I, Harris AL (2010) Regulation of autophagy by ATF4 in response to severe hypoxia. Oncogene 29(31):4424–4435. https://doi.org/10.1038/onc.2010.191

    Article  CAS  PubMed  Google Scholar 

  118. Pike LR, Singleton DC, Buffa F, Abramczyk O, Phadwal K, Li JL, Simon AK, Murray JT, Harris AL (2013) Transcriptional upregulation of ULK1 by ATF4 contributes to cancer cell survival. Biochem J 449(2):389–400. https://doi.org/10.1042/bj20120972

    Article  CAS  PubMed  Google Scholar 

  119. Anderson CM, Macleod KF (2019) Autophagy and cancer cell metabolism. Int Rev Cell Mol Biol 347:145–190. https://doi.org/10.1016/bs.ircmb.2019.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469(7329):221–225. https://doi.org/10.1038/nature09663

    Article  CAS  PubMed  Google Scholar 

  121. Chen Q, Sun L, Chen ZJ (2016) Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol 17(10):1142–1149. https://doi.org/10.1038/ni.3558

    Article  CAS  PubMed  Google Scholar 

  122. McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS, Oorschot V, Geoghegan ND, Chappaz S, Davidson S, San Chin H, Lane RM, Dramicanin M, Saunders TL, Sugiana C, Lessene R, Osellame LD, Chew TL, Dewson G, Lazarou M, Ramm G, Lessene G, Ryan MT, Rogers KL, van Delft MF, Kile BT (2018) BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science. https://doi.org/10.1126/science.aao6047

    Article  PubMed  Google Scholar 

  123. Aarreberg LD, Esser-Nobis K, Driscoll C, Shuvarikov A, Roby JA, Gale M Jr (2019) Interleukin-1β induces mtDNA release to activate innate immune signaling via cGAS-STING. Mol Cell 74(4):801-815.e806. https://doi.org/10.1016/j.molcel.2019.02.038

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhong Z, Liang S, Sanchez-Lopez E, He F, Shalapour S, Lin XJ, Wong J, Ding S, Seki E, Schnabl B, Hevener AL, Greenberg HB, Kisseleva T, Karin M (2018) New mitochondrial DNA synthesis enables NLRP3 inflammasome activation. Nature 560(7717):198–203. https://doi.org/10.1038/s41586-018-0372-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36(3):401–414. https://doi.org/10.1016/j.immuni.2012.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S (2013) Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 14(5):454–460. https://doi.org/10.1038/ni.2550

    Article  CAS  PubMed  Google Scholar 

  127. Elliott EI, Sutterwala FS (2015) Initiation and perpetuation of NLRP3 inflammasome activation and assembly. Immunol Rev 265(1):35–52. https://doi.org/10.1111/imr.12286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, McGeough MD, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M (2016) NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164(5):896–910. https://doi.org/10.1016/j.cell.2015.12.057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Yu JJ, Nagasu H, Murakami T, Hoang H, Broderick L, Hoffman HM, Horng T (2014) Inflammasome activation leads to caspase-1 dependent mitochondrial damage and block of mitophagy. Proc Natl Acad Sci U S A 111(43):15514–15519

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Moore AS, Holzbaur EL (2016) Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy. Proc Natl Acad Sci U S A 113(24):E3349-3358. https://doi.org/10.1073/pnas.1523810113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Richter B, Sliter DA, Herhaus L, Stolz A, Wang C, Beli P, Zaffagnini G, Wild P, Martens S, Wagner SA, Youle RJ, Dikic I (2016) Phosphorylation of OPTN by TBK1 enhances its binding to Ub chains and promotes selective autophagy of damaged mitochondria. Proc Natl Acad Sci U S A 113(15):4039–4044. https://doi.org/10.1073/pnas.1523926113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gui X, Yang H, Li T, Tan X, Shi P, Li M, Du F, Chen ZJ (2019) Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 567(7747):262–266. https://doi.org/10.1038/s41586-019-1006-9

    Article  CAS  PubMed  Google Scholar 

  133. Gaidt MM, Ebert TS, Chauhan D, Ramshorn K, Pinci F, Zuber S, O’Duill F, Schmid-Burgk JL, Hoss F, Buhmann R, Wittmann G, Latz E, Subklewe M, Hornung V (2017) The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell 171(5):1110-1124.e1118. https://doi.org/10.1016/j.cell.2017.09.039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12(3):222–230. https://doi.org/10.1038/ni.1980

    Article  CAS  PubMed  Google Scholar 

  135. Drake LE, Springer MZ, Poole LP, Kim CJ, Macleod KF (2017) Expanding perspectives on the significance of mitophagy in cancer. Semin Cancer Biol 47:110–124. https://doi.org/10.1016/j.semcancer.2017.04.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Cesari R, Martin ES, Calin GA, Pentimalli F, Bichi R, McAdams H, Trapasso F, Drusco A, Shimizu M, Masciullo V, D’Andrilli G, Scambia G, Picchio MC, Alder H, Godwin AK, Croce CM (2003) Parkin, a gene implicated in autosomal recessive juvenile parkinsonism, is a candidate tumor suppressor gene on chromosome 6q25-q27. Proc Natl Acad Sci U S A 100(10):5956–5961

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Veeriah S, Taylor BS, Meng S, Fang F, Yilmaz E, Vivanco I, Janakiraman M, Schultz N, Hanrahan AJ, Pao W, Ladanyi M, Sander C, Heguy A, Holland EC, Paty PB, Mischel PS, Liau L, Cloughesy TF, Mellinghoff IK, Solit DB, Chan TA (2010) Somatic mutations of the Parkinson’s disease-associated gene PARK2 in glioblastoma and other human malignancies. Nat Genet 42(1):77–82. https://doi.org/10.1038/ng.491

    Article  CAS  PubMed  Google Scholar 

  138. Agnihotri S, Golbourn B, Huang X, Remke M, Younger S, Cairns RA, Chalil A, Smith CA, Krumholtz SL, Mackenzie D, Rakopoulos P, Ramaswamy V, Taccone MS, Mischel PS, Fuller GN, Hawkins C, Stanford WL, Taylor MD, Zadeh G, Rutka JT (2016) PINK1 is a negative regulator of growth and the warburg effect in glioblastoma. Can Res 76(16):4708–4719. https://doi.org/10.1158/0008-5472.can-15-3079

    Article  CAS  Google Scholar 

  139. Fujiwara M, Marusawa H, Wang HQ, Iwai A, Ikeuchi K, Imai Y, Kataoka A, Nukina N, Takahashi R, Chiba T (2008) Parkin as a tumor suppressor gene for hepatocellular carcinoma. Oncogene 27:6002–6011

    CAS  PubMed  Google Scholar 

  140. Zhang C, Lin M, Wu R, Wang X, Yang BG, Levine AJ, Hu W, Feng Z (2011) Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci U S A 108(39):16259–16264

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Bernardini JP, Lazarou M, Dewson G (2016) Parkin and mitophagy in cancer. Oncogene. https://doi.org/10.1038/onc.2016.302

    Article  PubMed  Google Scholar 

  142. Kim KY, Stevens MV, Akter MH, Rusk SE, Huang RJ, Cohen A, Noguchi A, Springer D, Bocharov AV, Eggerman TL, Suen DF, Youle RJ, Amar M, Remaley AT, M.N. S, (2011) Parkin is a lipid-responsive regulator of fat uptake in mice and mutant human cells. J Clin Invest 121:3701–3712

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Sarraf SA, Sideris DP, Giagtzoglou N, Ni L, Kankel MW, Sen A, Bochicchio LE, Huang CH, Nussenzweig SC, Worley SH, Morton PD, Artavanis-Tsakonas S, Youle RJ, Pickrell AM (2019) PINK1/parkin influences cell cycle by sequestering TBK1 at damaged mitochondria. Inhibiting Mitosis Cell Rep 29(1):225-235.e225. https://doi.org/10.1016/j.celrep.2019.08.085

    Article  CAS  PubMed  Google Scholar 

  144. Gong Y, Zack TI, Morris LG, Lin K, Hukkelhoven E, Raheja R, Tan IL, Turcan S, Veeriah S, Meng S, Viale A, Schumacher SE, Palmedo P, Beroukhim R, Chan TA (2014) Pan-cancer genetic analysis identifies PARK2 as a master regulator of G1/S cyclins. Nat Genet 46(6):588–594. https://doi.org/10.1038/ng.2981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Lee SB, Kim JJ, Nam HJ, Gao B, Yin P, Qin B, Yi SY, Ham H, Evans D, Kim SH, Zhang J, Deng M, Liu T, Zhang H, Billadeau DD, Wang L, Giaime E, Shen J, Pang YP, Jen J, van Deursen JM, Lou Z (2015) Parkin regulates mitosis and genomic stability through Cdc20/Cdh1. Mol Cell 60(1):21–34. https://doi.org/10.1016/j.molcel.2015.08.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Pillai S, Nguyen J, Johnson J, Haura E, Coppola D, Chellappan S (2015) Tank binding kinase 1 is a centrosome-associated kinase necessary for microtubule dynamics and mitosis. Nat Commun 6:10072. https://doi.org/10.1038/ncomms10072

    Article  CAS  PubMed  Google Scholar 

  147. Villa E, Marchetti S, Ricci JE (2018) No parkin zone: mitophagy without parkin. Trends Cell Biol 28(11):882–895. https://doi.org/10.1016/j.tcb.2018.07.004

    Article  CAS  PubMed  Google Scholar 

  148. Sowter HM, Ferguson M, Pym C, Watson P, Fox SB, Han C, Harris AL (2003) Expression of the cell death genes BNip3 and Nix in ductal carcinoma in situ of the breast; correlation of BNip3 levels with necrosis and grade. JPath 201:573–580

    CAS  Google Scholar 

  149. Okami J, Simeone DM, Logsdon CD (2004) Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Cancer Res 64(15):5338–5346

    CAS  PubMed  Google Scholar 

  150. Erkan M, Kleef J, Esposito I, Giese T, Ketterer K, Buchler MW, Giese NA, Friess H (2005) Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene 24:4421–4432

    CAS  PubMed  Google Scholar 

  151. Murai M, Toyota M, Suzuki H, Satoh A, Sasaki Y, Akino K, Ueno M, Takahashi F, Kusano M, Mita H, Yanagihara K, Endo T, Hinoda Y, Tokino T, Imai K (2005) Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. Clin Cancer Res 11(3):1021–1027

    CAS  PubMed  Google Scholar 

  152. Akada M, Crnogorac-Jurcevic T, Lattimore S, Mahon P, Lopes R, Sunamura M, Matsuno S, Lemoine NR (2005) Intrinsic chemoresistance to gemcitabine is associated with decreased expression of BNIP3 in pancreatic cancer. Clin Cancer Res 11(8):3094–3101

    CAS  PubMed  Google Scholar 

  153. Humpton TJ, Alagesan B, DeNicola GM, Lu D, Yordanov GN, Leonhardt CS, Yao MA, Alagesan P, Zaatari MN, Park Y, Skepper JN, Macleod KF, Perez-Mancera PA, Murphy MP, Evan GI, Vousden KH, Tuveson DA (2019) Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer. Cancer Discov 9(9):1268–1287. https://doi.org/10.1158/2159-8290.cd-18-1409

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry KT, Pinchback RM, Ligon AH, Cho YJ, Haery L, Greulich H, Reich M, Winckler W, Lawrence MS, Weir BA, Tanaka KE, Chiang DY, Bass AJ, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S, Maher E, Kaye FJ, Sasaki H, Tepper JE, Fletcher J, Tabernero J, Baselga J, Tsao MS, Demichelis F, Rubin MA, Janne PA, Daly MJ, Nucera C, Levine RL, Ebert BL, Gabriel S, Rustgi AK, Antonescu CR, Ladanyi M, Letai A, Garraway LA, Loda M, Beer DG, True LD, Okamoto A, Pomeroy SL, Singer S, Golub TR, Lander ES, Getz G, Sellers WR, Meyerson M (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Koop EA, van Laar T, Weger RA, van der Wall E, van Diest PJ (2009) Expression of BNIP3 in invasive breast cancer: correlations with the hypoxic response and clinicopathological features. BMC Cancer 9:175–182

    PubMed  PubMed Central  Google Scholar 

  156. Chourasia AH, Tracy K, Frankenberger C, Boland ML, Sharifi MN, Drake LE, Sachleben JR, Asara JM, Locasale JW, Karczmar GS, Macleod KF (2015) Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep 16(9):1145–1163. https://doi.org/10.15252/embr.201540759

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Montagner M, Enzo E, Forcato M, Zanconato F, Parenti A, Rampazzo E, Basso G, Leo G, Rosato A, Bicciato S, Cordenonsi M, Piccolo S (2012) SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors. Nature 487(7407):380–384. https://doi.org/10.1038/nature11207

    Article  CAS  PubMed  Google Scholar 

  158. Guha M, Srinivasan S, Raman P, Jiang Y, Kaufman BA, Taylor D, Dong D, Chakrabarti R, Picard M, Carstens RP, Kijima Y, Feldman M (1864) Avadhani NG (2018) Aggressive triple negative breast cancers have unique molecular signature on the basis of mitochondrial genetic and functional defects. Biochim Biophys Acta Mol Basis Dis 4:1060–1071. https://doi.org/10.1016/j.bbadis.2018.01.002

    Article  CAS  Google Scholar 

  159. Lee J, Yesilkanal AE, Wynne JP, Frankenberger C, Liu J, Yan J, Elbaz M, Rabe DC, Rustandy FD, Tiwari P, Grossman EA, Hart PC, Kang C, Sanderson SM, Andrade J, Nomura DK, Bonini MG, Locasale JW, Rosner MR (2019) Effective breast cancer combination therapy targeting BACH1 and mitochondrial metabolism. Nature 568(7751):254–258. https://doi.org/10.1038/s41586-019-1005-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Manka D, Spicer Z, Millhorn DE (2005) Bcl-2/Adenovirus E1B 19 kDa interacting protein-3 knockdown enables growth of breast cancer metastases in the lung, liver and bone. Cancer Res 65:11689–11693

    CAS  PubMed  Google Scholar 

  161. Labuschagne CF, Cheung EC, Blagih J, Domart MC, Vousden KH (2019) Cell clustering promotes a metabolic switch that supports metastatic colonization. Cell Metab 30(4):720-734.e725. https://doi.org/10.1016/j.cmet.2019.07.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Smith AG, Macleod KF (2019) Autophagy, cancer stem cells and drug resistance. J Pathol 247(5):708–718. https://doi.org/10.1002/path.5222

    Article  PubMed  PubMed Central  Google Scholar 

  163. Liu K, Lee J, Kim JY, Wang L, Tian Y, Chan ST, Cho C, Machida K, Chen D, Ou JJ (2017) Mitophagy controls the activities of tumor suppressor p53 to regulate hepatic cancer stem cells. Mol Cell 68(2):281–292. https://doi.org/10.1016/j.molcel.2017.09.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Katajisto P, Dohla J, Chaffer CL, Pentinmikko N, Marjanovic N, Iqbal S, Zoncu R, Chen W, Weinberg RA, Sabatini DM (2015) Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science 348(6232):340–343. https://doi.org/10.1126/science.1260384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Ho TT, Warr MR, Adelman ER, Lansinger OM, Flach J, Verovskaya EV, Figueroa ME, Passegue E (2017) Autophagy maintains the metabolism and function of young and old stem cells. Nature 543(7644):205–210. https://doi.org/10.1038/nature21388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Ito K, Turcotte R, Cui J, Zimmerman SE, Pinho S, Mizoguchi T, Arai F, Runnels JM, Alt C, Teruya-Feldstein J, Mar JC, Singh R, Suda T, Lin CP, Frenette PS, Ito K (2016) Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance. Science 354(6316):1156–1160. https://doi.org/10.1126/science.aaf5530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Vannini N, Girotra M, Naveiras O, Nikitin G, Campos V, Giger S, Roch A, Auwerx J, Lutolf MP (2016) Specification of haematopoietic stem cell fate via modulation of mitochondrial activity. Nat Commun 7:13125. https://doi.org/10.1038/ncomms13125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Vannini N, Campos V, Girotra M, Trachsel V, Rojas-Sutterlin S, Tratwal J, Ragusa S, Stefanidis E, Ryu D, Rainer PY, Nikitin G, Giger S, Li TY, Semilietof A, Oggier A, Yersin Y, Tauzin L, Pirinen E, Cheng WC, Ratajczak J, Canto C, Ehrbar M, Sizzano F, Petrova TV, Vanhecke D, Zhang L, Romero P, Nahimana A, Cherix S, Duchosal MA, Ho PC, Deplancke B, Coukos G, Auwerx J, Lutolf MP, Naveiras O (2019) The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance. Cell Stem Cell 24(3):405-418.e407. https://doi.org/10.1016/j.stem.2019.02.012

    Article  CAS  PubMed  Google Scholar 

  169. Li J, Agarwal E, Bertolini I, Seo JH, Caino MC, Ghosh JC, Kossenkov AV, Liu Q, Tang HY, Goldman AR, Languino LR, Speicher DW, Altieri DC (2020) The mitophagy effector FUNDC1 controls mitochondrial reprogramming and cellular plasticity in cancer cells. Sci Signal. https://doi.org/10.1126/scisignal.aaz8240

    Article  PubMed  PubMed Central  Google Scholar 

  170. Wu L, Zhang D, Zhou L, Pei Y, Zhuang Y, Cui W, Chen J (2019) FUN14 domain-containing 1 promotes breast cancer proliferation and migration by activating calcium-NFATC1-BMI1 axis. EBioMedicine 41:384–394. https://doi.org/10.1016/j.ebiom.2019.02.032

    Article  PubMed  PubMed Central  Google Scholar 

  171. Cleaver JE (2005) Cancer in xeroderma pigmentosum and related disorders of DNA repair. Nat Rev Cancer 5(7):564–573. https://doi.org/10.1038/nrc1652

    Article  CAS  PubMed  Google Scholar 

  172. Kee Y, D’Andrea AD (2012) Molecular pathogenesis and clinical management of Fanconi anemia. J Clin Investig 122(11):3799–3806. https://doi.org/10.1172/jci58321

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Shiloh Y, Ziv Y (2013) The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 14(4):197–210

    CAS  PubMed  Google Scholar 

  174. Sumpter R Jr, Sirasanagandla S, Fernandez AF, Wei Y, Dong X, Franco L, Zou Z, Marchal C, Lee MY, Clapp DW, Hanenberg H, Levine B (2016) Fanconi anemia proteins function in mitophagy and immunity. Cell 165(4):867–881. https://doi.org/10.1016/j.cell.2016.04.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Orvedahl A, Sumpter R Jr, Xiao G, Ng A, Zou Z, Tang Y, Narimatsu M, Gilpin C, Sun Q, Roth M, Forst CV, Wrana JL, Zhang YE, Luby-Phelps K, Xavier RJ, Xie Y, Levine B (2011) Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 480(7375):113–117. https://doi.org/10.1038/nature10546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. de Vries Y, Lwiwski N, Levitus M, Kuyt B, Israels SJ, Arwert F, Zwaan M, Greenberg CR, Alter BP, Joenje H, Meijers-Heijboer H (2012) A dutch fanconi anemia FANCC founder mutation in Canadian manitoba mennonites. Anemia 2012:865170. https://doi.org/10.1155/2012/865170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Ambrose M, Goldstine JV, Gatti RA (2007) Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum Mol Genet 16(18):2154–2164. https://doi.org/10.1093/hmg/ddm166

    Article  CAS  PubMed  Google Scholar 

  178. Eaton JS, Lin ZP, Sartorelli AC, Bonawitz ND, Shadel GS (2007) Ataxia-telangiectasia mutated kinase regulates ribonucleotide reductase and mitochondrial homeostasis. J Clin Investig 117(9):2723–2734. https://doi.org/10.1172/jci31604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, Cleveland JL, Green DR, Kastan MB (2012) Mitochondrial dysfunction in ataxia-telangiectasia. Blood 119(6):1490–1500

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13(5):589–598. https://doi.org/10.1038/ncb2220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J (2011) Tubular network formation protects mitochondrial from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci U S A 108(25):10190–10195

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Yamada T, Murata D, Adachi Y, Itoh K, Kameoka S, Igarashi A, Kato T, Araki Y, Huganir RL, Dawson TM, Yanagawa T, Okamoto K, Iijima M, Sesaki H (2018) Mitochondrial stasis reveals p62-mediated ubiquitination in parkin-independent mitophagy and mitigates nonalcoholic fatty liver disease. Cell Metab 28(4):588-604.e585. https://doi.org/10.1016/j.cmet.2018.06.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Mishra P, Chan DC (2014) Mitochondrial dynamics and inheritance during cell division, development and disease. Nat Rev Mol Cell Biol 15(10):634–646. https://doi.org/10.1038/nrm3877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S, Youle RJ, Mihara K (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191(6):1141–1158. https://doi.org/10.1083/jcb.201007152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Wong YC, Ysselstein D, Krainc D (2018) Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis. Nature 554(7692):382–386. https://doi.org/10.1038/nature25486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yamano K, Fogel AI, Wang C, van der Bliek AM, Youle RJ (2014) Mitochondrial Rab GAPs govern autophagosome biogenesis during mitophagy. eLife 3:e01612. https://doi.org/10.7554/eLife.01612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Shen Q, Yamano K, Head BP, Kawajiri S, Cheung JT, Wang C, Cho JH, Hattori N, Youle RJ, van der Bliek AM (2014) Mutations in Fis1 disrupt orderly disposal of defective mitochondria. Mol Biol Cell 25(1):145–159. https://doi.org/10.1091/mbc.E13-09-0525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Cho HM, Ryu JR, Jo Y, Seo TW, Choi YN, Kim JH, Chung JM, Cho B, Kang HC, Yu SW, Yoo SJ, Kim H, Sun W (2019) Drp1-Zip1 interaction regulates mitochondrial quality surveillance system. Mol Cell 73(2):364-376.e368. https://doi.org/10.1016/j.molcel.2018.11.009

    Article  CAS  PubMed  Google Scholar 

  189. Lee YK, Lee HY, Hanna RA, Gustafsson AB (2011) Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes. Am j Physiol Heart Circ Physiol 301(5):H1924-1931

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Kashatus JA, Nascimento A, Myers LJ, Sher A, Byrne FL, Hoehn KL, Counter CM, Kashatus DF (2015) Erk2 phosphorylation of Drp1 promotes mitochondrial fission and MAPK-driven tumor growth. Mol Cell 57(3):537–551. https://doi.org/10.1016/j.molcel.2015.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Serasinghe MN, Wieder SY, Renault TT, Elkholi R, Asciolla JJ, Yao JL, Jabado O, Hoehn K, Kageyama Y, Sesaki H, Chipuk JE (2015) Mitochondrial division is requisite to RAS-induced transformation and targeted by oncogenic MAPK pathway inhibitors. Mol Cell 57(3):521–536. https://doi.org/10.1016/j.molcel.2015.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Wieder SY, Serasinghe MN, Sung JC, Choi DC, Birge MB, Yao JL, Bernstein E, Celebi JT, Chipuk JE (2015) Activation of the mitochondrial fragmentation protein DRP1 correlates with BRAF(V600E) melanoma. J Invest Dermatol 135(10):2544–2547. https://doi.org/10.1038/jid.2015.196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Trotta AP, Gelles JD, Serasinghe MN, Loi P, Arbiser JL, Chipuk JE (2017) Disruption of mitochondrial electron transport chain function potentiates the pro-apoptotic effects of MAPK inhibition. J Biol Chem 292(28):11727–11739. https://doi.org/10.1074/jbc.M117.786442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Nagdas S, Kashatus JA, Nascimento A, Hussain SS, Trainor RE, Pollock SR, Adair SJ, Michaels AD, Sesaki H, Stelow EB, Bauer TW, Kashatus DF (2019) Drp1 promotes KRas-driven metabolic changes to drive pancreatic tumor growth. Cell Rep 28(7):1845-1859.e1845. https://doi.org/10.1016/j.celrep.2019.07.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, Schuman SS, Shea JE, Seipp MT, Yap JT, Burrell LD, Lum DH, Whisenant JR, Gilcrease GW 3rd, Cavalieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL, McMahon M (2019) Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med 25(4):620–627. https://doi.org/10.1038/s41591-019-0367-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP, Gunda V, Pierobon M, Waters AM, George SD, Tomar G, Papke B, Hobbs GA, Yan L, Hayes TK, Diehl JN, Goode GD, Chaika NV, Wang Y, Zhang GF, Witkiewicz AK, Knudsen ES, PetricoinSingh EFPK, Macdonald JM, Tran NL, Lyssiotis CA, Ying H, Kimmelman AC, Cox AD, Der CJ (2019) Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nat Med 25(4):628–640. https://doi.org/10.1038/s41591-019-0368-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Kalas W, Swiderek E, Rapak A, Kopij M, Rak JW, Strzadala L (2011) H-ras up-regulates expression of BNIP3. Anticancer Res 31(9):2869–2875

    CAS  PubMed  Google Scholar 

  198. Ishikawa K, Takenaga K, Akimoto M, Koshikawa N, Yaaguchi A, Imanishi H, Nakada K, Honma Y, Hayashi JI (2008) ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis. Science 320:661–664

    CAS  PubMed  Google Scholar 

  199. Porporato PE, Payen VL, Perez-Escuredo J, De Saedeleer CJ, Danhier P, Copetti T, Dhup S, Tardy M, Vazeille T, Bouzin C, Feron O, Michiels C, Gallez B, Sonveaux P (2014) A mitochondrial switch promotes tumor metastasis. Cell Rep 8(3):754–766. https://doi.org/10.1016/j.celrep.2014.06.043

    Article  CAS  PubMed  Google Scholar 

  200. Tan A, Baty JW, Dong LF, Bezawork-Geleta A, Endaya B, Goodwin J, Bajzikova M, Kovarova J, Peterka M, Yan B, Pesdar EA, Sobol M, Filimonenko A, Stuart S, Vondrusova M, Kluckova K, Sachaphibulkij K, Rohlena J, Hozak P, Truksa J, Eccles D, Haupt LM, Griffiths LR, Neuzil J, Berridge MV (2015) Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab 21:81–94

    CAS  PubMed  Google Scholar 

  201. Dong LF, Kovarova J, Bajzikova M, Bezawork-Geleta A, Svec D, Endaya B, Sachaphibulkij K, Coelho AR, Sebkova N, Ruzickova A, Tan AS, Kluckova K, Judasova K, Zamecnikova K, Rychtarcikova Z, Gopalan V, Andera L, Sobol M, Yan B, Pattnaik B, Bhatraju N, Truksa J, Stopka P, Hozak P, Lam AK, Sedlacek R, Oliveira PJ, Kubista M, Agrawal A, Dvorakova-Hortova K, Rohlena J, Berridge MV, Neuzil J (2017) Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. eLife. https://doi.org/10.7554/eLife.22187

    Article  PubMed  PubMed Central  Google Scholar 

  202. Cheung EC, DeNicola GM, Nixon C, Blyth K, Labuschagne CF, Tuveson DA, Vousden KH (2020) Dynamic ROS control by TIGAR regulates the initiation and progression of pancreatic cancer. Cancer Cell 37(2):168-182.e164. https://doi.org/10.1016/j.ccell.2019.12.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Radisky DC, Levy E, Littlepage LE, Liu H, Nelson CM, Fata JE, Leake D, Godden EL, Albertson DG, Nieto MA, Werb Z, Bissell MJ (2005) Rac1b and reactive oxygen species mediate MMP3-induced EMT and genomic instability. Nature 436:123–127

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Yang MH, Wu MZ, Chiou SH, Chen PM, Chang SY, Liu CJ, Teng SC, Wu KJ (2008) Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nat Cell Biol 10(3):295–305. https://doi.org/10.1038/ncb1691

    Article  CAS  PubMed  Google Scholar 

  205. Holmstrom KM, Finkel T (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15:411–421

    CAS  PubMed  Google Scholar 

  206. Sabharwal SS, Schumacker PT (2014) Mitochondrial ROS in cancer: initiators, amplifiers or an Achilles’ heel? Nat Rev Cancer 14(11):709–721. https://doi.org/10.1038/nrc3803

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Piskounova E, Agathocleous M, Murphy MM, Hu Z, Huddlestun SE, Zhao Z, Leitch AM, Johnson TM, DeBerardinis RJ, Morrison SJ (2015) Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527(7577):186–191. https://doi.org/10.1038/nature15726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, Dalin MG, Akyurek LM, Lindahl P, Nilsson J, Bergo MO (2015) Antioxidants can increase melanoma metastasis in mice. Sci Transl Med 7(308):308. https://doi.org/10.1126/scitranslmed.aad3740

    Article  Google Scholar 

  209. Kenny TC, Gomez ML, Germain D (2019) Mitohormesis, UPR(mt), and the complexity of mitochondrial DNA landscapes in cancer. Can Res. https://doi.org/10.1158/0008-5472.can-19-1395

    Article  Google Scholar 

  210. Kenny TC, Craig AJ, Villanueva A, Germain D (2019) Mitohormesis primes tumor invasion and metastasis. Cell Rep 27(8):2292-2303.e2296. https://doi.org/10.1016/j.celrep.2019.04.095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Chourasia AH, Macleod KF (2015) Tumor suppressor functions of BNIP3 and mitophagy. Autophagy 11(10):1937–1938. https://doi.org/10.1080/15548627.2015.1085136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Pedanou VE, Gobeil S, Tabaries S, Simone TM, Zhu LJ, Siegel PM, Green MR (2016) The histone H3K9 demethylase KDM3A promotes anoikis by transcriptionally activating pro-apoptotic genes BNIP3 and BNIP3L. eLife. https://doi.org/10.7554/eLife.16844

    Article  PubMed  PubMed Central  Google Scholar 

  213. Maes H, Van Eygen S, Krysko DV, Vandenabeele P, Nys K, Rillaerts K, Garg AD, Verfaillie T, Agostinis P (2014) BNIP3 supports melanoma cell migration and vasculogenic mimicry by orchestrating the actin cytoskeleton. Cell Death Dis 5(3):e1127. https://doi.org/10.1038/cddis.2014.94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Zhang J, Zhang C, Jiang X, Li L, Zhang D, Tang D, Yan T, Zhang Q, Yuan H, Jia J, Hu J, Zhang J, Huang Y (2019) Involvement of autophagy in hypoxia-BNIP3 signaling to promote epidermal keratinocyte migration. Cell Death Dis 10(3):234. https://doi.org/10.1038/s41419-019-1473-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Zhang N, Yang X, Yuan F, Zhang L, Wang Y, Wang L, Mao Z, Luo J, Zhang H, Zhu WG, Zhao Y (2018) Increased amino acid uptake supports autophagy-deficient cell survival upon glutamine deprivation. Cell Rep 23(10):3006–3020. https://doi.org/10.1016/j.celrep.2018.05.006

    Article  CAS  PubMed  Google Scholar 

  216. Towers CG, Fitzwalter BE, Regan D, Goodspeed A, Morgan MJ, Liu CW, Gustafson DL, Thorburn A (2019) Cancer cells upregulate NRF2 signaling to adapt to autophagy inhibition. Dev Cell 50(6):690-703.e696. https://doi.org/10.1016/j.devcel.2019.07.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Lau A, Wang XJ, Zhao F, Villeneuve NF, Wu T, Jiang T, Sun Z, White E, Zhang DD (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30(13):3275–3285

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Fearon KC, Glass DJ, Guttridge DC (2012) Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab 16(2):153–166. https://doi.org/10.1016/j.cmet.2012.06.011

    Article  CAS  PubMed  Google Scholar 

  219. Biswas AK, Acharyya S (2020) Understanding cachexia in the context of metastatic progression. Nat Rev Cancer 20(5):274–284. https://doi.org/10.1038/s41568-020-0251-4

    Article  CAS  PubMed  Google Scholar 

  220. Porporato PE (2016) Understanding cachexia as a cancer metabolism syndrome. Oncogenesis 5:e200. https://doi.org/10.1038/oncsis.2016.3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Petruzzelli M, Wagner EF (2016) Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev 30(5):489–501. https://doi.org/10.1101/gad.276733.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Tsoli M, Robertson G (2013) Cancer cachexia: malignant inflammation, tumorkines, and metabolic mayhem. Trends Endocrinol Metab TEM 24(4):174–183. https://doi.org/10.1016/j.tem.2012.10.006

    Article  CAS  PubMed  Google Scholar 

  223. Stephens NA, Skipworth RJ, Gallagher IJ, Greig CA, Guttridge DC, Ross JA, Fearon KC (2015) Evaluating potential biomarkers of cachexia and survival in skeletal muscle of upper gastrointestinal cancer patients. J Cachexia Sarcopenia Muscle 6(1):53–61. https://doi.org/10.1002/jcsm.12005

    Article  PubMed  PubMed Central  Google Scholar 

  224. Julienne CM, Dumas JF, Goupille C, Pinault M, Berri C, Collin A, Tesseraud S, Couet C, Servais S (2012) Cancer cachexia is associated with a decrease in skeletal muscle mitochondrial oxidative capacities without alteration of ATP production efficiency. J Cachexia Sarcopenia Muscle 3(4):265–275. https://doi.org/10.1007/s13539-012-0071-9

    Article  PubMed  PubMed Central  Google Scholar 

  225. Antunes D, Padrao AI, Maciel E, Santinha D, Oliveira P, Vitorino R, Moreira-Goncalves D, Colaco B, Pires MJ, Nunes C, Santos LL, Amado F, Duarte JA, Domingues MR (2014) Molecular insights into mitochondrial dysfunction in cancer-related muscle wasting. Biochem Biophys Acta 6:896–905. https://doi.org/10.1016/j.bbalip.2014.03.004

    Article  CAS  Google Scholar 

  226. Amaravadi R, Kimmelman A, Debnath J (2019) Targeting autophagy in cancer: recent advances, future directions. Cancer Discov Under review

  227. Levy JMM, Towers CG, Thorburn A (2017) Targeting autophagy in cancer. Nat Rev Cancer 17(9):528–542. https://doi.org/10.1038/nrc.2017.53

    Article  CAS  PubMed  Google Scholar 

  228. Briceno E, Reyes S, Sotelo J (2003) Therapy of glioblastoma multiforme improved by the antimutagenic chloroquine. Neurosurg Focus 14(2):e3

    PubMed  Google Scholar 

  229. Sotelo J, Briceno E, Lopez-Gonzalez MA (2006) Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 144(5):337–343

    CAS  PubMed  Google Scholar 

  230. Pascolo S (2016) Time to use a dose of Chloroquine as an adjuvant to anti-cancer chemotherapies. Eur J Pharmacol 771:139–144. https://doi.org/10.1016/j.ejphar.2015.12.017

    Article  CAS  PubMed  Google Scholar 

  231. Elliott IA, Dann AM, Xu S, Kim SS, Abt ER, Kim W, Poddar S, Moore A, Zhou L, Williams JL, Capri JR, Ghukasyan R, Matsumura C, Tucker DA, Armstrong WR, Cabebe AE, Wu N, Li L, Le TM, Radu CG, Donahue TR (2019) Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion. Proc Natl Acad Sci U S A 116(14):6842–6847. https://doi.org/10.1073/pnas.1812410116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, Jiang X (2019) Role of mitochondria in ferroptosis. Mol Cell 73(2):354-363.e353. https://doi.org/10.1016/j.molcel.2018.10.042

    Article  CAS  PubMed  Google Scholar 

  233. Georgakopoulos ND, Wells G, Campanella M (2017) The pharmacological regulation of cellular mitophagy. Nat Chem Biol 13(2):136–146. https://doi.org/10.1038/nchembio.2287

    Article  CAS  PubMed  Google Scholar 

  234. Chourasia AH, Boland ML, Macleod KF (2015) Mitophagy and cancer. Cancer Metab 3:4. https://doi.org/10.1186/s40170-015-0130-8

    Article  PubMed  PubMed Central  Google Scholar 

  235. Rao VA, Klein SR, Bonar SJ, Zielonka J, Mizuno N, Dickey JS, Keller PW, Joseph J, Kalyanaraman B, Shacter E (2010) The antioxidant transcription factor Nrf2 negatively regulates autophagy and growth arrest induced by the anticancer redox agent mitoquinone. J Biol Chem 285(45):34447–34459. https://doi.org/10.1074/jbc.M110.133579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Meyer N, Zielke S, Michaelis JB, Linder B, Warnsmann V, Rakel S, Osiewacz HD, Fulda S, Mittelbronn M, Münch C, Behrends C, Kögel D (2018) AT 101 induces early mitochondrial dysfunction and HMOX1 (heme oxygenase 1) to trigger mitophagic cell death in glioma cells. Autophagy 14(10):1693–1709. https://doi.org/10.1080/15548627.2018.1476812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Georgakopoulos ND, Frison M, Alvarez MS, Bertrand H, Wells G, Campanella M (2017) Reversible Keap1 inhibitors are preferential pharmacological tools to modulate cellular mitophagy. Sci Rep 7(1):10303. https://doi.org/10.1038/s41598-017-07679-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Heo JM, Ordureau A, Paulo JA, Rinehart J, Harper J (2015) The PINK1-PARKIN mitochondrial ubiquitylation pathway drives a program of OPTN/NDP52 recruitment and TBK1 activation to promote mitophagy. Mol Cell 60:7–20

    CAS  PubMed  PubMed Central  Google Scholar 

  239. Wong YC, Holzbaur EL (2014) Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc Natl Acad Sci USA 111(42):E4439-4448. https://doi.org/10.1073/pnas.1405752111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Li L, Shen C, Nakamura E, Ando K, Signoretti S, Beroukhim R, Cowley GS, Lizotte P, Liberzon E, Bair S, Root DE, Tamayo P, Tsherniak A, Cheng SC, Tabak B, Jacobsen A, Hakimi AA, Schultz N, Ciriello G, Sander C, Hsieh JJ, Kaelin WGJ (2013) SQSTM1 is a pathogenic target of 5q copy number gains in kidney cancer. Cancer Cell 24(6):738–750

    CAS  PubMed  PubMed Central  Google Scholar 

  241. Moscat J, Karin M, Diaz-Meco MT (2016) p62 in cancer: signaling adaptor beyond autophagy. Cell 167(3):606–609. https://doi.org/10.1016/j.cell.2016.09.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Hsieh CH, Shaltouki A, Gonzalez AE, Bettencourt da Cruz A, Burbulla LF, St Lawrence E, Schule B, Krainc D, Palmer TD, Wang X (2016) Functional impairment in miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 19(6):709–724. https://doi.org/10.1016/j.stem.2016.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Sugiura A, Nagashima S, Tokuyama T, Amo T, Matsuki Y, Ishido S, Kudo Y, McBride HM, Fukuda T, Matsushita N, Inatome R, Yanagi S (2013) MITOL regulates endoplasmic reticulum-mitochondria contacts via Mitofusin2. Mol Cell 51(1):20–34. https://doi.org/10.1016/j.molcel.2013.04.023

    Article  CAS  PubMed  Google Scholar 

  244. Szargel R, Shani V, Abd Elghani F, Mekies LN, Liani E, Rott R, Engelender S (2016) The PINK1, synphilin-1 and SIAH-1 complex constitutes a novel mitophagy pathway. Hum Mol Genet 25(16):3476–3490. https://doi.org/10.1093/hmg/ddw189

    Article  CAS  PubMed  Google Scholar 

  245. Anding AL, Wang C, Chang TK, Sliter DA, Powers CM, Hofmann K, Youle RJ, Baehrecke EH (2018) Vps13D encodes a ubiquitin-binding protein that is required for the regulation of mitochondrial size and clearance. Curr Biol CB 28(2):287-295.e286. https://doi.org/10.1016/j.cub.2017.11.064

    Article  CAS  PubMed  Google Scholar 

  246. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146(3):408–420. https://doi.org/10.1016/j.cell.2011.06.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Winter RN, Kramer A, Borkowski A, Kyprianou N (2001) Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. Can Res 61(3):1227–1232

    CAS  Google Scholar 

  248. Yang YM, Ramadani M, Huang YT (2003) Overexpression of Caspase-1 in adenocarcinoma of pancreas and chronic pancreatitis. World J Gastroenterol 9(12):2828–2831. https://doi.org/10.3748/wjg.v9.i12.2828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Feng Q, Li P, Salamanca C, Huntsman D, Leung PC, Auersperg N (2005) Caspase-1alpha is down-regulated in human ovarian cancer cells and the overexpression of caspase-1alpha induces apoptosis. Can Res 65(19):8591–8596. https://doi.org/10.1158/0008-5472.can-05-0239

    Article  CAS  Google Scholar 

  250. Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD (2010) IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol 185(8):4912–4920. https://doi.org/10.4049/jimmunol.1002046

    Article  CAS  PubMed  Google Scholar 

  251. Daley D, Mani VR, Mohan N, Akkad N, Pandian G, Savadkar S, Lee KB, Torres-Hernandez A, Aykut B, Diskin B, Wang W, Farooq MS, Mahmud AI, Werba G, Morales EJ, Lall S, Wadowski BJ, Rubin AG, Berman ME, Narayanan R, Hundeyin M, Miller G (2017) NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J Exp Med 214(6):1711–1724. https://doi.org/10.1084/jem.20161707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Vanpouille-Box C, Demaria S, Formenti SC, Galluzzi L (2018) Cytosolic DNA sensing in organismal tumor control. Cancer Cell 34(3):361–378. https://doi.org/10.1016/j.ccell.2018.05.013

    Article  CAS  PubMed  Google Scholar 

  253. Rzymski T, Milani M, Singleton DC, Harris AL (2009) Role of ATF4 in regulation of autophagy and resistance to drugs and hypoxia. Cell Cycle 8(23):3838–3847. https://doi.org/10.4161/cc.8.23.10086

    Article  CAS  PubMed  Google Scholar 

  254. Dey S, Sayers CM, Verginadis II, Lehman SL, Cheng Y, Cerniglia GJ, Tuttle SW, Feldman MD, Zhang PJ, Fuchs SY, Diehl JA, Koumenis C (2015) ATF4-dependent induction of heme oxygenase 1 prevents anoikis and promotes metastasis. J Clin Investig 125(7):2592–2608. https://doi.org/10.1172/jci78031

    Article  PubMed  PubMed Central  Google Scholar 

  255. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, Lecker SH, Goldberg AL (2007) FoxO3 coordinately activates protein degradation by tthe autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6:472–483

    CAS  PubMed  Google Scholar 

  256. Zhao Y, Yang J, Liao W, Liu X, Zhang H, Wang S, Wang D, Feng J, Yu L, Zhu WG (2010) Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity. Nat Cell Biol 12(7):665–675. https://doi.org/10.1038/ncb2069

    Article  CAS  PubMed  Google Scholar 

  257. Warr MR, Binnewies M, Flach J, Reynaud D, Garg T, Malhotra R, Debnath J, Passegue E (2013) FOXO3A directs a protective autophagy program in haematopoietic stem cells. Nature 494(7437):323–327. https://doi.org/10.1038/nature11895

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Fitzwalter BE, Towers CG, Sullivan KD, Andrysik Z, Hoh M, Ludwig M, O’Prey J, Ryan KM, Espinosa JM, Morgan MJ, Thorburn A (2018) Autophagy inhibition mediates apoptosis sensitization in cancer therapy by relieving FOXO3a turnover. Dev Cell 44(5):555-565.e553. https://doi.org/10.1016/j.devcel.2018.02.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Keith B, Simon MC (2007) Hypoxia-inducible factors, stem cells and cancer. Cell 129:465–472

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Semenza GL (2016) Hypoxia-inducible factors: coupling glucose metabolism and redox regulation with induction of the breast cancer stem cell phenotype. Embo J. https://doi.org/10.15252/embj.201695204

    Article  PubMed  PubMed Central  Google Scholar 

  261. Perera RM, Stoykova S, Nicolay BN, Ross KN, Fitamant J, Boukhali M, Lengrand J, Deshpande V, Selig MK, Ferrone CR, Settleman J, Stephanopoulos G, Dyson NJ, Zoncu R, Ramaswamy S, Haas W, Bardeesy N (2015) Transcriptional control of the autophagy-lysosome system in pancreatic cancer. Nature 524:361–365

    CAS  PubMed  PubMed Central  Google Scholar 

  262. Strappazzon F, Nazio F, Corrado M, Cianfanelli V, Romagnoli A, Fimia GM, Campello S, Nardacci R, Piacentini M, Campanella M, Cecconi F (2015) AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell Death Differ 22(3):419–432. https://doi.org/10.1038/cdd.2014.139

    Article  CAS  PubMed  Google Scholar 

  263. Falasca L, Torino F, Marconi M, Costantini M, Pompeo V, Sentinelli S, De Salvo L, Patrizio M, Padula C, Gallucci M, Piacentini M, Malorni W (2015) AMBRA1 and SQSTM1 expression pattern in prostate cancer. Apoptosis 20(12):1577–1586. https://doi.org/10.1007/s10495-015-1176-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Strappazzon F, Cecconi F (2015) AMBRA1-induced mitophagy: a new mechanism to cope with cancer? Mol Cell Oncol 2(2):e975647. https://doi.org/10.4161/23723556.2014.975647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Cianfanelli V, Fuoco C, Lorente M, Salazar M, Quondamatteo F, Gherardini PF, De Zio D, Nazio F, Antonioli M, D’Orazio M, Skobo T, Bordi M, Rohde M, Dalla Valle L, Helmer-Citterich M, Gretzmeier C, Dengjel J, Fimia GM, Piacentini M, Di Bartolomeo S, Velasco G, Cecconi F (2015) AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol 17(1):20–30. https://doi.org/10.1038/ncb3072

    Article  CAS  PubMed  Google Scholar 

  266. Schoenherr C, Byron A, Sandilands E, Paliashvili K, Baillie GS, Garcia-Munoz A, Valacca C, Cecconi F, Serrels B, Frame MC (2017) Ambra1 spatially regulates Src activity and Src/FAK-mediated cancer cell invasion via trafficking networks. eLife. https://doi.org/10.7554/eLife.23172

    Article  PubMed  PubMed Central  Google Scholar 

  267. Park S, Choi SG, Yoo SM, Son JH, Jung YK (2014) Choline dehydrogenase interacts with SQSTM1/p62 to recruit LC3 and stimulate mitophagy. Autophagy 10(11):1906–1920. https://doi.org/10.4161/auto.32177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Karbowski M, Jeong SY, Youle RJ (2004) Endophilin B1 is required for the maintenance of mitochondrial morphology. J Cell Biol 166(7):1027–1039. https://doi.org/10.1083/jcb.200407046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Takahashi Y, Hori T, Cooper TK, Liao J, Desai N, Serfass JM, Young MM, Park S, Izu Y, Wang HG (2013) Bif-1 haploinsufficiency promotes chromosomal instability and accelerates Myc-driven lymphomagenesis via suppression of mitophagy. Blood 121(9):1622–1632. https://doi.org/10.1182/blood-2012-10-459826

    Article  PubMed  PubMed Central  Google Scholar 

  270. Bhujabal Z, Birgisdottir AB, Sjottem E, Brenne HB, Overvatn A, Habisov S, Kirkin V, Lamark T, Johansen T (2017) FKBP8 recruits LC3A to mediate Parkin-independent mitophagy. EMBO Rep 18(6):947–961. https://doi.org/10.15252/embr.201643147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Shlevkov E, Kramer T, Schapansky J, LaVoie MJ, Schwarz TL (2016) Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. Proc Natl Acad Sci U S A 113(41):E6097-e6106. https://doi.org/10.1073/pnas.1612283113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Le Guerroue F, Eck F, Jung J, Starzetz T, Mittelbronn M, Kaulich M, Behrends C (2017) Autophagosomal content profiling reveals an LC3C-dependent piecemeal mitophagy pathway. Mol Cell 68(4):786-796.e786. https://doi.org/10.1016/j.molcel.2017.10.029

    Article  CAS  PubMed  Google Scholar 

  273. D’Amico D, Mottis A, Potenza F, Sorrentino V, Li H, Romani M, Lemos V, Schoonjans K, Zamboni N, Knott G, Schneider BL, Auwerx J (2019) The RNA-binding protein PUM2 impairs mitochondrial dynamics and mitophagy during aging. Mol Cell 73(4):775-787.e710. https://doi.org/10.1016/j.molcel.2018.11.034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Schneider AT, Gautheron J, Feoktistova M, Roderburg C, Loosen SH, Roy S, Benz F, Schemmer P, Büchler MW, Nachbur U, Neumann UP, Tolba R, Luedde M, Zucman-Rossi J, Panayotova-Dimitrova D, Leverkus M, Preisinger C, Tacke F, Trautwein C, Longerich T, Vucur M, Luedde T (2017) RIPK1 suppresses a TRAF2-dependent pathway to liver cancer. Cancer Cell 31(1):94–109. https://doi.org/10.1016/j.ccell.2016.11.009

    Article  CAS  PubMed  Google Scholar 

  275. Hawk MA, Gorsuch CL, Fagan P, Lee C, Kim SE, Hamann JC, Mason JA, Weigel KJ, Tsegaye MA, Shen L, Shuff S, Zuo J, Hu S, Jiang L, Chapman S, Leevy WM, DeBerardinis RJ, Overholtzer M, Schafer ZT (2018) RIPK1-mediated induction of mitophagy compromises the viability of extracellular-matrix-detached cells. Nat Cell Biol 20(3):272–284. https://doi.org/10.1038/s41556-018-0034-2

    Article  CAS  PubMed  Google Scholar 

  276. Hamasaki M, Furuta N, Matsuda A, Nezu A, Yamamoto A, Fujita N, Oomori H, Noda T, Haraguchi T, Hiraoka Y, Amano A, Yoshimori T (2013) Autophagosomes form at ER-mitochondria contact sites. Nature 495(7441):389–393. https://doi.org/10.1038/nature11910

    Article  CAS  PubMed  Google Scholar 

  277. Arasaki K, Nagashima H, Kurosawa Y, Kimura H, Nishida N, Dohmae N, Yamamoto A, Yanagi S, Wakana Y, Inoue H, Tagaya M (2018) MAP1B-LC1 prevents autophagosome formation by linking syntaxin 17 to microtubules. EMBO Rep. https://doi.org/10.15252/embr.201745584

    Article  PubMed  PubMed Central  Google Scholar 

  278. Sugo M, Kimura H, Arasaki K, Amemiya T, Hirota N, Dohmae N, Imai Y, Inoshita T, Shiba-Fukushima K, Hattori N, Cheng J, Fujimoto T, Wakana Y, Inoue H, Tagaya M (2018) Syntaxin 17 regulates the localization and function of PGAM5 in mitochondrial division and mitophagy. Embo J. https://doi.org/10.15252/embj.201798899

    Article  PubMed  PubMed Central  Google Scholar 

  279. Xian H, Yang Q, Xiao L, Shen HM, Liou YC (2019) STX17 dynamically regulated by Fis1 induces mitophagy via hierarchical macroautophagic mechanism. Nat Commun 10(1):2059. https://doi.org/10.1038/s41467-019-10096-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Kumar S, Gu Y, Abudu YP, Bruun JA, Jain A, Farzam F, Mudd M, Anonsen JH, Rusten TE, Kasof G, Ktistakis N, Lidke KA, Johansen T, Deretic V (2019) Phosphorylation of syntaxin 17 by TBK1 controls autophagy initiation. Dev Cell 49(1):130–144. https://doi.org/10.1016/j.devcel.2019.01.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Poole, L.P., Macleod, K.F. Mitophagy in tumorigenesis and metastasis. Cell. Mol. Life Sci. 78, 3817–3851 (2021). https://doi.org/10.1007/s00018-021-03774-1

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