Skip to main content
SpringerLink
Log in

Mitochondrial dynamics and cell death in heart failure

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

The highly regulated processes of mitochondrial fusion (joining), fission (division) and trafficking, collectively called mitochondrial dynamics, determine cell-type specific morphology, intracellular distribution and activity of these critical organelles. Mitochondria are critical for cardiac function, while their structural and functional abnormalities contribute to several common cardiovascular diseases, including heart failure (HF). The tightly balanced mitochondrial fusion and fission determine number, morphology and activity of these multifunctional organelles. Although the intracellular architecture of mature cardiomyocytes greatly restricts mitochondrial dynamics, this process occurs in the adult human heart. Fusion and fission modulate multiple mitochondrial functions, ranging from energy and reactive oxygen species production to Ca2+ homeostasis and cell death, allowing the heart to respond properly to body demands. Tightly controlled balance between fusion and fission is of utmost importance in the high energy-demanding cardiomyocytes. A shift toward fission leads to mitochondrial fragmentation, while a shift toward fusion results in the formation of enlarged mitochondria and in the fusion of damaged mitochondria with healthy organelles. Mfn1, Mfn2 and OPA1 constitute the core machinery promoting mitochondrial fusion, whereas Drp1, Fis1, Mff and MiD49/51 are the core components of fission machinery. Growing evidence suggests that fusion/fission factors in adult cardiomyocytes play essential noncanonical roles in cardiac development, Ca2+ signaling, mitochondrial quality control and cell death. Impairment of this complex circuit causes cardiomyocyte dysfunction and death contributing to heart injury culminating in HF. Pharmacological targeting of components of this intricate network may be a novel therapeutic modality for HF treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Hoppel CL, Tandler B, Fujioka H, Riva A (2009) Dynamic organization of mitochondria in human heart and in myocardial disease. Int J Biochem Cell Biol 41:1949–1956

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Ong SB, Hausenloy DJ (2010) Mitochondrial morphology and cardiovascular disease. Cardiovasc Res 88:16–29

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Ventura-Clapier R, Garnier A, Veksler V, Joubert F (2011) Bioenergetics of the failing heart. Biochim Biophys Acta 1813:1360–1372

    Article  CAS  PubMed  Google Scholar 

  4. Soubannier V, McBride HM (2009) Positioning mitochondrial plasticity within cellular signaling cascades. Biochim Biophys Acta 1793:154–170

    Article  CAS  PubMed  Google Scholar 

  5. Hausenloy DJ, Ruiz-Meana M (2010) Not just the powerhouse of the cell: emerging roles for mitochondria in the heart. Cardiovasc Res 88:5–6

    Article  CAS  PubMed  Google Scholar 

  6. Nunnari J, Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148:1145–1159

    Article  CAS  PubMed  Google Scholar 

  7. Brown DA, O’Rourke B (2010) Cardiac mitochondria and arrhythmias. Cardiovasc Res 88:241–249

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Cadenas S, Aragones J, Landazuri MO (2010) Mitochondrial reprogramming through cardiac oxygen sensors in ischaemic heart disease. Cardiovasc Res 88:219–228

    Article  CAS  PubMed  Google Scholar 

  9. Rosca MG, Hoppel CL (2010) Mitochondria in heart failure. Cardiovasc Res 88:40–50

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Verdejo HE, del Campo A, Troncoso R, Gutierrez T, Toro B et al (2012) Mitochondria, myocardial remodeling, and cardiovascular disease. Curr Hypertens Rep 14:532–539

    Article  CAS  PubMed  Google Scholar 

  11. Liesa M, Palacin M, Zorzano A (2009) Mitochondrial dynamics in mammalian health and disease. Physiol Rev 89:799–845

    Article  CAS  PubMed  Google Scholar 

  12. Westermann B (2010) Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol 11:872–884

    Article  CAS  PubMed  Google Scholar 

  13. Youle RJ, van der Bliek AM (2012) Mitochondrial fission, fusion, and stress. Science 337:1062–1065

    Article  CAS  PubMed  Google Scholar 

  14. Friedman JR, Nunnari J (2014) Mitochondrial form and function. Nature 505:335–343

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Archer SL (2013) Mitochondrial dynamics—mitochondrial fission and fusion in human diseases. N Engl J Med 369:2236–2251

    Article  CAS  PubMed  Google Scholar 

  16. Hoppins S (2014) The regulation of mitochondrial dynamics. Curr Opin Cell Biol 29:46–52

    Article  CAS  PubMed  Google Scholar 

  17. Elgass K, Pakay J, Ryan MT, Palmer CS (2013) Recent advances into the understanding of mitochondrial fission. Biochim Biophys Acta 1833:150–161

    Article  CAS  PubMed  Google Scholar 

  18. Chung S, Dzeja PP, Faustino RS, Perez-Terzic C, Behfar A et al (2007) Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat Clin Pract Cardiovasc Med 4(Suppl 1):S60–S67

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Youle RJ, Karbowski M (2005) Mitochondrial fission in apoptosis. Nat Rev Mol Cell Biol 6:657–663

    Article  CAS  PubMed  Google Scholar 

  20. Hall AR, Burke N, Dongworth RK, Hausenloy DJ (2014) Mitochondrial fusion and fission proteins: novel therapeutic targets for combating cardiovascular disease. Br J Pharmacol 171:1890–1906

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Dorn GW 2nd, Kitsis RN (2015) The mitochondrial dynamism-mitophagy-cell death interactome: multiple roles performed by members of a mitochondrial molecular ensemble. Circ Res 116:167–182

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Itoh K, Nakamura K, Iijima M, Sesaki H (2013) Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 23:64–71

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Ong SB, Hall AR, Hausenloy DJ (2013) Mitochondrial dynamics in cardiovascular health and disease. Antioxid Redox Signal 19:400–414

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Dorn GW 2nd (2015) Mitochondrial dynamism and heart disease: changing shape and shaping change. EMBO Mol Med 7:865–877

    Article  CAS  PubMed  Google Scholar 

  25. Sharp WW, Archer SL (2015) Mitochondrial dynamics in cardiovascular disease: fission and fusion foretell form and function. J Mol Med (Berl) 93:225–228

    Article  Google Scholar 

  26. Sharma VK, Ramesh V, Franzini-Armstrong C, Sheu SS (2000) Transport of Ca2+ from sarcoplasmic reticulum to mitochondria in rat ventricular myocytes. J Bioenerg Biomembr 32:97–104

    Article  CAS  PubMed  Google Scholar 

  27. Bers DM (2008) Calcium cycling and signaling in cardiac myocytes. Annu Rev Physiol 70:23–49

    Article  CAS  PubMed  Google Scholar 

  28. Dorn GW 2nd, Maack C (2013) SR and mitochondria: calcium cross-talk between kissing cousins. J Mol Cell Cardiol 55:42–49

    Article  CAS  PubMed  Google Scholar 

  29. Chen Y, Liu Y, Dorn GW 2nd (2011) Mitochondrial fusion is essential for organelle function and cardiac homeostasis. Circ Res 109:1327–1331

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Papanicolaou KN, Kikuchi R, Ngoh GA, Coughlan KA, Dominguez I et al (2012) Mitofusins 1 and 2 are essential for postnatal metabolic remodeling in heart. Circ Res 111:1012–1026

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Kageyama Y, Hoshijima M, Seo K, Bedja D, Sysa-Shah P et al (2014) Parkin-independent mitophagy requires Drp1 and maintains the integrity of mammalian heart and brain. EMBO J 33:2798–2813

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Ishihara T, Ban-Ishihara R, Maeda M, Matsunaga Y, Ichimura A et al (2015) Dynamics of mitochondrial DNA nucleoids regulated by mitochondrial fission is essential for maintenance of homogeneously active mitochondria during neonatal heart development. Mol Cell Biol 35:211–223

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  33. Song M, Mihara K, Chen Y, Scorrano L, Dorn GW 2nd (2015) Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab 21:273–285

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Westermann B (2008) Molecular machinery of mitochondrial fusion and fission. J Biol Chem 283:13501–13505

    Article  CAS  PubMed  Google Scholar 

  35. Schmid SL, Frolov VA (2011) Dynamin: functional design of a membrane fission catalyst. Annu Rev Cell Dev Biol 27:79–105

    Article  CAS  PubMed  Google Scholar 

  36. Ishihara N, Otera H, Oka T, Mihara K (2013) Regulation and physiologic functions of GTPases in mitochondrial fusion and fission in mammals. Antioxid Redox Signal 19:389–399

    Article  CAS  PubMed  Google Scholar 

  37. Ranieri M, Brajkovic S, Riboldi G, Ronchi D, Rizzo F et al (2013) Mitochondrial fusion proteins and human diseases. Neurol Res Int 2013:293893

    PubMed Central  PubMed  Google Scholar 

  38. Rojo M, Legros F, Chateau D, Lombes A (2002) Membrane topology and mitochondrial targeting of mitofusins, ubiquitous mammalian homologs of the transmembrane GTPase Fzo. J Cell Sci 115:1663–1674

    CAS  PubMed  Google Scholar 

  39. Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE et al (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160:189–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Koshiba T, Detmer SA, Kaiser JT, Chen H, McCaffery JM et al (2004) Structural basis of mitochondrial tethering by mitofusin complexes. Science 305:858–862

    Article  CAS  PubMed  Google Scholar 

  41. de Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605–610

    Article  PubMed  CAS  Google Scholar 

  42. Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C et al (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26:207–210

    Article  CAS  PubMed  Google Scholar 

  43. Olichon A, Baricault L, Gas N, Guillou E, Valette A et al (2003) Loss of OPA1 perturbates the mitochondrial inner membrane structure and integrity, leading to cytochrome c release and apoptosis. J Biol Chem 278:7743–7746

    Article  CAS  PubMed  Google Scholar 

  44. Delettre C, Griffoin JM, Kaplan J, Dollfus H, Lorenz B et al (2001) Mutation spectrum and splicing variants in the OPA1 gene. Hum Genet 109:584–591

    Article  CAS  PubMed  Google Scholar 

  45. Pellegrini L, Passer BJ, Canelles M, Lefterov I, Ganjei JK et al (2001) PAMP and PARL, two novel putative metalloproteases interacting with the COOH-terminus of Presenilin-1 and -2. J Alzheimers Dis 3:181–190

    CAS  PubMed  Google Scholar 

  46. Cipolat S, Rudka T, Hartmann D, Costa V, Serneels L et al (2006) Mitochondrial rhomboid PARL regulates cytochrome c release during apoptosis via OPA1-dependent cristae remodeling. Cell 126:163–175

    Article  CAS  PubMed  Google Scholar 

  47. Ishihara N, Fujita Y, Oka T, Mihara K (2006) Regulation of mitochondrial morphology through proteolytic cleavage of OPA1. EMBO J 25:2966–2977

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Griparic L, Kanazawa T, van der Bliek AM (2007) Regulation of the mitochondrial dynamin-like protein Opa1 by proteolytic cleavage. J Cell Biol 178:757–764

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Ehses S, Raschke I, Mancuso G, Bernacchia A, Geimer S et al (2009) Regulation of OPA1 processing and mitochondrial fusion by m-AAA protease isoenzymes and OMA1. J Cell Biol 187:1023–1036

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Head B, Griparic L, Amiri M, Gandre-Babbe S, van der Bliek AM (2009) Inducible proteolytic inactivation of OPA1 mediated by the OMA1 protease in mammalian cells. J Cell Biol 187:959–966

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Song Z, Chen H, Fiket M, Alexander C, Chan DC (2007) OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J Cell Biol 178:749–755

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Baker MJ, Tatsuta T, Langer T (2011) Quality control of mitochondrial proteostasis. Cold Spring Harb Perspect Biol doi:10.1101/cshperspect.a007559

    PubMed Central  PubMed  Google Scholar 

  53. Duvezin-Caubet S, Jagasia R, Wagener J, Hofmann S, Trifunovic A et al (2006) Proteolytic processing of OPA1 links mitochondrial dysfunction to alterations in mitochondrial morphology. J Biol Chem 281:37972–37979

    Article  CAS  PubMed  Google Scholar 

  54. Song Z, Ghochani M, McCaffery JM, Frey TG, Chan DC (2009) Mitofusins and OPA1 mediate sequential steps in mitochondrial membrane fusion. Mol Biol Cell 20:3525–3532

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Sesaki H, Jensen RE (2001) UGO1 encodes an outer membrane protein required for mitochondrial fusion. J Cell Biol 152:1123–1134

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Sesaki H, Jensen RE (2004) Ugo1p links the Fzo1p and Mgm1p GTPases for mitochondrial fusion. J Biol Chem 279:28298–28303

    Article  CAS  PubMed  Google Scholar 

  57. Guillery O, Malka F, Landes T, Guillou E, Blackstone C et al (2008) Metalloprotease-mediated OPA1 processing is modulated by the mitochondrial membrane potential. Biol Cell 100:315–325

    Article  CAS  PubMed  Google Scholar 

  58. Otera H, Ishihara N, Mihara K (2013) New insights into the function and regulation of mitochondrial fission. Biochim Biophys Acta 1833:1256–1268

    Article  CAS  PubMed  Google Scholar 

  59. Smirnova E, Shurland DL, Ryazantsev SN, van der Bliek AM (1998) A human dynamin-related protein controls the distribution of mitochondria. J Cell Biol 143:351–358

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Labrousse AM, Zappaterra MD, Rube DA, van der Bliek AM (1999) C. elegans dynamin-related protein DRP-1 controls severing of the mitochondrial outer membrane. Mol Cell 4:815–826

    Article  CAS  PubMed  Google Scholar 

  61. Smirnova E, Griparic L, Shurland DL, van der Bliek AM (2001) Dynamin-related protein Drp1 is required for mitochondrial division in mammalian cells. Mol Biol Cell 12:2245–2256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Bhar D, Karren MA, Babst M, Shaw JM (2006) Dimeric Dnm1-G385D interacts with Mdv1 on mitochondria and can be stimulated to assemble into fission complexes containing Mdv1 and Fis1. J Biol Chem 281:17312–17320

    Article  CAS  PubMed  Google Scholar 

  63. Chang CR, Manlandro CM, Arnoult D, Stadler J, Posey AE et al (2010) A lethal de novo mutation in the middle domain of the dynamin-related GTPase Drp1 impairs higher order assembly and mitochondrial division. J Biol Chem 285:32494–32503

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Yoon Y, Krueger EW, Oswald BJ, McNiven MA (2003) The mitochondrial protein hFis1 regulates mitochondrial fission in mammalian cells through an interaction with the dynamin-like protein DLP1. Mol Cell Biol 23:5409–5420

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Otera H, Wang C, Cleland MM, Setoguchi K, Yokota S et al (2010) Mff is an essential factor for mitochondrial recruitment of Drp1 during mitochondrial fission in mammalian cells. J Cell Biol 191:1141–1158

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  66. Palmer CS, Osellame LD, Laine D, Koutsopoulos OS, Frazier AE et al (2011) MiD49 and MiD51, new components of the mitochondrial fission machinery. EMBO Rep 12:565–573

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Loson OC, Song Z, Chen H, Chan DC (2013) Fis1, Mff, MiD49, and MiD51 mediate Drp1 recruitment in mitochondrial fission. Mol Biol Cell 24:659–667

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Mozdy AD, McCaffery JM, Shaw JM (2000) Dnm1p GTPase-mediated mitochondrial fission is a multi-step process requiring the novel integral membrane component Fis1p. J Cell Biol 151:367–380

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. James DI, Parone PA, Mattenberger Y, Martinou JC (2003) hFis1, a novel component of the mammalian mitochondrial fission machinery. J Biol Chem 278:36373–36379

    Article  CAS  PubMed  Google Scholar 

  70. Suzuki M, Jeong SY, Karbowski M, Youle RJ, Tjandra N (2003) The solution structure of human mitochondria fission protein Fis1 reveals a novel TPR-like helix bundle. J Mol Biol 334:445–458

    Article  CAS  PubMed  Google Scholar 

  71. Suzuki M, Neutzner A, Tjandra N, Youle RJ (2005) Novel structure of the N terminus in yeast Fis1 correlates with a specialized function in mitochondrial fission. J Biol Chem 280:21444–21452

    Article  CAS  PubMed  Google Scholar 

  72. Zhang Y, Chan DC (2007) Structural basis for recruitment of mitochondrial fission complexes by Fis1. Proc Natl Acad Sci USA 104:18526–18530

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  73. Jofuku A, Ishihara N, Mihara K (2005) Analysis of functional domains of rat mitochondrial Fis1, the mitochondrial fission-stimulating protein. Biochem Biophys Res Commun 333:650–659

    Article  CAS  PubMed  Google Scholar 

  74. Gandre-Babbe S, van der Bliek AM (2008) The novel tail-anchored membrane protein Mff controls mitochondrial and peroxisomal fission in mammalian cells. Mol Biol Cell 19:2402–2412

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  75. Ashrafian H, Docherty L, Leo V, Towlson C, Neilan M et al (2010) A mutation in the mitochondrial fission gene Dnm1l leads to cardiomyopathy. PLoS Genet 6:e1001000

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  76. Loson OC, Liu R, Rome ME, Meng S, Kaiser JT et al (2014) The mitochondrial fission receptor MiD51 requires ADP as a cofactor. Structure 22:367–377

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Richter V, Palmer CS, Osellame LD, Singh AP, Elgass K et al (2014) Structural and functional analysis of MiD51, a dynamin receptor required for mitochondrial fission. J Cell Biol 204:477–486

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  78. Zorzano A (2009) Regulation of mitofusin-2 expression in skeletal muscle. Appl Physiol Nutr Metab 34:433–439

    Article  CAS  PubMed  Google Scholar 

  79. Ryan JJ, Marsboom G, Fang YH, Toth PT, Morrow E et al (2013) PGC1alpha-mediated mitofusin-2 deficiency in female rats and humans with pulmonary arterial hypertension. Am J Respir Crit Care Med 187:865–878

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  80. Ryan J, Dasgupta A, Huston J, Chen KH, Archer SL (2015) Mitochondrial dynamics in pulmonary arterial hypertension. J Mol Med (Berl) 93:229–242

    Article  CAS  Google Scholar 

  81. Garedew A, Andreassi C, Moncada S (2012) Mitochondrial dynamics, biogenesis, and function are coordinated with the cell cycle by APC/C CDH1. Cell Metab 15:466–479

    Article  CAS  PubMed  Google Scholar 

  82. Leboucher GP, Tsai YC, Yang M, Shaw KC, Zhou M et al (2012) Stress-induced phosphorylation and proteasomal degradation of mitofusin 2 facilitates mitochondrial fragmentation and apoptosis. Mol Cell 47:547–557

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  83. Poole AC, Thomas RE, Andrews LA, McBride HM, Whitworth AJ et al (2008) The PINK1/Parkin pathway regulates mitochondrial morphology. Proc Natl Acad Sci USA 105:1638–1643

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  84. Poole AC, Thomas RE, Yu S, Vincow ES, Pallanck L (2010) The mitochondrial fusion-promoting factor mitofusin is a substrate of the PINK1/Parkin pathway. PLoS ONE 5:e10054

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  85. Gegg ME, Cooper JM, Chau KY, Rojo M, Schapira AH et al (2010) Mitofusin 1 and mitofusin 2 are ubiquitinated in a PINK1/Parkin-dependent manner upon induction of mitophagy. Hum Mol Genet 19:4861–4870

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  86. Glauser L, Sonnay S, Stafa K, Moore DJ (2011) Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. J Neurochem 118:636–645

    Article  CAS  PubMed  Google Scholar 

  87. Rakovic A, Grunewald A, Kottwitz J, Bruggemann N, Pramstaller PP et al (2011) Mutations in PINK1 and Parkin impair ubiquitination of Mitofusins in human fibroblasts. PLoS ONE 6:e16746

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  88. Narendra D, Tanaka A, Suen DF, Youle RJ (2008) Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J Cell Biol 183:795–803

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Narendra DP, Jin SM, Tanaka A, Suen DF, Gautier CA et al (2010) PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol 8:e1000298

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  90. Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL et al (2010) PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc Natl Acad Sci USA 107:378–383

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  92. Geisler S, Holmstrom KM, Skujat D, Fiesel FC, Rothfuss OC et al (2010) PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat Cell Biol 12:119–131

    Article  CAS  PubMed  Google Scholar 

  93. Chan NC, Salazar AM, Pham AH, Sweredoski MJ, Kolawa NJ et al (2011) Broad activation of the ubiquitin-proteasome system by Parkin is critical for mitophagy. Hum Mol Genet 20:1726–1737

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  94. Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K (2007) Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem 282:11521–11529

    Article  CAS  PubMed  Google Scholar 

  95. Marsboom G, Toth PT, Ryan JJ, Hong Z, Wu X et al (2012) Dynamin-related protein 1-mediated mitochondrial mitotic fission permits hyperproliferation of vascular smooth muscle cells and offers a novel therapeutic target in pulmonary hypertension. Circ Res 110:1484–1497

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  96. Kashatus DF, Lim KH, Brady DC, Pershing NL, Cox AD et al (2011) RALA and RALBP1 regulate mitochondrial fission at mitosis. Nat Cell Biol 13:1108–1115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  97. Qi X, Disatnik MH, Shen N, Sobel RA, Mochly-Rosen D (2011) Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol Biol Cell 22:256–265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  98. Chang CR, Blackstone C (2007) Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem 282:21583–21587

    Article  CAS  PubMed  Google Scholar 

  99. Cribbs JT, Strack S (2007) Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep 8:939–944

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Gomes LC, Di Benedetto G, Scorrano L (2011) During autophagy mitochondria elongate, are spared from degradation and sustain cell viability. Nat Cell Biol 13:589–598

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  101. Rambold AS, Kostelecky B, Elia N, Lippincott-Schwartz J (2011) Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation. Proc Natl Acad Sci USA 108:10190–10195

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Cereghetti GM, Stangherlin A, Martins de Brito O, Chang CR, Blackstone C et al (2008) Dephosphorylation by calcineurin regulates translocation of Drp1 to mitochondria. Proc Natl Acad Sci USA 105:15803–15808

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Costa V, Giacomello M, Hudec R, Lopreiato R, Ermak G et al (2010) Mitochondrial fission and cristae disruption increase the response of cell models of Huntington’s disease to apoptotic stimuli. EMBO Mol Med 2:490–503

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  104. Wang Z, Jiang H, Chen S, Du F, Wang X (2012) The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148:228–243

    Article  CAS  PubMed  Google Scholar 

  105. Chang CR, Blackstone C (2010) Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci 1201:34–39

    Article  CAS  PubMed  Google Scholar 

  106. Makino A, Suarez J, Gawlowski T, Han W, Wang H et al (2011) Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regul Integr Comp Physiol 300:R1296–R1302

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  107. Gawlowski T, Suarez J, Scott B, Torres-Gonzalez M, Wang H et al (2012) Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-beta-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem 287:30024–30034

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  108. Han XJ, Lu YF, Li SA, Kaitsuka T, Sato Y et al (2008) CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol 182:573–585

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  109. Wang W, Wang Y, Long J, Wang J, Haudek SB et al (2012) Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab 15:186–200

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  110. Westermann B (2002) Merging mitochondria matters: cellular role and molecular machinery of mitochondrial fusion. EMBO Rep 3:527–531

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  111. Li J, Zhou J, Li Y, Qin D, Li P (2010) Mitochondrial fission controls DNA fragmentation by regulating endonuclease G. Free Radic Biol Med 49:622–631

    Article  CAS  PubMed  Google Scholar 

  112. Papanicolaou KN, Ngoh GA, Dabkowski ER, O’Connell KA, Ribeiro RF Jr et al (2012) Cardiomyocyte deletion of mitofusin-1 leads to mitochondrial fragmentation and improves tolerance to ROS-induced mitochondrial dysfunction and cell death. Am J Physiol Heart Circ Physiol 302:H167–H179

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  113. Papanicolaou KN, Khairallah RJ, Ngoh GA, Chikando A, Luptak I et al (2011) Mitofusin-2 maintains mitochondrial structure and contributes to stress-induced permeability transition in cardiac myocytes. Mol Cell Biol 31:1309–1328

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  114. Chen Y, Csordas G, Jowdy C, Schneider TG, Csordas N et al (2012) Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca(2+) crosstalk. Circ Res 111:863–875

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  115. Frezza C, Cipolat S, Martins de Brito O, Micaroni M, Beznoussenko GV et al (2006) OPA1 controls apoptotic cristae remodeling independently from mitochondrial fusion. Cell 126:177–189

    Article  CAS  PubMed  Google Scholar 

  116. Chen L, Liu T, Tran A, Lu X, Tomilov AA et al (2012) OPA1 mutation and late-onset cardiomyopathy: mitochondrial dysfunction and mtDNA instability. J Am Heart Assoc 1:e003012

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  117. Piquereau J, Caffin F, Novotova M, Prola A, Garnier A et al (2012) Down-regulation of OPA1 alters mouse mitochondrial morphology, PTP function, and cardiac adaptation to pressure overload. Cardiovasc Res 94:408–417

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  118. Chen L, Gong Q, Stice JP, Knowlton AA (2009) Mitochondrial OPA1, apoptosis, and heart failure. Cardiovasc Res 84:91–99

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  119. Sugioka R, Shimizu S, Tsujimoto Y (2004) Fzo1, a protein involved in mitochondrial fusion, inhibits apoptosis. J Biol Chem 279:52726–52734

    Article  CAS  PubMed  Google Scholar 

  120. Neuspiel M, Zunino R, Gangaraju S, Rippstein P, McBride H (2005) Activated mitofusin 2 signals mitochondrial fusion, interferes with Bax activation, and reduces susceptibility to radical induced depolarization. J Biol Chem 280:25060–25070

    Article  CAS  PubMed  Google Scholar 

  121. Bhandari P, Song M, Chen Y, Burelle Y, Dorn GW 2nd (2014) Mitochondrial contagion induced by Parkin deficiency in Drosophila hearts and its containment by suppressing mitofusin. Circ Res 114:257–265

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  122. Hoshino A, Mita Y, Okawa Y, Ariyoshi M, Iwai-Kanai E et al (2013) Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart. Nat Commun 4:2308

    Article  PubMed  CAS  Google Scholar 

  123. Kubli DA, Zhang X, Lee Y, Hanna RA, Quinsay MN et al (2013) Parkin protein deficiency exacerbates cardiac injury and reduces survival following myocardial infarction. J Biol Chem 288:915–926

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  124. Dorn GW 2nd (2013) Mitochondrial dynamics in heart disease. Biochim Biophys Acta 1833:233–241

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  125. Dorn GW 2nd (2013) Mitochondrial dynamism and cardiac fate—a personal perspective. Circ J 77:1370–1379

    Article  CAS  PubMed  Google Scholar 

  126. Zhao T, Huang X, Han L, Wang X, Cheng H et al (2012) Central role of mitofusin 2 in autophagosome-lysosome fusion in cardiomyocytes. J Biol Chem 287:23615–23625

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  127. Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila Parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 107:5018–5023

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  128. Ziviani E, Whitworth AJ (2010) How could Parkin-mediated ubiquitination of mitofusin promote mitophagy? Autophagy 128:660–662

    Article  Google Scholar 

  129. Youle RJ, Narendra DP (2011) Mechanisms of mitophagy. Nat Rev Mol Cell Biol 12:9–14

    Article  CAS  PubMed  Google Scholar 

  130. Eiyama A, Okamoto K (2015) PINK1/Parkin-mediated mitophagy in mammalian cells. Curr Opin Cell Biol 33:95–101

    Article  CAS  PubMed  Google Scholar 

  131. Corti O, Lesage S, Brice A (2011) What genetics tells us about the causes and mechanisms of Parkinson’s disease. Physiol Rev 91:1161–1218

    Article  CAS  PubMed  Google Scholar 

  132. Deas E, Wood NW, Plun-Favreau H (2011) Mitophagy and Parkinson’s disease: the PINK1-Parkin link. Biochim Biophys Acta 1813:623–633

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  133. Billia F, Hauck L, Konecny F, Rao V, Shen J et al (2011) PTEN-inducible kinase 1 (PINK1)/Park6 is indispensable for normal heart function. Proc Natl Acad Sci USA 108:9572–9577

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  134. Song M, Chen Y, Gong G, Murphy E, Rabinovitch PS et al (2014) Super-suppression of mitochondrial reactive oxygen species signaling impairs compensatory autophagy in primary mitophagic cardiomyopathy. Circ Res 115:348–353

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  135. Twig G, Elorza A, Molina AJ, Mohamed H, Wikstrom JD et al (2008) Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27:433–446

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  136. Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T et al (2010) Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6:600–606

    Article  CAS  PubMed  Google Scholar 

  137. Kimura T, Takabatake Y, Takahashi A, Kaimori JY, Matsui I et al (2011) Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol 22:902–913

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  138. Jung HS, Lee MS (2009) Macroautophagy in homeostasis of pancreatic beta-cell. Autophagy 5:241–243

    Article  CAS  PubMed  Google Scholar 

  139. Arnoult D, Rismanchi N, Grodet A, Roberts RG, Seeburg DP et al (2005) Bax/Bak-dependent release of DDP/TIMM8a promotes Drp1-mediated mitochondrial fission and mitoptosis during programmed cell death. Curr Biol 15:2112–2118

    Article  CAS  PubMed  Google Scholar 

  140. Gomes LC, Scorrano L (2008) High levels of Fis1, a pro-fission mitochondrial protein, trigger autophagy. Biochim Biophys Acta 1777:860–866

    Article  CAS  PubMed  Google Scholar 

  141. Parone PA, Da Cruz S, Tondera D, Mattenberger Y, James DI et al (2008) Preventing mitochondrial fission impairs mitochondrial function and leads to loss of mitochondrial DNA. PLoS ONE 3:e3257

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  142. Lee Y, 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:H1924–H1931

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  143. Ikeda Y, Shirakabe A, Maejima Y, Zhai P, Sciarretta S et al (2015) Endogenous Drp1 mediates mitochondrial autophagy and protects the heart against energy stress. Circ Res 116:264–278

    Article  CAS  PubMed  Google Scholar 

  144. Tolkovsky AM (2009) Mitophagy. Biochim Biophys Acta 1793:1508–1515

    Article  CAS  PubMed  Google Scholar 

  145. Gomes LC, Scorrano L (2013) Mitochondrial morphology in mitophagy and macroautophagy. Biochim Biophys Acta 1833:205–212

    Article  CAS  PubMed  Google Scholar 

  146. Martinou JC, Youle RJ (2006) Which came first, the cytochrome c release or the mitochondrial fission? Cell Death Differ 13:1291–1295

    Article  CAS  PubMed  Google Scholar 

  147. Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y et al (2009) SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J 28:1589–1600

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  148. Frank S, Gaume B, Bergmann-Leitner ES, Leitner WW, Robert EG et al (2001) The role of dynamin-related protein 1, a mediator of mitochondrial fission, in apoptosis. Dev Cell 1:515–525

    Article  CAS  PubMed  Google Scholar 

  149. Lee YJ, Jeong SY, Karbowski M, Smith CL, Youle RJ (2004) Roles of the mammalian mitochondrial fission and fusion mediators Fis1, Drp1, and Opa1 in apoptosis. Mol Biol Cell 15:5001–5011

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  150. Germain M, Mathai JP, McBride HM, Shore GC (2005) Endoplasmic reticulum BIK initiates DRP1-regulated remodelling of mitochondrial cristae during apoptosis. EMBO J 24:1546–1556

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  151. Cassidy-Stone A, Chipuk JE, Ingerman E, Song C, Yoo C et al (2008) Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization. Dev Cell 14:193–204

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  152. Ishihara N, Nomura M, Jofuku A, Kato H, Suzuki SO et al (2009) Mitochondrial fission factor Drp1 is essential for embryonic development and synapse formation in mice. Nat Cell Biol 11:958–966

    Article  CAS  PubMed  Google Scholar 

  153. Landes T, Martinou JC (2011) Mitochondrial outer membrane permeabilization during apoptosis: the role of mitochondrial fission. Biochim Biophys Acta 1813:540–545

    Article  CAS  PubMed  Google Scholar 

  154. Suen DF, Norris KL, Youle RJ (2008) Mitochondrial dynamics and apoptosis. Genes Dev 22:1577–1590

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  155. Montessuit S, Somasekharan SP, Terrones O, Lucken-Ardjomande S, Herzig S et al (2010) Membrane remodeling induced by the dynamin-related protein Drp1 stimulates Bax oligomerization. Cell 142:889–901

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  156. Martinou JC, Youle RJ (2011) Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Dev Cell 21:92–101

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  157. Wasiak S, Zunino R, McBride HM (2007) Bax/Bak promote sumoylation of DRP1 and its stable association with mitochondria during apoptotic cell death. J Cell Biol 177:439–450

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  158. Wang JX, Jiao JQ, Li Q, Long B, Wang K et al (2011) miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med 17:71–78

    Article  PubMed  CAS  Google Scholar 

  159. Ong SB, Subrayan S, Lim SY, Yellon DM, Davidson SM et al (2010) Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation 121:2012–2022

    Article  CAS  PubMed  Google Scholar 

  160. Tondera D, Czauderna F, Paulick K, Schwarzer R, Kaufmann J et al (2005) The mitochondrial protein MTP18 contributes to mitochondrial fission in mammalian cells. J Cell Sci 118:3049–3059

    Article  CAS  PubMed  Google Scholar 

  161. Dorn GW 2nd (2010) Mitochondrial pruning by Nix and BNip3: an essential function for cardiac-expressed death factors. J Cardiovasc Transl Res 3:374–383

    Article  PubMed Central  PubMed  Google Scholar 

  162. Ding WX, Ni HM, Li M, Liao Y, Chen X et al (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 285:27879–27890

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  163. Diwan A, Krenz M, Syed FM, Wansapura J, Ren X et al (2007) Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice. J Clin Invest 117:2825–2833

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  164. Galvez AS, Brunskill EW, Marreez Y, Benner BJ, Regula KM et al (2006) Distinct pathways regulate proapoptotic Nix and BNip3 in cardiac stress. J Biol Chem 281:1442–1448

    Article  CAS  PubMed  Google Scholar 

  165. Yussman MG, Toyokawa T, Odley A, Lynch RA, Wu G et al (2002) Mitochondrial death protein Nix is induced in cardiac hypertrophy and triggers apoptotic cardiomyopathy. Nat Med 8:725–730

    CAS  PubMed  Google Scholar 

  166. Syed F, Odley A, Hahn HS, Brunskill EW, Lynch RA et al (2004) Physiological growth synergizes with pathological genes in experimental cardiomyopathy. Circ Res 95:1200–1206

    Article  CAS  PubMed  Google Scholar 

  167. Diwan A, Wansapura J, Syed FM, Matkovich SJ, Lorenz JN et al (2008) Nix-mediated apoptosis links myocardial fibrosis, cardiac remodeling, and hypertrophy decompensation. Circulation 117:396–404

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  168. Diwan A, Matkovich SJ, Yuan Q, Zhao W, Yatani A et al (2009) Endoplasmic reticulum-mitochondria crosstalk in NIX-mediated murine cell death. J Clin Invest 119:203–212

    PubMed Central  CAS  PubMed  Google Scholar 

  169. Chen Y, Lewis W, Diwan A, Cheng EH, Matkovich SJ et al (2010) Dual autonomous mitochondrial cell death pathways are activated by Nix/BNip3L and induce cardiomyopathy. Proc Natl Acad Sci USA 107:9035–9042

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  170. Shires SE, Gustafsson AB (2015) Mitophagy and heart failure. J Mol Med (Berl) 93:253–262

    Article  CAS  Google Scholar 

  171. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S et al (2000) Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406:906–910

    Article  CAS  PubMed  Google Scholar 

  172. Zesiewicz TA, Strom JA, Borenstein AR, Hauser RA, Cimino CR et al (2004) Heart failure in Parkinson’s disease: analysis of the United States medicare current beneficiary survey. Parkinsonism Relat Disord 10:417–420

    Article  CAS  PubMed  Google Scholar 

  173. Kasahara A, Cipolat S, Chen Y, Dorn GW 2nd, Scorrano L (2013) Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and notch signaling. Science 342:734–737

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Molecular Cardiology and Neuromuscular Institute, 75 Raritan Avenue, Highland Park, NJ, 08904, USA

    José Marín-García & Alexander T. Akhmedov

Authors
  1. José Marín-García
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alexander T. Akhmedov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to José Marín-García.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Marín-García, J., Akhmedov, A.T. Mitochondrial dynamics and cell death in heart failure. Heart Fail Rev 21, 123–136 (2016). https://doi.org/10.1007/s10741-016-9530-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-016-9530-2

Keywords

Search

Navigation