Skip to main content

Advertisement

SpringerLink
Log in

Functional diversity of complex I subunits in Candida albicans mitochondria

  • Review
  • Published:
Current Genetics Aims and scope Submit manuscript

Abstract

Our interest in the mitochondria of Candida albicans has progressed to the identification of several proteins that are critical to complex I (CI) activity. We speculated that there should be major functional differences at the protein level between mammalian and fungal mitochondria CI. In our pursuit of this idea, we were helped by published data of CI subunit proteins from a broad diversity of species that included two subunit proteins that are not found in mammals. These subunit proteins have been designated as Nuo1p and Nuo2p (NADH-ubiquinone oxidoreductases). Since functional assignments of both C. albicans proteins were unknown, other than having a putative NADH-oxidoreductase activity, we constructed knock-out strains that could be compared to parental cells. The relevance of our research relates to the critical roles of both proteins in cell biology and pathogenesis and their absence in mammals. These features suggest they may be exploited in antifungal drug discovery. Initially, we characterized Goa1p that apparently regulates CI activity but is not a CI subunit protein. We have used the goa1∆ for comparisons to Nuo1p and Nuo2p. We have demonstrated the critical role of these proteins in maintaining CI activities, virulence, and prolonging life span. More recently, transcriptional profiling of the three mutants and an ndh51∆ (protein is a highly conserved CI subunit) has revealed that there are overlapping yet also different functional assignments that suggest subunit specificity. The differences and similarities of each are described below along with our hypotheses to explain these data. Our conclusion and perspective is that the C. albicans CI subunit proteins are highly conserved except for two that define non-mammalian functions.

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

Similar content being viewed by others

References

  • Antonicka H, Ogilvie I, Taivassalo T et al (2003) Identification and characterization of a common set of complex I assembly intermediates in mitochondria from patients with complex I deficiency. J Biol Chem 278:43081–43088

    Article  CAS  PubMed  Google Scholar 

  • Azevedo JE, Nehls U, Eckerskorn C et al (1992) Primary structure and mitochondrial import in vitro of the 20.9 kDa subunit of complex I from Neurospora crassa. Biochem J 288:29–34

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Bambach A, Fernandes MP, Ghosh A et al (2009) Goa1p of Candida albicans localizes to the mitochondria during stress and is required for mitochondrial function and virulence. Eukaryot Cell 8:1706–1720

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Böttinger L, Horvath SE, Kleinschroth T et al (2012) Phosphatidylethanolamine and cardiolipin differentially affect the stability of mitochondrial respiratory chain supercomplexes. J Mol Biol 423:677–686. doi:10.1016/j.jmb.2012.09.001

    Article  PubMed  Google Scholar 

  • Bourges I, Ramus C, Mousson de Camaret B et al (2004) Structural organization of mitochondrial human complex I: role of the ND4 and ND5 mitochondria-encoded subunits and interaction with prohibitin. Biochem J 383:491–499. doi:10.1042/BJ20040256

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Brandt U (2006) Energy converting NADH: quinone oxidoreductase (Complex I). Annu Rev Biochem 75:69–92

    Article  CAS  PubMed  Google Scholar 

  • Carroll J, Fearnley IM, Skehel JM et al (2005) The post-translational modifications of the nuclear encoded subunits of complex I from bovine heart mitochondria. Mol Cell Proteom 4:693–699

    Article  CAS  Google Scholar 

  • Chen H, Calderone R, Sun N et al (2012) Caloric restriction restores the chronological life span of the Goa1 null mutant of Candida albicans in spite of high cell levels of ROS. Fungal Genet Biol 49:1023–1032. doi:10.1016/j.fgb.2012.09.007

    Article  CAS  PubMed  Google Scholar 

  • Chou JY, Leu JY (2010) Speciation through cytonuclear incompatibility: insights from yeast and implications for higher eukaryotes. BioEssays 32:401–411. doi:10.1002/bies.200900162

    Article  CAS  PubMed  Google Scholar 

  • Dagley MJ, Gentle IE, Beilharz TH et al (2011) Cell wall integrity is linked to mitochondria and phospholipid homeostasis in Candida albicans through the activity of the post-transcriptional regulator Ccr4-Pop2. Mol Microbiol 79:968–989. doi:10.1111/j.1365-2958.2010.07503.x

    Article  CAS  PubMed  Google Scholar 

  • Dobrynin K, Abdrakhmanova A, Richers S et al (2010) Characterization of two different acyl carrier proteins in complex I from Yarrowia lipolytica. Biochim Biophys Acta 1797:152–159. doi:10.1016/j.bbabio.2009.09.007

    Article  CAS  PubMed  Google Scholar 

  • Dunning CJR, McKenzie M, Sugiana C et al (2007) Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO J 26:3227–3237. doi:10.1038/sj.emboj.7601748

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Efremov RG, Baradaran R, Sazanov LA (2010) The architecture of respiratory complex I. Nature 465:441–445. doi:10.1038/nature09066

    Article  CAS  PubMed  Google Scholar 

  • Fabre E, Sfihi-Loualia G, Pourcelot M et al (2014) Characterization of the recombinant Candida albicans β-mannosylation of cell wall phosphopeptidomannan. Biochem J 457:347–360

    Article  CAS  PubMed  Google Scholar 

  • Friedrich T, Scheide D (2000) The respiratory complex I of bacteria, archaea and eukarya and its module common with membrane-bound multisubunit hydrogenases. FEBS Lett 479:1–5

    Article  CAS  PubMed  Google Scholar 

  • Gabaldón T, Rainey D, Huynen MA (2005) Tracing the evolution of a large protein complex in the eukaryotes, NADH:ubiquinone oxidoreductase (Complex I). J Mol Biol 348:857–870

    Article  PubMed  Google Scholar 

  • Ghannoum MA, Burns GR, Elteen KA, Radwan SS (1986) Experimental evidence for the role of lipids in adherence of Candida spp. to human buccal epithelial cells. Infect Immun 54:189–193

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gonçalves AP, Cordeiro JM, Monteiro J et al (2015) Involvement of mitochondrial proteins in calcium signaling and cell death induced by staurosporine in Neurospora crassa. Biochim Biophys Acta 1847:1064–1074. doi:10.1016/j.bbabio.2015.05.011

    Article  PubMed  Google Scholar 

  • Gow NA, Hube B (2012) Importance of the Candida albicans cell wall during commensalism and infection. Curr Opin Microbiol 15:406–412. doi:10.1016/j.mib.2012.04.005

    Article  CAS  PubMed  Google Scholar 

  • Gray MW, Burger G, Lang BF (2001) The origin and early evolution of mitochondria. Genome Biology 2:10181–10185 (reviews)

    Article  Google Scholar 

  • Guénebaut V, Schlitt A, Weiss H et al (1998) Consistent structure between bacterial and mitochondrial NADH: ubiquinone oxidoreductase (complex I). J Mol Biol 276:105–112

    Article  PubMed  Google Scholar 

  • Hegedusova E, Brejova B, Tomaska L et al (2014) Mitochondria genome of the basidiomycetous yeast Jaminea angkorensis. Curr Genet 60:49–59

    Article  CAS  PubMed  Google Scholar 

  • Helmerhorst EJ, Murphy MP, Troxler RF, Oppenheim FG (2002) Characterization of the mitochondrial respiratory pathways in Candida albicans. Biochim Biophys Acta 1556:73–80

    Article  CAS  PubMed  Google Scholar 

  • Hsu FF, Turk J, Rhoades ER et al (2005) Structural characterization of cardiolipin by tandem quadrupole and multiple-stage quadrupole ion-trap mass spectrometry with electrospray ionization. J Am Soc Mass Spectr 16:491–504

    Article  CAS  Google Scholar 

  • Janssen R, Smeitink J, Smeets R, van Den Heuvel L (2002) CIA30 complex I assembly factor: a candidate for human complex I deficiency? Hum Genet 110:264–270

    Article  CAS  PubMed  Google Scholar 

  • Kmita K, Zickermann V (2013) Accessory subunits of mitochondrial complex I. Biochem Soc Trans 41:1272–1279. doi:10.1042/BST20130091

    Article  CAS  PubMed  Google Scholar 

  • Kollár R, Reinhold BB, Petráková E et al (1997) Architecture of the yeast cell wall. Beta (1– > 6)-glucan interconnects mannoprotein, beta(1– >)3-glucan, and chitin. J Biol Chem 272:17762–17775

    Article  PubMed  Google Scholar 

  • Koszul R, Malpertuy A, Frangeul L et al (2003) The complete mitochondrial genome sequence of the pathogenic yeast Candida (Torulopsis) glabrata. FEBS Lett 534:39–48

    Article  CAS  PubMed  Google Scholar 

  • Küffner R, Rohr A, Schmiede A et al (1998) Involvement of two novel chaperones in the assembly of mitochondrial NADH: ubiquinone oxidoreductase (complex I). J Mol Biol 283:409–417

    Article  PubMed  Google Scholar 

  • Lattif AA, Mukherjee PK, Chandra J et al (2011) Lipidomics of Candida albicans biofilms reveals phase-dependent production of phospholipid molecular classes and role for lipid rafts in biofilm formation. Microbiology 157:3232–3242. doi:10.1099/mic.0.051086-0

    Article  PubMed Central  PubMed  Google Scholar 

  • Li D, Chen H, Florentino A et al (2011) Enzymatic dysfunction of mitochondrial complex I of the Candida albicans goa1 mutant is associated with increased reactive oxidants and cell death. Eukaryot Cell 10:672–682. doi:10.1128/EC.00303-10

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lorenz MC, Bender JA, Fink GR (2004) Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell 3:1076–1087

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Maas MF, Sellem CH, Krause F et al (2010) Molecular gene therapy: overexpression of the alternative NADH dehydrogenase NDI1 restores overall physiology in a fungal model of respiratory complex I deficiency. J Mol Biol 399:31–40. doi:10.1016/j.jmb.2010.04.015

    Article  CAS  PubMed  Google Scholar 

  • Marcotte EM, Xenarios I, van Der Bliek AM, Eisenberg D (2000) Localizing proteins in the cell from their phylogenetic profiles. Proc Natl Acad Sci USA 97:12115–12120

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Marques I, Duarte M, Assunção J et al (2005) Composition of complex I from Neurospora crassa and disruption of two “accessory” subunits. Biochim Biophys Acta 1707:211–220

    Article  CAS  PubMed  Google Scholar 

  • Mathe L, Van Dijck P (2013) Recent insights into Candida albicans biofilm resistance mechanisms. Curr Genet 59:251–264

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • McDonough JA, Bhattacherjee V, Sadlon T, Hostetter MK (2002) _Involvement of Candida albicans NADH dehydrogenase complex I in filamentation. Fung Genet, Biol 36:117–127

    Article  CAS  Google Scholar 

  • McKenzie M, Ryan MT (2010) Assembly factors of human mitochondrial complex I and their defects in disease. IUBMB Life 62:497–502

    Article  CAS  PubMed  Google Scholar 

  • Merico A, Sulo P, Piskur J, Compagno C (2007) Fermentative lifestyle in yeasts belonging to the Saccharomyces complex. FEBS J 274:976–989

    Article  CAS  PubMed  Google Scholar 

  • Mille C, Bobrowicz P, Trinel P et al (2008) Identification of a new family of genes involved in β-1,2 mannosylation of glycans in Pichia pastoris and Candida albicans. J Biol Chem 283:9724–9736

    Article  CAS  PubMed  Google Scholar 

  • Minkler PE, Hoppel CL (2010) Separation and characterization of cardiolipin molecular species by reverse-phase ion pair high-performance liquid chromatography-mass spectrometry. J Lipid Res 51:856–865. doi:10.1194/jlr.D002857

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Mollinedo F (2012) Lipid raft involvement in yeast cell growth and death. Front Oncol 2(140):2012. doi:10.3389/fonc.00140

    Google Scholar 

  • Papon N, Savini V, Lanoue A et al (2013) Candida guilliermondi: biotechnological applications, perspectives for biological control, emerging importance and recent advances in genetics. Curr Genet 59:73–90

    Article  CAS  PubMed  Google Scholar 

  • Pike LJ (2004) Lipid rafts: heterogeneity on the high seas. Biochem J 378:281–292

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Runswick MJ, Fearnley IM, Skehel JM, Walker JE (1991) Presence of an acyl carrier protein in NADH:ubiquinone oxidoreductase from bovine heart mitochondria. FEBS Lett 286:121–124

    Article  CAS  PubMed  Google Scholar 

  • Sackmann U, Zensen R, Röhlen D et al (1991) The acyl-carrier protein in Neurospora crassa mitochondria is a subunit of NADH:ubiquinone reductase (complex I). Eur J Biochem 200:463–469

    Article  CAS  PubMed  Google Scholar 

  • Schatz G, Racker E, Tyler DD et al (1966) Studies of the DPNH-cytochrome b segment of the respiratory chain of baker’s yeast. Biochem Biophys Res Commun 22:585–590

    Article  CAS  PubMed  Google Scholar 

  • Schneider R, Massow M, Lisowsky T, Weiss H (1995) Different respiratory-defective phenotypes of Neurospora crassa and Saccharomyces cerevisiae after inactivation of the gene encoding the mitochondrial acyl carrier protein. Curr Genet 29:10–17

    Article  CAS  PubMed  Google Scholar 

  • She X, Zhang L, Chen H et al (2013) Cell surface changes in the Candida albicans mitochondrial mutant goa1Δ are associated with reduced recognition by innate immune cells. Cell Microbiol 15:1572–1584. doi:10.1111/cmi.12135

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • She X, Khamooshi K, Gao Y et al (2015) Fungal-specific subunits of the Candida albicans mitochondrial complex I drive diverse cell functions including cell wall synthesis. Cell Microbiol. doi:10.1111/cmi.12438

    PubMed  Google Scholar 

  • Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3:a004697. doi:10.1101/cshperspect.a004697

    Article  PubMed Central  PubMed  Google Scholar 

  • Solotroff V, Moseler R, Schulte U (2015) Two pentatricopeptide repeat domain proteins are required for the synthesis of respiratory complex I. Curr Genet 61:19–29

    Article  Google Scholar 

  • Sun N, Fonzi W, Chen H et al (2013a) Azole susceptibility and transcriptome profiling in Candida albicans mitochondrial electron transport chain complex I mutants. Antimicrob Agents Chemother 57:532–542. doi:10.1128/AAC.01520-12

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sun N, Li D, Fonzi W et al (2013b) Multidrug-resistant transporter mdr1p-mediated uptake of a novel antifungal compound. Antimicrob Agents Chemother 57:5931–5939. doi:10.1128/AAC.01504-13

    Article  PubMed Central  PubMed  Google Scholar 

  • Thomas E, Roman E, Claypool S et al (2013) Mitochondria influence CDR1 efflux pump activity, Hog1-mediated oxidative stress pathway, iron homeostasis, and ergosterol levels in Candida albicans. Antimicrob Agents Chemother 57:5580–5599

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Tuschen G, Sackmann U, Nehls U et al (1990) Assembly of NADH: ubiquinone reductase (complex I) in Neurospora mitochondria. Independent pathways of nuclear-encoded and mitochondrially encoded subunits. J Mol Biol 213:845–857

    Article  CAS  PubMed  Google Scholar 

  • Ugalde C, Janssen RJ, van den Heuvel LP et al (2004) Differences in assembly or stability of complex I and other mitochondrial OXPHOS complexes in inherited complex I deficiency. Hum Mol Genet 13:659–667

    Article  CAS  PubMed  Google Scholar 

  • Vellucci VF, Gygax SE, Hostetter MK (2007) Involvement of Candida albicans pyruvate dehydrogenase complex protein X (Pdx1) in filamentation. Fungal Genet Biol 44:979–990

    Article  CAS  PubMed  Google Scholar 

  • Vinothkumar KR, Zhu J, Hirst J (2014) Architecture of mammalian respiratory complex I. Nature 515:80–84. doi:10.1038/nature13686

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Vogel RO, Janssen RJ, van den Brand MA et al (2007) Cytosolic signaling protein Ecsit also localizes to mitochondria where it interacts with chaperone NDUFAF1 and functions in complex I assembly. Genes Dev 21:615–624

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Ziółkowska NE, Karotki L, Rehman M et al (2011) Eisosome-driven plasma membrane organization is mediated by BAR domains. Nat Struct Mol Biol 18:854–856. doi:10.1038/nsmb.2080

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This works is supported by research grants from Georgetown University Biomedical Research Organization (BGRO) to D.L., NIH-NIAID (AI090290) to R.C., and the National Natural Science Foundation of China (81401652) and National Natural Science Foundation of Jiangsu Province, China (BK20130063) to X.S.

Author information

Authors and Affiliations

  1. Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC, 20057, USA

    Dongmei Li & Richard Calderone

  2. Jiangsu Key Laboratory of Molecular Biology for Skin Disease and STIs, Institute of Dermatology, Chinese Academy of Medical Sciences (CAMS), Nanjing, 210029, China

    Xiaodong She

Authors
  1. Dongmei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaodong She
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Richard Calderone
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dongmei Li.

Additional information

Communicated by M. Kupiec.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, D., She, X. & Calderone, R. Functional diversity of complex I subunits in Candida albicans mitochondria. Curr Genet 62, 87–95 (2016). https://doi.org/10.1007/s00294-015-0518-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00294-015-0518-6

Keywords

Search

Navigation