Exploring and exploiting the connection between mitochondria and the virulence of human pathogenic fungi

References

• King N. Amino acids and the mitochondria. In: Schaffer SW, Suleiman MS, eds. Mitochondria: the Dynamic Organelle / Advances in Biochemistry in Health and Disease. New York, NY: Springer; 2007. 151–66.
   Google Scholar
• Muhlenhoff U, Hoffmann B, Richter N, et al. Compartmentalization of iron between mitochondria and the cytosol and its regulation. Eur J Cell Biol. 2015;94:292–308. http://doi.org/10.1016/j.ejcb.2015.05.003.
   PubMed Web of Science ®Google Scholar
• Ernster L, Schatz G. Mitochondria: a historical review. J Cell Biol. 1981;91:227s–55s. http://doi.org/10.1083/jcb.91.3.227s.
   PubMed Web of Science ®Google Scholar
• Luft R, Ikkos D, Palmieri G, et al. A case of severe hypermetabolism of nonthyroid origin with a defect in the maintenance of mitochondrial respiratory control: a correlated clinical, biochemical, and morphological study. J Clin Invest. 1962;41:1776–804. http://doi.org/10.1172/JCI104637.
   PubMed Web of Science ®Google Scholar
• Linnane AW, Saunders GW, Gingold EB, et al. The biogenesis of mitochondria. V. Cytoplasmic inheritance of erythromycin resistance in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1968;59:903–10. http://doi.org/10.1073/pnas.59.3.903.
   PubMed Web of Science ®Google Scholar
• Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988;331:717–9. http://doi.org/10.1038/331717a0.
   PubMed Web of Science ®Google Scholar
• Wallace DC, Singh G, Lott MT, et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988;242:1427–30. http://doi.org/10.1126/science.3201231.
   PubMed Web of Science ®Google Scholar
• Green DR, Reed JC. Mitochondria and apoptosis. Science. 1998;281:1309–12. http://doi.org/10.1126/science.281.5381.1309.
   PubMed Web of Science ®Google Scholar
• Parker WD, Jr., Boyson SJ, Parks JK. Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol. 1989;26:719–23. http://doi.org/10.1002/ana.410260606.
   PubMed Web of Science ®Google Scholar
• Parker WD, .Jr. Cytochrome oxidase deficiency in Alzheimer's disease. Ann N Y Acad Sci. 1991;640:59–64. http://doi.org/10.1111/j.1749-6632.1991.tb00191.x.
   PubMed Web of Science ®Google Scholar
• Sivitz WI, Yorek MA. Mitochondrial dysfunction in diabetes: from molecular mechanisms to functional significance and therapeutic opportunities. Antioxid Redox Signal. 2010;12:537–77. http://doi.org/10.1089/ars.2009.2531.
   PubMed Web of Science ®Google Scholar
• Birsoy K, Wang T, Chen WW, et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell. 2015;162:540–51. http://doi.org/10.1016/j.cell.2015.07.016.
   PubMed Web of Science ®Google Scholar
• Pellegrino MW, Nargund AM, Kirienko NV, et al. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature. 2014;516:414–7. http://doi.org/10.1038/nature13818.
   PubMed Web of Science ®Google Scholar
• Hadwiger LA, Polashock J. Fungal mitochondrial DNases: effectors with the potential to activate plant defenses in nonhost resistance. Phytopathology. 2013;103:81–90. http://doi.org/10.1094/PHYTO-04-12-0085-R.
   PubMed Web of Science ®Google Scholar
• Luckhart S, Pakpour N, Giulivi C. Host-pathogen interactions in malaria: cross-kingdom signaling and mitochondrial regulation. Curr Opin Immunol. 2015;36:73–9. http://doi.org/10.1016/j.coi.2015.07.002.
   PubMed Web of Science ®Google Scholar
• Rudel T, Kepp O, Kozjak-Pavlovic V. Interactions between bacterial pathogens and mitochondrial cell death pathways. Nat Rev Microbiol. 2010;8:693–705. http://doi.org/10.1038/nrmicro2421.
   PubMed Web of Science ®Google Scholar
• Makiuchi T, Nozaki T. Highly divergent mitochondrion-related organelles in anaerobic parasitic protozoa. Biochimie. 2014;100:3–17. http://doi.org/10.1016/j.biochi.2013.11.018.
   PubMed Web of Science ®Google Scholar
• Freibert S-A, Goldberg AV, Hacker C, et al. Evolutionary conservation and in vitro reconstitution of microsporidian iron-sulfur cluster biosynthesis. Nat Commun. 2017;8:13932. http://doi.org/10.1038/ncomms13932.
   PubMed Web of Science ®Google Scholar
• Ma H, Hagen F, Stekel DJ, et al. The fatal fungal outbreak on Vancouver Island is characterized by enhanced intracellular parasitism driven by mitochondrial regulation. Proc Natl Acad Sci U S A. 2009;106:12980–5. http://doi.org/10.1073/pnas.0902963106.
   PubMed Web of Science ®Google Scholar
• She X, Zhang L, Chen H, et al. Cell surface changes in the Candida albicans mitochondrial mutant goa1Δ are associated with reduced recognition by innate immune cells. Cell Microbiol. 2013;15:1572–84. http://doi.org/10.1111/cmi.12135.
   PubMed Web of Science ®Google Scholar
• Sun N, Fonzi W, Chen H, et al. Azole susceptibility and transcriptome profiling in Candida albicans mitochondrial electron transport chain complex I mutants. Antimicrob Agents Chemother. 2013;57:532–42. http://doi.org/10.1128/AAC.01520-12.
   PubMed Web of Science ®Google Scholar
• Bambach A, Fernandes MP, Ghosh A, et al. Goa1p of Candida albicans localizes to the mitochondria during stress and is required for mitochondrial function and virulence. Eukaryot Cell. 2009;8:1706–20. http://doi.org/10.1128/EC.00066-09.
   PubMed Web of Science ®Google Scholar
• Kretschmer M, Klose J, Kronstad JW. Defects in mitochondrial and peroxisomal β-oxidation influence virulence in the maize pathogen Ustilago maydis. Eukaryot Cell. 2012;11:1055–66. http://doi.org/10.1128/EC.00129-12.
   PubMedGoogle Scholar
• Olson Å, Stenlid J Plant pathogens: mitochondrial control of fungal hybrid virulence. Nature. 2001;411:438.
   PubMed Web of Science ®Google Scholar
• Mahlert M, Vogler C, Stelter K, et al. The a2 mating-type-locus gene lga2 of Ustilago maydis interferes with mitochondrial dynamics and fusion, partially in dependence on a Dnm1-like fission component. J Cell Sci. 2009;122:2402–12. http://doi.org/10.1242/jcs.039354.
   PubMed Web of Science ®Google Scholar
• Du Y, Zhang H, Hong L, et al. Acetolactate synthases MoIlv2 and MoIlv6 are required for infection-related morphogenesis in Magnaporthe oryzae. Mol Plant Pathol. 2013;14:870–84. http://doi.org/10.1111/mpp.12053.
   PubMed Web of Science ®Google Scholar
• Foury F, Roganti T, Lecrenier N, et al. The complete sequence of the mitochondrial genome of Saccharomyces cerevisiae. FEBS Lett. 1998;440:325–31. http://doi.org/10.1016/S0014-5793(98)01467-7.
   PubMed Web of Science ®Google Scholar
• Langkjaer RB, Casaregola S, Ussery DW, et al. Sequence analysis of three mitochondrial DNA molecules reveals interesting differences among Saccharomyces yeasts. Nucleic Acids Res. 2003;31:3081–91. http://doi.org/10.1093/nar/gkg423.
   PubMed Web of Science ®Google Scholar
• Koszul R, Malpertuy A, Frangeul L, et al. The complete mitochondrial genome sequence of the pathogenic yeast Candida (Torulopsis) glabrata. FEBS Lett. 2003;534:39–48. http://doi.org/10.1016/S0014-5793(02)03749-3.
   PubMed Web of Science ®Google Scholar
• Ma H, May RC. Mitochondria and the regulation of hypervirulence in the fatal fungal outbreak on Vancouver Island. Virulence. 2010;1:197–201. http://doi.org/10.4161/viru.1.3.11053.
   PubMed Web of Science ®Google Scholar
• Joardar V, Abrams NF, Hostetler J, et al. Sequencing of mitochondrial genomes of nine Aspergillus and Penicillium species identifies mobile introns and accessory genes as main sources of genome size variability. BMC Genomics. 2012;13:698. http://doi.org/10.1186/1471-2164-13-698.
   PubMed Web of Science ®Google Scholar
• Brown GD, Denning DW, Gow NAR, et al. Hidden killers: human fungal infections. Sci Transl Med. 2012;4:165.rv13. http://doi.org/10.1126/scitranslmed.3004404.
   Web of Science ®Google Scholar
• Calderone R, Li D, Traven A. System-level impact of mitochondria on fungal virulence: to metabolism and beyond. FEMS Yeast Res. 2015;15:fov027. http://doi.org/10.1093/femsyr/fov027.
   PubMed Web of Science ®Google Scholar
• Li D, Calderone R. Exploiting mitochondria as targets for the development of new antifungals. Virulence. 2017;8:159–68. http://doi.org/10.1080/21505594.2016.1188235.
   PubMed Web of Science ®Google Scholar
• Thangamani S, Maland M, Mohammad H, et al. Repurposing approach identifies auranofin with broad spectrum antifungal activity that targets Mia40-Erv1 pathway. Front Cell Infect Microbiol. 2017;7:4. http://doi.org/10.3389/fcimb.2017.00004.
   PubMed Web of Science ®Google Scholar
• Okamoto K, Shaw JM. Mitochondrial morphology and dynamics in yeast and multicellular eukaryotes. Annu Rev Genet. 2005;39:503–36. http://doi.org/10.1146/annurev.genet.38.072902.093019.
   PubMed Web of Science ®Google Scholar
• Youle RJ, van der Bliek AM. Mitochondrial fission, fusion, and stress. Science. 2012;337:1062–5. http://doi.org/10.1126/science.1219855.
   PubMed Web of Science ®Google Scholar
• Neubauer M, Zhu Z, Penka M, et al. Mitochondrial dynamics in the pathogenic mold Aspergillus fumigatus: therapeutic and evolutionary implications. Mol Microbiol. 2015;98:930–45. http://doi.org/10.1111/mmi.13167.
   PubMed Web of Science ®Google Scholar
• Hagen F, Khayhan K, Theelen B, et al. Recognition of seven species in the Cryptococcus gattii/Cryptococcus neoformans species complex. Fungal Genet Biol. 2015;78:16–48. http://doi.org/10.1016/j.fgb.2015.02.009.
   PubMed Web of Science ®Google Scholar
• Byrnes EJ, 3rd, Li W, Lewit Y, et al. Emergence and pathogenicity of highly virulent Cryptococcus gattii genotypes in the northwest United States. PLoS Pathog. 2010;6:e1000850. http://doi.org/10.1371/journal.ppat.1000850.
   PubMed Web of Science ®Google Scholar
• Voelz K, Johnston SA, Smith LM, et al. ‘Division of labour’ in response to host oxidative burst drives a fatal Cryptococcus gattii outbreak. Nat Commun. 2014;5:5194. http://doi.org/10.1038/ncomms6194.
   PubMed Web of Science ®Google Scholar
• Thomas E, Roman E, Claypool S, et al. Mitochondria influence CDR1 efflux pump activity, Hog1-mediated oxidative stress pathway, iron homeostasis, and ergosterol levels in Candida albicans. Antimicrob Agents Chemother. 2013;57:5580–99. http://doi.org/10.1128/AAC.00889-13.
   PubMed Web of Science ®Google Scholar
• Khan IA, Ning G, Liu X, et al. Mitochondrial fission protein MoFis1 mediates conidiation and is required for full virulence of the rice blast fungus Magnaporthe oryzae. Microbiol Res. 2015;178:51–8. http://doi.org/10.1016/j.micres.2015.06.002.
   PubMedGoogle Scholar
• Patkar RN, Ramos-Pamplona M, Gupta AP, et al. Mitochondrial β-oxidation regulates organellar integrity and is necessary for conidial germination and invasive growth in Magnaporthe oryzae. Mol Microbiol. 2012;86:1345–63. http://doi.org/10.1111/mmi.12060.
   PubMed Web of Science ®Google Scholar
• Ulrich JT, Mathre DE. Mode of action of oxathiin systemic fungicides. V. Effect on electron transport system of Ustilago maydis and Saccharomyces cerevisiae. J Bacteriol. 1972;110:628–32.
   PubMed Web of Science ®Google Scholar
• Walter H, Tobler H, Gribkov D, et al. Sedaxane, isopyrazam and solatenol: novel broad-spectrum fungicides inhibiting succinate dehydrogenase (SDH) – synthesis challenges and biological aspects. Chimia. 2015;69:425–34. http://doi.org/10.2533/chimia.2015.425.
   Web of Science ®Google Scholar
• Bartlett DW, Clough JM, Godwin JR, et al. The strobilurin fungicides. Pest Manag Sci. 2002;58:649–62. http://doi.org/10.1002/ps.520.
   PubMed Web of Science ®Google Scholar
• Sierotzki H, Scalliet G. A review of current knowledge of resistance aspects for the next-generation succinate dehydrogenase inhibitor fungicides. Phytopathology. 2013;103:880–7. http://doi.org/10.1094/PHYTO-01-13-0009-RVW.
   PubMed Web of Science ®Google Scholar
• Takahata S, Kubota N, Takei-Masuda N, et al. Mechanism of action of ME1111, a novel antifungal agent for topical treatment of onychomycosis. Antimicrob Agents Chemother. 2016;60:873–80. http://doi.org/10.1128/AAC.01790-15.
   PubMed Web of Science ®Google Scholar
• Oliver JD, Sibley GEM, Beckmann N, et al. F901318 represents a novel class of antifungal drug that inhibits dihydroorotate dehydrogenase. Proc Natl Acad Sci USA. 2016;113:12809–14. http://doi.org/10.1073/pnas.1608304113.
   PubMed Web of Science ®Google Scholar
• Vincent BM, Langlois J-B, Srinivas R, et al. A fungal-selective cytochrome bc1 inhibitor impairs virulence and prevents the evolution of drug resistance. Cell Chem Biol. 2016;23:978–91. http://doi.org/10.1016/j.chembiol.2016.06.016.
   PubMed Web of Science ®Google Scholar
• Guan G, Wang H, Liang W, et al. The mitochondrial protein Mcu1 plays important roles in carbon source utilization, filamentation, and virulence in Candida albicans. Fungal Genet Biol. 2015;81:150–9. http://doi.org/10.1016/j.fgb.2015.01.006.
   PubMed Web of Science ®Google Scholar
• Xu J, Yan Z, Guo H. Divergence, hybridization, and recombination in the mitochondrial genome of the human pathogenic yeast Cryptococcus gattii. Mol Ecol. 2009;18:2628–42.http://doi.org/10.1111/j.1365-294X.2009.04227.x.
   PubMed Web of Science ®Google Scholar
• Bovers M, Hagen F, Kuramae EE, et al. Promiscuous mitochondria in Cryptococcus gattii. FEMS Yeast Res. 2009;9:489–503.http://doi.org/10.1111/j.1567-1364.2009.00494.x.
   PubMed Web of Science ®Google Scholar
• Farrer RA, Desjardins CA, Sakthikumar S, et al. Genome evolution and innovation across the four major lineages of Cryptococcus gattii. mBio. 2015;6:e00868–15. http://doi.org/10.1128/mBio.00868-15.
   PubMed Web of Science ®Google Scholar
• Voelz K, Ma H, Phadke S, et al. Transmission of Hypervirulence traits via sexual reproduction within and between lineages of the human fungal pathogen Cryptococcus gattii. PLoS Genet. 2013;9:e1003771. http://doi.org/10.1371/journal.pgen.1003771.
   PubMed Web of Science ®Google Scholar
• Fraser JA, Giles SS, Wenink EC, et al. Same-sex mating and the origin of the Vancouver Island Cryptococcus gattii outbreak. Nature. 2005;437:1360–4. http://doi.org/10.1038/nature04220.
   PubMed Web of Science ®Google Scholar
• Fu C, Sun S, Billmyre RB, et al. Unisexual versus bisexual mating in Cryptococcus neoformans: Consequences and biological impacts. Fungal Genet Biol. 2015;78:65–75. http://doi.org/10.1016/j.fgb.2014.08.008.
   PubMed Web of Science ®Google Scholar
• Phadke SS, Feretzaki M, Clancey SA, et al. Unisexual reproduction of Cryptococcus gattii. PLoS One. 2014;9:e111089. http://doi.org/10.1371/journal.pone.0111089.
   PubMed Web of Science ®Google Scholar
• O'Gorman CM, Fuller HT, Dyer PS. Discovery of a sexual cycle in the opportunistic fungal pathogen Aspergillus fumigatus. Nature. 2009;457:471–4. http://doi.org/10.1038/nature07528.
   PubMed Web of Science ®Google Scholar
• Losada L, Sugui JA, Eckhaus MA, et al. Genetic analysis using an isogenic mating pair of Aspergillus fumigatus identifies Aazole resistance genes and lack of MAT locus's role in virulence. PLoS Pathog. 2015;11:e1004834. http://doi.org/10.1371/journal.ppat.1004834.
   PubMed Web of Science ®Google Scholar
• Forche A, Alby K, Schaefer D, et al. The parasexual cycle in Candida albicans provides an alternative pathway to meiosis for the formation of recombinant strains. PLoS Biol. 2008;6:e110. http://doi.org/10.1371/journal.pbio.0060110.
   PubMed Web of Science ®Google Scholar
• Bennett RJ, Johnson AD. Completion of a parasexual cycle in Candida albicans by induced chromosome loss in tetraploid strains. EMBO J. 2003;22:2505–15. http://doi.org/10.1093/emboj/cdg235.
   PubMed Web of Science ®Google Scholar
• Jacobsen MD, Rattray AMJ, Gow NAR, et al. Mitochondrial haplotypes and recombination in Candida albicans. Med Mycol. 2008;46:647–54. http://doi.org/10.1080/13693780801986631.
   PubMed Web of Science ®Google Scholar
• Valach M, Pryszcz LP, Tomaska L, et al. Mitochondrial genome variability within the Candida parapsilosis species complex. Mitochondrion. 2012;12:514–9. http://doi.org/10.1016/j.mito.2012.07.109.
   PubMed Web of Science ®Google Scholar
• Anderson JB, Wickens C, Khan M, et al. Infrequent genetic exchange and recombination in the mitochondrial genome of Candida albicans. J Bacteriol. 2001;183:865–72. http://doi.org/10.1128/JB.183.3.865-872.2001.
   PubMed Web of Science ®Google Scholar
• Pryszcz LP, Németh T, Saus E, et al. The genomic aftermath of hybridization in the opportunistic pathogen Candida metapsilosis. PLoS Genet. 2015;11:e1005626. http://doi.org/10.1371/journal.pgen.1005626.
   PubMed Web of Science ®Google Scholar
• Hamari Z, Toth B, Beer Z, et al. Interpretation of intraspecific variability in mtDNAs of Aspergillus niger strains and rearrangement of their mtDNAs following mitochondrial transmissions. FEMS Microbiol Lett. 2003;221:63–71. http://doi.org/10.1016/S0378-1097(03)00165-4.
   PubMed Web of Science ®Google Scholar
• Yan Z, Xu J. Mitochondria are inherited from the MATa parent in crosses of the basidiomycete fungus Cryptococcus neoformans. Genetics. 2003;163:1315–25.
   PubMed Web of Science ®Google Scholar
• Gyawali R, Lin X. Prezygotic and postzygotic control of uniparental mitochondrial DNA inheritance in Cryptococcus neoformans. mBio. 2013;4:e00112–13. http://doi.org/10.1128/mBio.00112-13.
   PubMed Web of Science ®Google Scholar
• Zhu P, Zhai B, Lin X, et al. Congenic strains for genetic analysis of virulence traits in Cryptococcus gattii. Infect Immun. 2013;81:2616–25. http://doi.org/10.1128/IAI.00018-13.
   PubMed Web of Science ®Google Scholar
• Shakya VPS, Idnurm A. Sex determination directs uniparental mitochondrial inheritance in Phycomyces. Eukaryot Cell. 2014;13:186–9. http://doi.org/10.1128/EC.00203-13.
   PubMedGoogle Scholar
• Parikh VS, Morgan MM, Scott R, et al. The mitochondrial genotype can influence nuclear gene expression in yeast. Science. 1987;235:576–80. http://doi.org/10.1126/science.3027892.
   PubMed Web of Science ®Google Scholar
• Liao X, Butow RA. RTG1 and RTG2: two yeast genes required for a novel path of communication from mitochondria to the nucleus. Cell. 1993;72:61–71. http://doi.org/10.1016/0092-8674(93)90050-Z.
   PubMed Web of Science ®Google Scholar
• Hallstrom TC, Moye-Rowley WS. Multiple signals from dysfunctional mitochondria activate the pleiotropic drug resistance pathway in Saccharomyces cerevisiae. J Biol Chem. 2000;275:37347–56. http://doi.org/10.1074/jbc.M007338200.
   PubMed Web of Science ®Google Scholar
• Moye-Rowley WS. Retrograde regulation of multidrug resistance in Saccharomyces cerevisiae. Gene. 2005;354:15–21. http://doi.org/10.1016/j.gene.2005.03.019.
   PubMed Web of Science ®Google Scholar
• Traven A, Wong JMS, Xu D, et al. Interorganellar communication. Altered nuclear gene expression profiles in a yeast mitochondrial DNA mutant. J Biol Chem. 2001;276:4020–7. http://doi.org/10.1074/jbc.M006807200.
   PubMed Web of Science ®Google Scholar
• Spinazzola A, Zeviani M. Mitochondrial diseases: a cross-talk between mitochondrial and nuclear genomes. Adv Exp Med Biol. 2009;652:69–84. http://doi.org/10.1007/978-90-481-2813-6_6.
   PubMed Web of Science ®Google Scholar
• Zhang X, Moye-Rowley WS. Saccharomyces cerevisiae multidrug resistance gene expression inversely correlates with the status of the F0 component of the mitochondrial ATPase. J Biol Chem. 2001;276:47844–52. http://doi.org/10.1074/jbc.M106285200.
   PubMed Web of Science ®Google Scholar
• Shingu-Vazquez M, Traven A. Mitochondria and fungal pathogenesis: drug tolerance, virulence, and potential for antifungal therapy. Eukaryot Cell. 2011;10:1376–83. http://doi.org/10.1128/EC.05184-11.
   PubMedGoogle Scholar
• Brun S, Bergès T, Poupard P, et al. Mechanisms of azole resistance in petite mutants of Candida glabrata. Antimicrob Agents Chemother. 2004;48:1788–96. http://doi.org/10.1128/AAC.48.5.1788-1796.2004.
   PubMed Web of Science ®Google Scholar
• Paul S, Schmidt JA, Moye-Rowley WS. Regulation of the CgPdr1 transcription factor from the pathogen Candida glabrata. Eukaryot Cell. 2011;10:187–97. http://doi.org/10.1128/EC.00277-10.
   PubMedGoogle Scholar
• Tsai H-F, Krol AA, Sarti KE, et al. Candida glabrata PDR1, a transcriptional regulator of a pleiotropic drug resistance network, mediates azole resistance in clinical isolates and petite mutants. Antimicrob Agents Chemother. 2006;50:1384–92. http://doi.org/10.1128/AAC.50.4.1384-1392.2006.
   PubMed Web of Science ®Google Scholar
• Paul S, Bair TB, Moye-Rowley WS. Identification of genomic binding sites for Candida glabrata Pdr1 transcription factor in wild-type and ρ0 cells. Antimicrob Agents Chemother. 2014;58:6904–12. http://doi.org/10.1128/AAC.03921-14.
   PubMed Web of Science ®Google Scholar
• Ferrari S, Ischer F, Calabrese D, et al. Gain of function mutations in CgPDR1 of Candida glabrata not only mediate antifungal resistance but also enhance virulence. PLoS Pathog. 2009;5:e1000268. http://doi.org/10.1371/journal.ppat.1000268.
   PubMed Web of Science ®Google Scholar
• Ferrari S, Sanguinetti M, De Bernardis F, Torelli R, et al. Loss of mitochondrial functions associated with azole resistance in Candida glabrata results in enhanced virulence in mice. Antimicrob Agents Chemother. 2011;55:1852–60. http://doi.org/10.1128/AAC.01271-10.
   PubMed Web of Science ®Google Scholar
• Devaux F, Carvajal E, Moye-Rowley S, et al. Genome-wide studies on the nuclear PDR3-controlled response to mitochondrial dysfunction in yeast. FEBS Lett. 2002;515:25–8. http://doi.org/10.1016/S0014-5793(02)02387-6.
   PubMed Web of Science ®Google Scholar
• Panwar SL, Moye-Rowley WS. Long chain base tolerance in Saccharomyces cerevisiae is induced by retrograde signals from the mitochondria. J Biol Chem. 2006;281:6376–84. http://doi.org/10.1074/jbc.M512115200.
   PubMed Web of Science ®Google Scholar
• Gulshan K, Schmidt JA, Shahi P, et al. Evidence for the bifunctional nature of mitochondrial phosphatidylserine decarboxylase: role in Pdr3-dependent retrograde regulation of PDR5 expression. Mol Cell Biol. 2008;28:5851–64. http://doi.org/10.1128/MCB.00405-08.
   PubMed Web of Science ®Google Scholar
• Batova M, Borecka-Melkusova S, Simockova M, et al. Functional characterization of the CgPGS1 gene reveals a link between mitochondrial phospholipid homeostasis and drug resistance in Candida glabrata. Curr Genet. 2008;53:313–22. http://doi.org/10.1007/s00294-008-0187-9.
   PubMed Web of Science ®Google Scholar
• Singh A, Yadav V, Prasad R. Comparative lipidomics in clinical isolates of Candida albicans reveal crosstalk between mitochondria, cell wall integrity and azole resistance. PLoS One. 2012;7:e39812. http://doi.org/10.1371/journal.pone.0039812.
   PubMed Web of Science ®Google Scholar
• López-Marqués RL, Poulsen LR, Bailly A, et al. Structure and mechanism of ATP-dependent phospholipid transporters. Biochim Biophys Acta. 2015;1850:461–75. http://doi.org/10.1016/j.bbagen.2014.04.008.
   PubMed Web of Science ®Google Scholar
• Bromley M, Johns A, Davies E, et al. Mitochondrial complex I Is a global regulator of secondary metabolism, virulence and azole sensitivity in fungi. PLoS One. 2016;11:e0158724. http://doi.org/10.1371/journal.pone.0158724.
   PubMed Web of Science ®Google Scholar
• Vandeputte P, Tronchin G, Rocher F, et al. Hypersusceptibility to azole antifungals in a clinical isolate of Candida glabrata with reduced aerobic growth. Antimicrob Agents Chemother. 2009;53:3034–41. http://doi.org/10.1128/AAC.01384-08.
   PubMed Web of Science ®Google Scholar
• Epstein CB, Waddle JA, Hale IV W, et al. Genome-wide responses to mitochondrial dysfunction. Mol Biol Cell. 2001;12:297–308. http://doi.org/10.1091/mbc.12.2.297.
   PubMed Web of Science ®Google Scholar
• Girvan HM, Munro AW. Heme sensor proteins. J Biol Chem. 2013;288:13194–203. http://doi.org/10.1074/jbc.R112.422642.
   PubMed Web of Science ®Google Scholar
• Cresnar B, Petric S. Cytochrome P450 enzymes in the fungal kingdom. Biochim Biophys Acta. 2011;1814:29–35. http://doi.org/10.1016/j.bbapap.2010.06.020.
   PubMed Web of Science ®Google Scholar
• Balding PR, Porro CS, McLean KJ, et al. How do azoles inhibit cytochrome P450 enzymes? A density functional study. J Phys Chem A. 2008;112:12911–8. http://doi.org/10.1021/jp802087w.
   PubMed Web of Science ®Google Scholar
• Lupetti A, Danesi R, Campa M, et al. Molecular basis of resistance to azole antifungals. Trends Mol Med. 2002;8:76–81. http://doi.org/10.1016/S1471-4914(02)02280-3.
   PubMed Web of Science ®Google Scholar
• Hosogaya N, Miyazaki T, Nagi M, et al. The heme-binding protein Dap1 links iron homeostasis to azole resistance via the P450 protein Erg11 in Candida glabrata. FEMS Yeast Res. 2013;13:411–21. http://doi.org/10.1111/1567-1364.12043.
   PubMed Web of Science ®Google Scholar
• Song J, Zhai P, Zhang Y, et al. The Aspergillus fumigatus damage resistance protein family coordinately regulates ergosterol biosynthesis and azole susceptibility. mBio. 2016;7:e01919–15. http://doi.org/10.1128/mBio.01919-15.
   PubMed Web of Science ®Google Scholar
• Mallory JC, Crudden G, Johnson BL, et al. Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae. Mol Cell Biol. 2005;25:1669–79. http://doi.org/10.1128/MCB.25.5.1669-1679.2005.
   PubMed Web of Science ®Google Scholar
• Hughes AL, Powell DW, Bard M, et al. Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes. Cell Metab. 2007;5:143–9. http://doi.org/10.1016/j.cmet.2006.12.009.
   PubMed Web of Science ®Google Scholar
• Long N, Xu X, Qian H, et al. A putative mitochondrial iron transporter MrsA in Aspergillus fumigatus plays important roles in azole-, oxidative stress responses and virulence. Front Microbiol. 2016;7:716. http://doi.org/10.3389/fmicb.2016.00716.
   PubMed Web of Science ®Google Scholar
• Schrettl M, Kim HS, Eisendle M, et al. SreA-mediated iron regulation in Aspergillus fumigatus. Mol Microbiol. 2008;70:27–43. http://doi.org/10.1111/j.1365-2958.2008.06376.x.
   PubMed Web of Science ®Google Scholar
• Stehling O, Lill R. The role of mitochondria in cellular iron-sulfur protein biogenesis: mechanisms, connected processes, and diseases. Cold Spring Harb Perspect Biol. 2013;5:a011312. http://doi.org/10.1101/cshperspect.a011312.
   PubMed Web of Science ®Google Scholar
• Braymer JJ, Lill R. Iron-sulfur cluster biogenesis and trafficking in mitochondria. J Biol Chem. 2017;292:12754–63. http://doi.org/10.1074/jbc.R117.787101.
   PubMed Web of Science ®Google Scholar
• Buschlen S, Amillet J-M, Guiard B, et al. The S. cerevisiae HAP complex, a key regulator of mitochondrial function, coordinates nuclear and mitochondrial gene expression. Comp Funct Genomics. 2003;4:37–46. http://doi.org/10.1002/cfg.254.
   PubMedGoogle Scholar
• McNabb DS, Xing Y, Guarente L. Cloning of yeast HAP5: a novel subunit of a heterotrimeric complex required for CCAAT binding. Genes Dev. 1995;9:47–58. http://doi.org/10.1101/gad.9.1.47.
   PubMed Web of Science ®Google Scholar
• Tanaka A, Kato M, Nagase T, et al. Isolation of genes encoding novel transcription factors which interact with the Hap complex from Aspergillus species. Biochim Biophys Acta. 2002;1576:176–82. http://doi.org/10.1016/S0167-4781(02)00286-5.
   PubMedGoogle Scholar
• Schrettl M, Beckmann N, Varga J, et al. HapX-mediated adaption to iron starvation is crucial for virulence of Aspergillus fumigatus. PLoS Pathog. 2010;6:e1001124. http://doi.org/10.1371/journal.ppat.1001124.
   PubMed Web of Science ®Google Scholar
• Hortschansky P, Eisendle M, Al-Abdallah Q, et al. Interaction of HapX with the CCAAT-binding complex—a novel mechanism of gene regulation by iron. EMBO J. 2007;26:3157–68. http://doi.org/10.1038/sj.emboj.7601752.
   PubMed Web of Science ®Google Scholar
• Hsu P-C, Yang C-Y, Lan C-Y. Candida albicans Hap43 is a repressor induced under low-iron conditions and is essential for iron-responsive transcriptional regulation and virulence. Eukaryot Cell. 2011;10:207–25. http://doi.org/10.1128/EC.00158-10.
   PubMedGoogle Scholar
• Jung WH, Saikia S, Hu G, et al. HapX positively and negatively regulates the transcriptional response to iron deprivation in Cryptococcus neoformans. PLoS Pathog. 2010;6:e1001209. http://doi.org/10.1371/journal.ppat.1001209.
   PubMed Web of Science ®Google Scholar
• López-Berges MS, Capilla J, Turrà D, et al. HapX-mediated iron homeostasis is essential for rhizosphere competence and virulence of the soilborne pathogen Fusarium oxysporum. Plant Cell. 2012;24:3805–22. http://doi.org/10.1105/tpc.112.098624.
   PubMed Web of Science ®Google Scholar
• Caza M, Hu G, Price M, et al. The zinc finger protein Mig1 regulates mitochondrial function and azole drug susceptibility in the pathogenic fungus Cryptococcus neoformans. mSphere. 2016;http://doi.org/10.1128/mSphere.00080-15.
   Google Scholar
• Garcia-Santamarina S, Uzarska MA, Festa RA, et al. Cryptococcus neoformans iron-sulfur protein biogenesis machinery is a novel layer of protection against Cu stress. mBio. 2017;8:e01742–17. http://doi.org/10.1128/mBio.01742-17.
   PubMed Web of Science ®Google Scholar
• Qu Y, Jelicic B, Pettolino F, et al. Mitochondrial sorting and assembly machinery subunit Sam37 in Candida albicans: insight into the roles of mitochondria in fitness, cell wall integrity, and virulence. Eukaryot Cell. 2012;11:532–44. http://doi.org/10.1128/EC.05292-11.
   PubMedGoogle Scholar
• Neupert W, Herrmann JM. Translocation of proteins into mitochondria. Annu Rev Biochem. 2007;76:723–49. http://doi.org/10.1146/annurev.biochem.76.052705.163409.
   PubMed Web of Science ®Google Scholar
• Chacinska A, Koehler CM, Milenkovic D, et al. Importing mitochondrial proteins: machineries and mechanisms. Cell. 2009;138:628–44. http://doi.org/10.1016/j.cell.2009.08.005.
   PubMed Web of Science ®Google Scholar
• Ellenrieder L, Opaliński Ł, Becker L, et al. Separating mitochondrial protein assembly and endoplasmic reticulum tethering by selective coupling of Mdm10. Nat Commun. 2016;7:13021. http://doi.org/10.1038/ncomms13021.
   PubMed Web of Science ®Google Scholar
• Dagley MJ, Gentle IE, Beilharz TH, et al. 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. 2011;79:968–89. http://doi.org/10.1111/j.1365-2958.2010.07503.x.
   PubMed Web of Science ®Google Scholar
• Hewitt VL, Heinz E, Shingu-Vazquez M, et al. A model system for mitochondrial biogenesis reveals evolutionary rewiring of protein import and membrane assembly pathways. Proc Natl Acad Sci U S A. 2012;109:E3358–66. http://doi.org/10.1073/pnas.1206345109.
   PubMed Web of Science ®Google Scholar
• Malhotra JD, Kaufman RJ. ER stress and its functional link to mitochondria: role in cell survival and death. Cold Spring Harb Perspect Biol. 2011;3:a004424. http://doi.org/10.1101/cshperspect.a004424.
   PubMed Web of Science ®Google Scholar
• Rainbolt TK, Saunders JM, Wiseman RL. Stress-responsive regulation of mitochondria through the ER unfolded protein response. Trends Endocrinol Metab. 2014;25:528–37. http://doi.org/10.1016/j.tem.2014.06.007.
   PubMed Web of Science ®Google Scholar
• Kornmann B, Currie E, Collins SR, et al. An ER-mitochondria tethering complex revealed by a synthetic biology screen. Science. 2009;325:477–81. http://doi.org/10.1126/science.1175088.
   PubMed Web of Science ®Google Scholar
• Tucey TM, Verma-Gaur J, Nguyen J, et al. The endoplasmic reticulum-mitochondrion tether ERMES orchestrates fungal immune evasion, illuminating inflammasome responses to hyphal signals. mSphere. 2016;1:e00074–16. http://doi.org/10.1128/mSphere.00074-16.
   PubMed Web of Science ®Google Scholar
• Becker JM, Kauffman SJ, Hauser M, et al. Pathway analysis of Candida albicans survival and virulence determinants in a murine infection model. Proc Natl Acad Sci U S A. 2010;107:22044–9. http://doi.org/10.1073/pnas.1009845107.
   PubMed Web of Science ®Google Scholar
• Friedman JR, Lackner LL, West M, et al. ER tubules mark sites of mitochondrial division. Science. 2011;334:358–62. http://doi.org/10.1126/science.1207385.
   PubMed Web of Science ®Google Scholar
• Michel AH, Kornmann B. The ERMES complex and ER-mitochondria connections. Biochem Soc Trans. 2012;40:445–50. http://doi.org/10.1042/BST20110758.
   PubMed Web of Science ®Google Scholar
• Geißel B, Penka M, Neubauer M, et al. The ER-mitochondria encounter structure contributes to hyphal growth, mitochondrial morphology and virulence of the pathogenic mold Aspergillus fumigatus. Int J Med Microbiol. 2017;307:37–43. http://doi.org/10.1016/j.ijmm.2016.11.005.
   PubMed Web of Science ®Google Scholar
• Jo A, Ham S, Lee GH, et al. Efficient mitochondrial genome editing by CRISPR/Cas9. Biomed Res Int. 2015;2015:305716. http://doi.org/10.1155/2015/305716.
   PubMed Web of Science ®Google Scholar
• Verma S, Idnurm A. The Uve1 endonuclease is regulated by the white collar complex to protect Cryptococcus neoformans from UV damage. PLoS Genet. 2013;9:e1003769. http://doi.org/10.1371/journal.pgen.1003769.
   PubMed Web of Science ®Google Scholar
• Rhodes J, Desjardins CA, Sykes SM, et al. Tracing genetic exchange and biogeography of Cryptococcus neoformans var. grubii at the global population level. Genetics. 2017;207:327–46. http://doi.org/10.1534/genetics.117.203836.
   PubMed Web of Science ®Google Scholar
• Ianiri G, Idnurm A. Essential gene discovery in the basidiomycete Cryptococcus neoformans for antifungal drug target prioritization. mBio. 2015;6:e02334–14. http://doi.org/10.1128/mBio.02334-14.
   PubMed Web of Science ®Google Scholar
• Scheckhuber CQ, Erjavec N, Tinazli A, et al. Reducing mitochondrial fission results in increased life span and fitness of two fungal ageing models. Nat Cell Biol. 2007;9:99–105. http://doi.org/10.1038/ncb1524.
   PubMed Web of Science ®Google Scholar
• Scheckhuber CQ, Osiewacz HD. Podospora anserina: a model organism to study mechanisms of healthy ageing. Mol Genet Genomics. 2008;280:365–74. http://doi.org/10.1007/s00438-008-0378-6.
   PubMed Web of Science ®Google Scholar
• Bouklas T, Pechuan X, Goldman DL, et al. Old Cryptococcus neoformans cells contribute to virulence in chronic cryptococcosis. mBio. 2013;4:e00455–13. http://doi.org/10.1128/mBio.00455-13.
   PubMed Web of Science ®Google Scholar
• Bouklas T, Alonso-Crisóstomo L, Székely T, Jr., et al. Generational distribution of a Candida glabrata population: resilient old cells prevail, while younger cells dominate in the vulnerable host. PLoS Pathog. 2017;13:e1006355. http://doi.org/10.1371/journal.ppat.1006355.
   PubMed Web of Science ®Google Scholar
• Nakai K, Kanehisa M. A knowledge base for predicting protein localization sites in eukaryotic cells. Genomics. 1992;14:897–911. http://doi.org/10.1016/S0888-7543(05)80111-9.
   PubMed Web of Science ®Google Scholar
• Claros MG, Vincens P. Computational method to predict mitochondrially imported proteins and their targeting sequences. Eur J Biochem. 1996;241:779–86. http://doi.org/10.1111/j.1432-1033.1996.00779.x.
   PubMedGoogle Scholar
• Bassilana M, Blyth J, Arkowitz RA. Cdc24, the GDP-GTP exchange factor for Cdc42, is required for invasive hyphal growth of Candida albicans. Eukaryot Cell. 2003;2:9–18. http://doi.org/10.1128/EC.2.1.9-18.2003.
   PubMedGoogle Scholar
• Cleary IA, Lazzell AL, Monteagudo C, et al. BRG1 and NRG1 form a novel feedback circuit regulating Candida albicans hypha formation and virulence. Mol Microbiol. 2012;85:557–73. http://doi.org/10.1111/j.1365-2958.2012.08127.x.
   PubMed Web of Science ®Google Scholar
• Kingsbury JM, McCusker JH. Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2Δ) mutants is influenced by the carbon source and rapamycin. Microbiology. 2010;156:929–39. http://doi.org/10.1099/mic.0.034348-0.
   PubMed Web of Science ®Google Scholar
• Gabriel I, Kur K, Laforce-Nesbitt SS, et al. Phenotypic consequences of LYS4 gene disruption in Candida albicans. Yeast. 2014;31:299–308. http://doi.org/10.1002/yea.3021.
   PubMed Web of Science ®Google Scholar
• Li Y, Su C, Mao X, et al. Roles of Candida albicans Sfl1 in hyphal development. Eukaryot Cell. 2007;6:2112–21. http://doi.org/10.1128/EC.00199-07.
   PubMed Web of Science ®Google Scholar
• Jackson BE, Wilhelmus KR, Mitchell BM. Genetically regulated filamentation contributes to Candida albicans virulence during corneal infection. Microb Pathog. 2007;42:88–93. http://doi.org/10.1016/j.micpath.2006.11.005.
   PubMed Web of Science ®Google Scholar
• Chaves GM, Bates S, MacCallum DM, et al. Candida albicans GRX2, encoding a putative glutaredoxin, is required for virulence in a murine model. Genet Mol Res. 2007;6:1051–63.
   PubMed Web of Science ®Google Scholar
• Zakikhany K, Naglik JR, Schmidt-Westhausen A, et al. In vivo transcript profiling of Candida albicans identifies a gene essential for interepithelial dissemination. Cell Microbiol. 2007;9:2938–54. http://doi.org/10.1111/j.1462-5822.2007.01009.x.
   PubMed Web of Science ®Google Scholar
• Skrzypek MS, Binkley J, Binkley G, et al. The Candida Genome Database (CGD): incorporation of assembly 22, systematic identifiers and visualization of high throughput sequencing data. Nucleic Acids Res. 2017;45:D592–D6. http://doi.org/10.1093/nar/gkw924.
   PubMed Web of Science ®Google Scholar