title: Mitochondria influence CDR1 efflux pump activity, Hog1-mediated oxidative stress pathway, iron homeostasis, and ergosterol levels in Candida albicans.
abstract: Mitochondrial dysfunction in Candida albicans is known to be associated with drug susceptibility, cell wall integrity, phospholipid homeostasis, and virulence. In this study, we deleted CaFZO1, a key component required during biogenesis of functional mitochondria. Cells with FZO1 deleted displayed fragmented mitochondria, mitochondrial genome loss, and reduced mitochondrial membrane potential and were rendered sensitive to azoles and peroxide. In order to understand the cellular response to dysfunctional mitochondria, genome-wide expression profiling of fzo1Δ/Δ cells was performed. Our results show that the increased susceptibility to azoles was likely due to reduced efflux activity of CDR efflux pumps, caused by the missorting of Cdr1p into the vacuole. In addition, fzo1Δ/Δ cells showed upregulation of genes involved in iron assimilation, in iron-sufficient conditions, characteristic of iron-starved cells. One of the consequent effects was downregulation of genes of the ergosterol biosynthesis pathway with a commensurate decrease in cellular ergosterol levels. We therefore connect deregulated iron metabolism to ergosterol biosynthesis pathway in response to dysfunctional mitochondria. Impaired activation of the Hog1 pathway in the mutant was the basis for increased susceptibility to peroxide and increase in reactive oxygen species, indicating the importance of functional mitochondria in controlling Hog1-mediated oxidative stress response. Mitochondrial phospholipid levels were also altered as indicated by an increase in phosphatidylserine and phosphatidylethanolamine and decrease in phosphatidylcholine in fzo1Δ/Δ cells. Collectively, these findings reinforce the connection between functional mitochondria and azole tolerance, oxidant-mediated stress, and iron homeostasis in C. albicans.
authors: Yeast Molecular Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India.
authors: Edwina
authors: E
authors: Thomas
authors: Elvira
authors: E
authors: Roman
authors: Steven
authors: S
authors: Claypool
authors: Nikhat
authors: N
authors: Manzoor
authors: Jesús
authors: J
authors: Pla
authors: Sneh Lata
authors: SL
authors: Panwar
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology; D001393:Azoles / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000187:drug effects / Q000235:genetics; D004875:Ergosterol / Q000378:metabolism*; D005656:Fungal Proteins / Q000235:genetics* / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000172:deficiency / Q000235:genetics; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D054629:Genome, Mitochondrial; D006706:Homeostasis / Q000235:genetics; D007501:Iron / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D015398:Signal Transduction
chemical_list: D000935:Antifungal Agents; D001393:Azoles; C094693:CDR1 protein, Candida albicans; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D007501:Iron; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D004875:Ergosterol
references: Cell Calcium. 2008 Jul;44(1):24-35
references: 18395251
references: Mol Biol Cell. 2008 Dec;19(12):5143-55
references: 18799610
references: J Cell Biol. 2001 Mar 19;152(6):1123-34
references: 11257114
references: Science. 2009 Jul 24;325(5939):477-81
references: 19556461
references: Mol Gen Genet. 1984;198(2):179-82
references: 6394964
references: Antimicrob Agents Chemother. 2001 Apr;45(4):1174-83
references: 11257032
references: J Biol Chem. 2000 Jun 9;275(23):17249-55
references: 10748181
references: PLoS One. 2011 Apr 12;6(4):e18684
references: 21533276
references: Microbiology (Reading). 2005 Apr;151(Pt 4):1033-1049
references: 15817773
references: Cell. 2005 Jan 14;120(1):99-110
references: 15652485
references: Microbiology (Reading). 2005 Aug;151(Pt 8):2737-2749
references: 16079350
references: Mol Cell Biochem. 1998 Jul;184(1-2):101-5
references: 9746315
references: PLoS Biol. 2010 Mar 09;8(3):e1000329
references: 20231876
references: J Biol Chem. 2004 Jul 30;279(31):32294-300
references: 15169766
references: Antimicrob Agents Chemother. 2001 Dec;45(12):3366-74
references: 11709310
references: Gene. 2005 Jul 18;354:15-21
references: 15896930
references: J Biol Chem. 1999 Nov 12;274(46):33025-34
references: 10551871
references: Antimicrob Agents Chemother. 2008 Feb;52(2):694-704
references: 18056285
references: Microbiology (Reading). 2009 Feb;155(Pt 2):413-423
references: 19202089
references: Mol Microbiol. 2011 Feb;79(4):968-89
references: 21299651
references: Science. 2008 Mar 28;319(5871):1797-9
references: 18369141
references: Mol Gen Genet. 1993 Oct;241(1-2):177-84
references: 8232202
references: J Cell Biol. 2000 Oct 16;151(2):341-52
references: 11038181
references: J Biol Chem. 2005 Oct 21;280(42):35410-6
references: 16036913
references: Proc Natl Acad Sci U S A. 1999 Aug 31;96(18):10206-11
references: 10468587
references: Eukaryot Cell. 2004 Dec;3(6):1639-52
references: 15590837
references: PLoS Genet. 2005 Jul;1(1):36-57
references: 16103911
references: Clin Microbiol Infect. 2001 Nov;7(11):609-18
references: 11737085
references: Annu Rev Microbiol. 2012;66:39-63
references: 22703054
references: Genes Dev. 1997 May 15;11(10):1277-88
references: 9171372
references: J Biol Chem. 2012 May 4;287(19):15205-18
references: 22403410
references: Eukaryot Cell. 2009 Nov;8(11):1706-20
references: 19717740
references: Biochem J. 2001 Jun 1;356(Pt 2):595-604
references: 11368790
references: FEMS Yeast Res. 2008 Aug;8(5):744-55
references: 18547332
references: J Biol Chem. 2008 Mar 28;283(13):8318-30
references: 18227070
references: J Biol Chem. 2000 Dec 1;275(48):37347-56
references: 10980204
references: FEMS Yeast Res. 2012 Nov;12(7):844-58
references: 22846114
references: Eukaryot Cell. 2011 May;10(5):672-82
references: 21398508
references: Cell Microbiol. 2013 Sep;15(9):1572-84
references: 23490206
references: Antimicrob Agents Chemother. 2004 May;48(5):1600-13
references: 15105111
references: Antimicrob Agents Chemother. 2013 Jan;57(1):532-42
references: 23147730
references: Mol Microbiol. 2003 Mar;47(5):1185-97
references: 12603727
references: Antimicrob Agents Chemother. 2011 May;55(5):1852-60
references: 21321146
references: Antimicrob Agents Chemother. 2007 May;51(5):1855-8
references: 17325226
references: J Biol Chem. 2013 Jan 18;288(3):1696-705
references: 23192348
references: Antimicrob Agents Chemother. 2005 Aug;49(8):3442-52
references: 16048959
references: Nat Protoc. 2008;3(6):1101-8
references: 18546601
references: Biochim Biophys Acta. 2009 Oct;1788(10):2059-68
references: 19422785
references: Antimicrob Agents Chemother. 2004 May;48(5):1778-87
references: 15105135
references: Eukaryot Cell. 2011 Nov;10(11):1376-83
references: 21926328
references: Eukaryot Cell. 2011 Feb;10(2):187-97
references: 21131438
references: Mol Microbiol. 2010 Mar;75(5):1112-32
references: 20132453
references: Eukaryot Cell. 2012 Apr;11(4):532-44
references: 22286093
references: Cell. 2009 Jun 26;137(7):1247-58
references: 19563757
references: Mol Microbiol. 2004 Sep;53(5):1451-69
references: 15387822
references: EMBO J. 1999 Jul 15;18(14):3981-9
references: 10406803
references: Mol Biol Cell. 2009 Jul;20(14):3363-73
references: 19477921
references: J Cell Biol. 2004 Oct 11;167(1):87-98
references: 15479738
references: Gene. 2003 Dec 24;323:43-55
references: 14659878
references: J Cell Biol. 2006 Jul 31;174(3):379-90
references: 16880272
references: J Biol Chem. 2001 May 11;276(19):15996-6007
references: 11278394
references: J Cell Biol. 1998 Oct 19;143(2):359-73
references: 9786948
references: Antimicrob Agents Chemother. 2008 Apr;52(4):1481-92
references: 18268086
references: Curr Genet. 2004 Oct;46(4):193-204
references: 15309505
references: J Med Microbiol. 2000 Nov;49(11):977-984
references: 11073151
references: Yeast. 1999 Oct;15(14):1555-64
references: 10514572
references: BMC Microbiol. 2013 Jan 24;13:16
references: 23347662
references: Nat Rev Mol Cell Biol. 2010 Dec;11(12):872-84
references: 21102612
references: Eukaryot Cell. 2003 Apr;2(2):351-61
references: 12684384
references: J Biol Chem. 2000 Jul 21;275(29):22387-94
references: 10777514
references: Antimicrob Agents Chemother. 2006 Nov;50(11):3597-606
references: 16954314
references: Mol Cell Biol. 2001 Jul;21(13):4140-8
references: 11390643
references: Nat Rev Mol Cell Biol. 2003 Jun;4(6):468-78
references: 12778126
references: Mol Biol Cell. 2004 Mar;15(3):1233-43
references: 14668481
references: PLoS One. 2011 Apr 29;6(4):e19266
references: 21559392
references: Antimicrob Agents Chemother. 2006 Apr;50(4):1365-71
references: 16569853
references: Science. 1997 Jun 13;276(5319):1709-12
references: 9180083
references: EMBO J. 1995 Mar 15;14(6):1231-9
references: 7720713
references: Antimicrob Agents Chemother. 2011 May;55(5):2061-6
references: 21343453
references: Drug Resist Updat. 2011 Jun;14(3):164-76
references: 21353623
references: Mol Microbiol. 2002 Jun;44(6):1551-60
references: 12067343
references: Gene. 2004 Oct 27;341:119-27
references: 15474295
references: Mol Cell Biol. 2008 Oct;28(19):5851-64
references: 18644857
references: Hum Mol Genet. 2002 Aug 15;11(17):2025-36
references: 12165564
references: Mol Cell. 2008 Mar 14;29(5):552-62
references: 18342603
references: Essays Biochem. 2011 Sep 7;50(1):101-19
references: 21967054
references: Biosci Rep. 1997 Jun;17(3):319-33
references: 9337486
references: Antimicrob Agents Chemother. 1998 Dec;42(12):3065-72
references: 9835492
references: HPB (Oxford). 2004;6(4):195-6
references: 18333076