| Enzymatic dysfunction of mitochondrial complex I of the Candida albicans goa1 mutant is associated with increased reactive oxidants and cell death. | |
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MedLine Citation:
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PMID: 21398508 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We have previously shown that deletion of GOA1 (growth and oxidant adaptation) of Candida albicans results in a loss of mitochondrial membrane potential, ATP synthesis, increased sensitivity to oxidants and killing by human neutrophils, and avirulence in a systemic model of candidiasis. We established that translocation of Goa1p to mitochondria occurred during peroxide stress. In this report, we show that the goa1Δ (GOA31), compared to the wild type (WT) and a gene-reconstituted (GOA32) strain, exhibits sensitivity to inhibitors of the classical respiratory chain (CRC), including especially rotenone (complex I [CI]) and salicylhydroxamic acid (SHAM), an inhibitor of the alternative oxidase pathway (AOX), while potassium cyanide (KCN; CIV) causes a partial inhibition of respiration. In the presence of SHAM, however, GOA31 has an enhanced respiration, which we attribute to the parallel respiratory (PAR) pathway and alternative NADH dehydrogenases. Interestingly, deletion of GOA1 also results in a decrease in transcription of the alternative oxidase gene AOX1 in untreated cells as well as negligible AOX1 and AOX2 transcription in peroxide-treated cells. To explain the rotenone sensitivity, we measured enzyme activities of complexes I to IV (CI to CIV) and observed a major loss of CI activity in GOA31 but not in control strains. Enzymatic data of CI were supported by blue native polyacrylamide gel electrophoresis (BN-PAGE) experiments which demonstrated less CI protein and reduced enzyme activity. The consequence of a defective CI in GOA31 is an increase in reactive oxidant species (ROS), loss of chronological aging, and programmed cell death ([PCD] apoptosis) in vitro compared to control strains. The increase in PCD was indicated by an increase in caspase activity and DNA fragmentation in GOA31. Thus, GOA1 is required for a functional CI and partially for the AOX pathway; loss of GOA1 compromises cell survival. Further, the loss of chronological aging is new to studies of Candida species and may offer an insight into therapies to control these pathogens. Our observation of increased ROS production associated with a defective CI and PCD is reminiscent of mitochondrial studies of patients with some types of neurodegenerative diseases where CI and/or CIII dysfunctions lead to increased ROS and apoptosis. |
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Authors:
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Dongmei Li; Hui Chen; Abigail Florentino; Deepu Alex; Patricia Sikorski; William A Fonzi; Richard Calderone |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-03-11 |
Journal Detail:
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Title: Eukaryotic cell Volume: 10 ISSN: 1535-9786 ISO Abbreviation: Eukaryotic Cell Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-03 Completed Date: 2011-10-31 Revised Date: 2011-11-01 |
Medline Journal Info:
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Nlm Unique ID: 101130731 Medline TA: Eukaryot Cell Country: United States |
Other Details:
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Languages: eng Pagination: 672-82 Citation Subset: IM |
Affiliation:
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Georgetown University Medical Center, Department of Microbiology and Immunology, SE305 Med-Dent Building, 3900 Reservoir Rd. NW, Washington, DC 20057, USA. dl33@georgetown.edu |
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| MeSH Terms | |
Descriptor/Qualifier:
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Candida albicans
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metabolism* Cell Death Cell Respiration Fungal Proteins / genetics, metabolism* Membrane Potential, Mitochondrial Mitochondria / metabolism* Mitochondrial Proteins / genetics, metabolism Mutation* Oxidants / metabolism* Reactive Oxygen Species / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Fungal Proteins; 0/Mitochondrial Proteins; 0/Oxidants; 0/Reactive Oxygen Species |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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