Inhibition of electron transport chain assembly and function promotes photodynamic killing of Candida.
Respiratory deficiency increases the sensitivity of the pathogenic fungi Candida albicans and Candida glabrata to oxidative stress induced by photodynamic therapy (PDT) sensitized by the cationic porphyrin meso-tetra (N-methyl-4-pyridyl) porphine tetra tosylate (TMP-1363). Since disruption of electron transport chain (ETC) function increases intracellular levels of reactive oxygen species in yeast, we determined whether interference with ETC assembly or function increased sensitivity to TMP-1363-PDT in C. albicans, C. glabrata and the non-pathogenic yeast Saccharomyces cerevisiae. Metabolic inhibitor antimycin A and defined genetic mutants were used to identify ETC components that contribute to the sensitivity to PDT. Inhibition of cytochrome bc(1) (Complex III) with antimycin A increases mitochondrial levels of reactive oxygen species. PDT performed following pre-treatment with antimycin A reduced colony forming units (CFU) of C. albicans and C. glabrata by approximately two orders of magnitude relative to PDT alone. A S. cerevisiae mitochondrial glutaredoxin grx5 mutant, defective in assembly of Fe-S clusters critical for Complex III function, displayed increased sensitivity to PDT. Furthermore, C. glabrata and S.cerevisiae mutants in cytochrome c oxidase (Complex IV) synthesis and assembly were also significantly more sensitive to PDT. These included suv3, encoding an ATP-dependent RNA helicase critical for maturation of cytochrome c oxidase subunit transcripts, and pet117, encoding an essential cytochrome c oxidase assembly factor. Following PDT, the reduction in CFU of these mutants was one to two orders of magnitude greater than in their respective parental strains. The data demonstrate that selective inhibition of ETC Complexes III and IV significantly increases the sensitivity of C. albicans, C. glabrata and S. cerevisiae to PDT sensitized with TMP-1363.
Chabrier-Roselló
Yeissa
Y
Department of Microbiology and Immunology, University of Rochester Medical Center, Box 672, 601 Elmwood Ave., Rochester, NY 14642, USA.
Giesselman
Benjamin R
BR
De Jesús-Andino
Francisco J
FJ
Foster
Thomas H
TH
Mitra
Soumya
S
Haidaris
Constantine G
CG
D000968:Antimycin A / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects / Q000528:radiation effects*; D041221:Candida glabrata / Q000187:drug effects / Q000528:radiation effects*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D018384:Oxidative Stress; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000633:toxicity; D011166:Porphyrins / Q000633:toxicity; D017382:Reactive Oxygen Species / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism
D017319:Photosensitizing Agents; D011166:Porphyrins; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; C057459:tetra(3-N-methylpyridyl)porphine; D000968:Antimycin A; D003576:Electron Transport Complex IV; C075918:SUV3 protein, S cerevisiae; D053487:DEAD-box RNA Helicases; D014450:Electron Transport Complex III
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