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Control of Mitochondrial Function by SPFH Proteins in Pathogenic Yeast

Award Number: SC3GM135016
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/16/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Control of Mitochondrial Function by SPFH Proteins in Pathogenic Yeast - The mitochondrion is the major energy-producing organelle of the cell and coordinates key activities such as signaling, apoptosis, and phospholipid synthesis. These processes are essential for survival and pathogenesis of Candida albicans, the most common fungal pathogen in humans. C. albicans respiration occurs via three distinct pathways compared to vertebrates and is associated with virulence properties such as morphogenesis and cell wall synthesis. Our long-term research goal is to understand the cellular and molecular mechanisms that govern C. albicans survival in response to environmental stress and antifungal drugs. We previously discovered that gene classes involved mitochondrial functions are highly transcribed in response to osmotic and cell wall stress, and the gene SLP3 (stomatin like protein 3) was significantly upregulated. SLP3 is a member of the conserved SPFH (Stomatin, Prohibitin, Flotillin, HflK/HflC) protein superfamily. In eukaryotes, SPFH proteins are required for essential mitochondrial processes such as respiration, mitophagy, and apoptosis and mediate pathogenicity in several parasites. Our objective in this proposal is to determine the role of the C. albicans SPFH protein family in mitochondrial function. We were the first to demonstrate that Slp3p overproduction disrupted mitochondrial membrane potential and triggered apoptotic-like death specifically following prolonged exposure to oxidative stress. However, the molecular function Slp3p remains unknown. Thus, our central hypothesis is that C. albicans SPFH proteins form membrane complexes to coordinate mitochondrial function. This hypothesis is based upon observations with mammalian SPFH proteins and our published and preliminary findings. Human SPFH complexes appear as punctate foci when viewed using fluorescence microscopy. We found that Slp3p form puncta at the plasma membrane. Further, we identified a mitochondrial targeting signal in Slp2p, Phb1p and Phb2p, and our Slp2p-GFP fusion protein formed mitochondrial puncta. We will utilize a high-throughput molecular genetic and cellular approach that is cost-effective and time-saving to determine SPFH protein localization, protein complex composition, cellular function, and role in C. albicans infection. We will create SPFH-GFP fusion proteins and use fluorescence microscopy to determine cellular localization. We will construct SPFH-epitope-tagged strains and perform Co-IP and LC-MS/MS analyses to identify putative SPFH protein binding partners. We will create SPFH mutants via CRISPR-Cas9 genome editing and phenotypically characterize mutant strains in growth and cellular assays. We will examine SPFH function in C. albicans pathogenesis using a novel invertebrate infection system. Our findings will address a poorly understood area in C. albicans biology and provide a model for studying SPFH proteins in pathogenic fungi. This proposal is innovative as we will characterize the SPFH family in the context of a critical, yet poorly understood area in C albicans biology: the molecular framework underlying mitochondrial function.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = -$2 )
2026	2024	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	524 W 59TH ST	NEW YORK	NY	10019	NEW YORK	USA	Biomedical Research and Research Training	000	4	3/31/2026	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$2

Issue Date FY: 2024 ( Subtotal = $121,637 )
2024	2024	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	524 W 59TH ST	NEW YORK	NY	10019	NEW YORK	USA	Biomedical Research and Research Training	000	4	8/16/2024	NON-COMPETING CONTINUATION	$121,637
														Subtotal = $121,637

Issue Date FY: 2023 ( Subtotal = $121,784 )
2023	2023	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	524 W 59TH ST	NEW YORK	NY	10019	NEW YORK	USA	Biomedical Research and Research Training	000	3	8/30/2023	NON-COMPETING CONTINUATION	$121,784
														Subtotal = $121,784

Issue Date FY: 2022 ( Subtotal = $120,421 )
2022	2022	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	524 W 59TH ST	NEW YORK	NY	10019	NEW YORK	USA	Biomedical Research and Research Training	000	2	8/1/2022	NON-COMPETING CONTINUATION	$120,421
														Subtotal = $120,421

Issue Date FY: 2021 ( Subtotal = $119,098 )
2021	2021	RESEARCH FOUNDATION OF THE CITY UNIVERSITY OF NEW YORK	524 W 59TH ST	NEW YORK	NY	10019	NEW YORK	USA	Biomedical Research and Research Training	000	1	9/16/2021	NEW	$119,098
														Subtotal = $119,098

Grand Total All Awards = $482,938

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Control of Mitochondrial Function by SPFH Proteins in Pathogenic Yeast

Award Number: SC3GM135016

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/16/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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