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Regulation of Mitochondrial Lipid Homeostasis by mTORC1

Award Number: F30DK145140
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/15/2025
PERIOD OF PERFORMANCE END DATE: 09/14/2029

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Regulation of Mitochondrial Lipid Homeostasis by mTORC1 - Project Summary/Abstract Mechanistic target of rapamycin complex 1 (mTORC1) is a major cytosolic regulator of cellular anabolism and governs many downstream metabolic processes. Mitochondria are semi-autonomous organelles that are major hubs of compartmentalized biochemical reactions within cells. While the role of mTORC1 in coordinating metabolic balance in the cytosol are consistent with its ability to sense and respond to perturbations in the cellular nutrient state, the effect of mTORC1 on mitochondria remain poorly defined. To identify how mitochondria are impacted by loss of mTORC1 signaling, I performed quantitative proteomic analysis on immunopurified mitochondria from cells treated with mTORC1 inhibitors and identified several proteins involved in mitochondrial lipid homeostasis. We identified PRELI Domain Containing 1 (PRELID1) as an essential, short-lived mitochondrial protein that is downregulated upon mTOR inhibition. While mTORC1 is active in the cytosol, it remains unclear how the stability of PRELID1 in mitochondria is affected. In my preliminary work, I identified that inhibition of proteasome function protects PRELID1 against degradation induced by mTOR inhibition. To identify the genes responsible for this phenomenon, I developed a CRISPR/Cas9 genetic screening approach to individually knock out components of the Ubiquitin-Proteasome system (UPS) and interrogate how mTOR status in the cytosol maintains stability of PRELID1. The top-scoring gene in my preliminary genetic screen was Seven in Absentia Homolog 1 (SIAH1), an E3 Ubiquitin ligase with previously reported mitochondrial targets. I hypothesize that mTORC1 regulates mitochondrial lipid homeostasis, in part, through the action of SIAH1 and that this axis may be a suitable drug target in metabolic diseases such as nonalcoholic fatty liver disease (NAFLD). A lack of insight into the mechanistic role of mTORC1 in regulating mitochondrial function precludes investigation of this hypothesis. In this proposal, building on my preliminary work, I will test the hypothesis that mTORC1 regulates mitochondrial function by regulating the lipid composition of mitochondria. In Aim 1, I will investigate the mechanism by which mTORC1 regulates mitochondrial lipid homeostasis. In Aim 2, I will determine how mTORC1 orchestrates mitochondrial lipid homeostasis in mouse liver models and the role cardiolipin plays in the pathogenesis of NAFLD. I anticipate that these studies will determine: 1) the mechanistic role of SIAH1 in shaping mitochondrial function under metabolic stress and 2) the contribution of mitochondrial dysfunction to the development and progression of NAFLD. The work and training plan outlined in this proposal will be completed in the laboratory of Dr. Kivanc Birsoy at the Rockefeller University and will best prepare me for a career as an independent academic physician-scientist.


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 = $55,114 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/27/2026	NON-COMPETING CONTINUATION	$55,114
														Subtotal = $55,114

Issue Date FY: 2025 ( Subtotal = $54,538 )
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/12/2025	NEW	$54,538
2025	2025	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	9/12/2025	NEW	$0
														Subtotal = $54,538

Grand Total All Awards = $109,652

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Regulation of Mitochondrial Lipid Homeostasis by mTORC1

Award Number: F30DK145140

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/15/2025

PERIOD OF PERFORMANCE END DATE: 09/14/2029

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