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The Role of Mitophagy and Mitochondrial Biogenesis in Mitochondria Transplant Therapy for Leigh Syndrome

Award Number: F30AI203655
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 02/18/2027
PERIOD OF PERFORMANCE END DATE: 02/17/2028

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The Role of Mitophagy and Mitochondrial Biogenesis in Mitochondria Transplant Therapy for Leigh Syndrome - PROJECT SUMMARY/ABSTRACT: Leigh Syndrome (LS) is an inherited mitochondrial disease that presents with prominent neurologic symptoms and typically death in childhood. There are currently no effective therapies, highlighting an urgent need to identify novel biological pathways that can be targeted to treat LS and other inherited mitochondrial diseases. Our recent studies demonstrated that transplantation of functional mitochondria to Ndufs4–/– mice, which recapitulate all major features of LS, rescues aerobic respiration in peritoneal macrophages, significantly improves neurologic dysfunction, and extends lifespan. This strongly supports the therapeutic potential of mitochondria transplantation for LS, although the mechanisms by which mitochondria transplantation mediates these benefits are unknown. Emerging studies in other model systems indicate that mitochondria transplantation significantly impacts multiple cellular processes including the degradation of damaged mitochondria (mitophagy), the generation of new mitochondria (mitochondrial biogenesis), and the inflammatory state of recipient cells. Mitochondria transplantation has been shown to induce mitophagy and mitochondrial biogenesis in healthy recipient cells but reduce mitophagy in recipient cells with significantly damaged endogenous mitochondria. Mitochondria transplantation also restricts pro-inflammatory gene expression and cytokine secretion in multiple models. The goal of this study is to understand the mechanisms by which mitochondria transplantation rescues cell-intrinsic metabolic defects, improves neurologic function, and extends lifespan in LS. We hypothesize that mitochondria transplantation regulates mitophagy, mitochondrial biogenesis, and recipient cell inflammatory state in order to stimulate these benefits. In Aim 1, I will investigate how mitochondria transplantation impacts mitophagy of endogenous mitochondria and whether mitophagy is necessary to confer therapeutic benefit. In Aim 2, I will determine how mitochondria transplantation alters mitochondrial biogenesis and the inflammatory state of macrophages, a key mitochondria recipient cell in Ndufs4–/– mice. By elucidating the mechanisms through which mitochondria transplantation is beneficial in LS, our study will directly facilitate translation of mitochondria transplantation from preclinical models to humans and support compassionate use clinical trials of this therapeutic approach in LS patients. As an MD/PhD student, my career goal is to become a physician-scientist leading a research lab in immunometabolism. Completion of this project will equip me with rigorous training at the intersection of immunology, mitochondrial biology, and immunometabolic diseases, fields that often converge in endocrine and rheumatologic clinical presentations. My robust training plan at Washington University in St. Louis, one of the nation's leading MD/PhD programs, integrates strong mentorship, rigorous coursework, independent study, and participation in research forums spanning local to international communities. This environment is uniquely suited to support the successful execution of my research proposal and to position me for long-term success in achieving my career goals.


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 = $37,312 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Allergy and Infectious Diseases Research	000	1	8/17/2026	NEW	$37,312
														Subtotal = $37,312

Grand Total All Awards = $37,312

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The Role of Mitophagy and Mitochondrial Biogenesis in Mitochondria Transplant Therapy for Leigh Syndrome

Award Number: F30AI203655

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 02/18/2027

PERIOD OF PERFORMANCE END DATE: 02/17/2028

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