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Metabolic Plasticity and Neuronal Resilience: Unraveling Adaptive Responses to Chronic mtDNA Damage

Award Number: F31NS147610
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Metabolic Plasticity and Neuronal Resilience: Unraveling Adaptive Responses to Chronic mtDNA Damage - Project Summary Neurons are highly polarized cells with exceptionally high energy demands, met primarily by mitochondrial oxidative metabolism, which generates ~90% of neuronal ATP. Therefore, mitochondrial dysfunction resulting from impaired mitochondrial (mt)DNA maintenance has been consistently linked to age-related neurodegenerative disorders. However, the molecular cascade through which chronic mtDNA damage alters neuronal function during aging, especially under conditions of intense synaptic activity, remains poorly understood. Heteroplasmy of pathogenic mtDNA variants has been associated with disruptions in electron transport chain function, tricarboxylic acid cycle metabolites, and mitochondrial dynamics. Yet, the mechanisms by which mtDNA deficits reshape neuronal metabolism are still unclear. Given the essential role of mtDNA in encoding mitochondrial proteins required for energy homeostasis, we hypothesize that chronic mtDNA depletion and damage disrupt neuronal metabolism and contribute to age-dependent neuronal dysfunction. To test our hypothesis, we will use two complementary models to systematically modify mtDNA in mature neurons: (1) expression of a dominant-negative mutant of Polymerase Gamma, and (2) Cre-loxP mediated deletion of Tfam in neurons. In Aim 1, we will characterize mtDNA distribution and motility in healthy versus mtDNA-compromised neurons and investigate the molecular pathways that contribute to neuronal decline. Aim 2 will define how accumulating mtDNA mutations impact neuronal metabolism and identify compensatory responses. This work will uncover subcellular mechanisms linking mtDNA integrity to neuronal health and reveal molecular targets for preventing or reversing neurodegeneration.


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 = $43,446 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	4/22/2026	NEW	$576
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	1/21/2026	NEW	$0
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/21/2026	NEW	$42,870
														Subtotal = $43,446

Grand Total All Awards = $43,446

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Metabolic Plasticity and Neuronal Resilience: Unraveling Adaptive Responses to Chronic mtDNA Damage

Award Number: F31NS147610

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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