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

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. Project Number: 1F31NS147610-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Natasha Carlson | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $43,446 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F03A-L (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11313526