Metabolic plasticity and neuronal resilience: unraveling adaptive responses to chronic mtdna damage

The National Institute of Neurological Disorders and Stroke awarded the University of California, San Diego $129,186 on July 15, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to investigate metabolic plasticity and neuronal resilience in response to chronic mitochondrial DNA damage.

The research will characterize mitochondrial DNA distribution and motility in healthy versus mitochondrial DNA-compromised neurons using two complementary models to systematically modify mitochondrial DNA in mature neurons: expression of a dominant-negative mutant of polymerase gamma and Cre-loxP mediated deletion of TFAM in neurons. The project will investigate molecular pathways contributing to neuronal decline, define how accumulating mitochondrial DNA mutations impact neuronal metabolism, and identify compensatory responses. The work aims to uncover subcellular mechanisms linking mitochondrial DNA integrity to neuronal health and reveal molecular targets for preventing or reversing neurodegeneration.

Performance occurs at UC San Diego's La Jolla, California campus. The period of performance extends from July 15, 2026, through January 31, 2028. This is a project grant, an assistance type supporting extramural research in neuroscience and neurological disorders.

Abstract

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.