Tissue-Specific Modulation of mtDNA Mutations: Exploring Aging and Lifestyle Interventions - SUMMARY Mitochondrial dysfunction (MD) resulting from mtDNA mutations has been implicated in a broad spectrum of human pathologies, including mitochondrial diseases, neurodegenerative disorders, metabolic syndromes, cancer and cardiovascular diseases. In addition, mtDNA mutations by contributing to mitochondrial dysfunction, oxidative stress, and cellular senescence are suspected to play a significant role in aging processes and age- related diseases. Differently from the nuclear genome, which is present as a single copy per cell, many mtDNA molecules (1000-10000 copies) co-exist in the same cell depending on the tissue and the energetic status of the cell. This can generate a phenomenon known as heteroplasmy, which describes the scenario when two or more mtDNA variants coexist within the same cell. New mutations represent a very low percentage of the total number of mtDNA molecules and are relatively harmless until they clonally expand and reach a critical threshold level that results in mitochondrial dysfunction compromising cellular homeostasis. mtDNA mutations and deletions can either be inherited through the maternal lineage (germline mutations) or sporadically occur in cells during or after development (somatic mutations). In both scenarios, their fate can differ depending on the tissue, with some losing the mutations and others retaining and expanding them to levels that cause MD and result in a disease state. However, the overall mechanisms that regulate cellular mtDNA mutations heteroplasmy have not been elucidated yet. This research proposal will investigate mtDNA regulation across several tissues. Using new genetic approaches and a mouse model that accumulates mtDNA mutations in a spatial and temporal controlled manner, this study aims to understand the mechanisms by which different tissues accumulate and clear mtDNA mutations, the effects of exercise and calorie restriction on these processes, and the impact of the timing of mutation-onset on aging. The proposal outlines three specific aims: (1) basal tissue-specific clearance of mtDNA mutations and its response to lifestyle interventions, (2) basal tissue-specific accumulation of mtDNA mutations and its response to lifestyle interventions, and (3) determining the effects of post-embryonic somatic mtDNA mutations on aging phenotypes. By addressing these aims, this research seeks to uncover the regulation of mtDNA mutations and develop targeted interventions to mitigate age-related diseases and enhance overall healthspan.
