Mitochondrial DNA Compaction and the Accumulation of Mutations with Age and Stress

PROJECT SUMMARY/ABSTRACT The primary goal of this project is to understand the impact of mitochondrial genome architecture on the accumulation of somatic mitochondrial DNA (mtDNA) mutations, which build up over an individual’s lifetime due to ongoing replication and oxidative stress. Because these mutations can cause or exacerbate cellular aging, this work has implications for the prevention and treatment of age-related degenerative diseases. The study will utilize innovative long-read sequencing approaches to quantify accessibility, mutations, and various types of damage all along individual mtDNA molecules. Mechanistic work in cultured human cells will quantify the role of mtDNA compaction in protection against mutations from various pharmacological, genetic, and environmental stressors as well as define the temporal dynamics of mtDNA architecture at single molecule resolution. Work in vivo will seek to define the consistency of mtDNA form across cell type and age. Together, these approaches will offer a comprehensive understanding of how mtDNA compaction influences mutation rates and mitochondrial health, potentially unveiling new avenues for therapeutic intervention to mitigate aging and related diseases.