Systems analysis of mitochondrial genome maintenance in physiological context

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Project Summary (No Change from Parent Award) Mitochondrial DNA (mtDNA) encodes RNAs and proteins critical for cell function. However, the pathways that regulate mtDNA synthesis and segregation in animal cells are not well understood. The goals of this work are to identify the protein components of mitochondrial DNA nucleoid complexes, to investigate how mitochondrial replication and dynamics are coordinated to homeostatically maintain mtDNA nucleoid segregation and abundance, and to probe the mechanisms underlying selection against mutant mtDNAs in somatic cells. These experiments will provide fundamental insights into the maintenance of the essential mitochondrial chromosome in animal cells and how maintenance processes are regulated, potentially leading to the discovery and characterization of novel pathways that regulate the inheritance of mtDNA disease alleles. We will employ cutting-edge microscopy of living cells and whole animals, proteomics, and single cell transcriptional analyses to interrogate the molecular functions of candidate proteins implicated in the maintenance of mtDNA integrity. These experiments will reconcile inconsistencies in the mitochondrial biology literature, provide fundamental insight into the mechanisms of mtDNA copy number control, and identify novel pathways that regulate the tissue-specific manifestations of mitochondrial dysfunction.