Segregation and intracellular distribution of the mammalian mtDNA nucleoid. Faithful inheritance of mitochondrial DNA (mtDNA) is essential for cellular respiration and thus for most eukaryotic life. Both maternally inherited mitochondrial DNA mutations and nuclear mutations that directly affect mtDNA maintenance can cause heritable respiratory chain deficiency and contribute to a diverse spectrum of diseases in humans, including metabolic disease, neurodegeneration and cancer. However, pathways that control mtDNA maintenance and segregation in mammalian cells are not well understood. My long-term goal is to understand the molecular mechanisms underlying the regulation of mammalian mtDNA, and how these contribute to the inheritance of mtDNA alleles that impact human health.
Mitochondrial genome replication. In mammalian cells, the mitochondrial genome (mtDNA) encodes only 13 protein subunits of the respiratory chain and the functional RNAs for their translation. As such, the vast majority of proteins required for mitochondrial function and regulation are encoded in the nucleus, including all components of the mtDNA nucleoid - the protein-DNA structure that is the unit of mtDNA inheritance. Thus, the regulation of mtDNA replication and maintenance must rely on anterograde and retrograde signaling communication between mitochondria and other cellular compartments. A minimal mtDNA replisome has been described, comprised of the polymerase gamma (POLG1/POLG2), helicase (Twinkle) and single-stranded DNA binding protein (MTSSB). However, the mechanisms that determine which of the 100s-1000s of nucleoids in each cell are licensed to replicate and when, i.e. the factors that determine the spatiotemporal regulation of mtDNA maintenance, are not understood. Ultimately, I hope to elucidate the molecular basis of mtDNA replication licensing in human cells, which could open up new strategies for the development of therapeutics for metabolic and neurodegenerative disease.