Overview: Defects in mitochondrial gene expression cause a multitude of inherited human diseases and contribute significantly to age-related pathologies, like neurodegenerative disorders and cancer. Study of the basic biochemical mechanisms governing mitochondrial DNA transcription and genome stability will allow for a deeper understanding of these diseases, for which there are few effective treatments.
Mitochondria exist at the center of cellular biosynthetic pathways and play a major role in energy production, apoptosis and oxidative stress. Mitochondria contain a DNA genome (mtDNA) encoding thirteen essential components of oxidative phosphorylation (OXPHOS), the metabolic pathway generating cellular energy currency in the form of ATP. The remaining 1500 member mitochondrial proteome is encoded by the nuclear genome, including an additional 70 OXPHOS components and the machinery required for mtDNA replication, transcription, and translation. Therefore, coordination of nuclear and mitochondrial gene expression is essential for mitochondrial function. While core components of mitochondrial transcription initiation are known, a detailed understanding of transcriptional control is lacking. The goal of the research is to uncover biochemical mechanisms that govern mitochondrial gene expression and mtDNA stability.
Specific project details: Regulation of mtDNA transcription by reversible protein post-translational modifications.
Protein post-translational modifications (PTMs), including reversible lysine acetylation and serine/threonine phosphorylation, can regulate protein function. Dynamic PTM of histone proteins and nuclear transcription factors control nuclear gene expression; however whether similar mechanisms exist in the mitochondria is unknown. My work and others has revealed proteins involved in mtDNA gene expression are subject to PTM. This project will determine the role of PTMs in regulating mtDNA transcription and mtDNA stability.
Students involved in this project will integrate chemical and biological course knowledge to carry out experiments and will learn lab techniques including: protein purification, enzyme assays, cell culture, western blotting, and genetic approaches.