Human cells contain hundreds of mitochondria, each housing multiple DNA molecules that encode essential components of oxidative phosphorylation (OXPHOS). While OXPHOS plays a critical role in providing cellular energy in the form of ATP, it generates reactive oxygen species (ROS) that can potentially damage mitochondrial DNA (mtDNA). Mutations in mtDNA can lead to mitochondrial disorders characterized by a wide range of clinical manifestations and have been associated with various conditions, including cancer, premature aging, cardiovascular disorders, skeletal muscle issues, and neurological disorders.
To counteract damage from ROS, mitochondria developed a robust DNA repair mechanism known as the DNA base excision repair (BER) pathway which serves as a primary defense mechanism against oxidative damage in human mitochondria. Strategically positioned in vicinity of the inner mitochondrial membrane, essential BER enzymes including EXOG, APE1, PolγAB, and Lig3 collaborate to create a large molecular complex known as the 'mitochondrial repairosome' which is capable of carrying out complete DNA repair.
The goal of this research project is to study the structure, mechanism and function of human mitochondrial repairosome. We will utilize a combination of structural biology (x-ray crystallography and electron microscopy), biochemistry and biophysics and cell biology by investigating the following aims:
Aim 1: Reconstitute a scaffold of mitochondrial repairosome on the membrane
Aim 2: Investigate functional synergy between components of mitochondrial repairosome
Aim 3: Investigate the structures of mitochondrial repairosome
