The role of ubiquitin ligases in mitochondrial damage responses and inflammation

• PhD

Mitochondrial dysfunction and inefficient mitochondrial damage control are implicated in neurodegenerative diseases including Parkinson’s Disease (PD). Literature reports and our own preliminary work suggest that one type of mitochondrial damage, mitochondrial outer membrane permeabilisation (MOMP), induces wide-spread and complex ubiquitin signals on mitochondrial proteins by unknown ubiquitin ligases. This project aims to identify and characterise these ubiquitin ligases involved and unravel how they dictate cellular responses to mitochondrial damage.

Students will utilise diverse techniques covering cell biology, including CRISPR/Cas9 genetic screens, assays of cell death and inflammatory signalling and fluorescence microscopy, and in vitro protein biochemistry and structural biology (X-ray crystallography or cryo-EM) to investigate the role of ubiquitin ligases in regulating inflammatory responses to mitochondrial damage.

Our labs (Lechtenberg, Dewson, Lazarou) combine expertise in mitochondrial biology and ubiquitin ligases. We cover diverse complementary techniques like cell biology, imaging, biochemistry and structural biology.

Mitochondria are the powerhouses of cells. Maintaining the integrity and function of mitochondria is essential for cells to survive and to grow. Mitochondria are also central to the process of cell death termed apoptosis. Defective function and integrity of mitochondria can lead to many diseases including Parkinson’s disease and cancer.

Ubiquitin ligases are molecular label makers that attach the protein ubiquitin to other proteins to induce protein degradation or regulate protein activity, subcellular localisation or interactions. Ubiquitination provides a complex signalling code and regulates almost all processes inside the human cell and is a central player in human physiology and disease.