Critical role of mitochondrial biogenesis in cancer cells
Supervisors:
Prof Konstantinos Tokatlidis, School of Molecular Biosciences
Prof Stephen Tait, School of Cancer Sciences
Summary:
Mitochondria are crucial for eucaryotic cells as they control energy metabolism, cell homeostasis and cell death. Mitochondria dysfunction is consequently tightly linked to several human pathologies including neurodegeneration and cancer, whilst mitochondria damage and decline is a hallmark of ageing. Pancreatic cancer will be the second deadliest cancer by 2030, whilst treatment efficacy is severely limited by increased chemoresistance. Intriguingly, such therapy-resistant cancer cells rely on mitochondria, whose biogenesis strictly depends on import of proteins from the cytosol as 99% of mitochondrial proteins are nuclear-encoded
(about 1300 proteins) These mitochondrial biogenesis mechanisms are therefore absolutely vital for cell homeostasis represent a central area of fundamental research for all eukaryotic cells. Keeping a healthy balance between biogenesis and selective clearance of damaged mitochondria requires precise coordination of the protein import process with that of quality control and mitophagy of damaged mitochondria that need to be cleared by the cell. This represents a unique vulnerability that can be exploited in future therapies to eradicate cancer cells by targeting specifically the mitochondria in such cells. However, fundamental knowledge on the mitochondria biogenesis in pancreatic cancers is extremely limited. In this project we will address this unresolved and critical question. We will use a combination of innovative techniques including small molecule inhibitors for specific import pathways, mitochondria analysis using omics, high resolution imaging, cell death assays and reconstituted assays. This interdisciplinary work will be hosted by the groups of Prof Tokatlidis and Prof Tait, two leading expert groups in the fields of mitochondrial biology and cancer biology.