Mitochondrial gene expression in health and disease

Mammalian mitochondria produce a small subset of proteins that are important components of the oxidative phosphorylation machinery, therefore their function is of fundamental importance to cellular metabolism.

Dysregulation of mitochondrial gene expression is increasingly recognized as a contributor to metabolic and neurodegenerative diseases, aging and cancer.

Several key proteins involved in this process have been directly associated with a range of human pathologies, but a detailed survey and investigation of factors involved in mitochondrial translation have not yet been performed.

The objective of this project is to describe the molecular mechanisms involved in human mitochondrial RNA metabolism and translation, as a means to identify pathways and factors relevant to disease.

I plan to employ advanced proteomics, high-resolution cryo-EM and single-molecule analysis to identify and characterize factors involved in mitochondrial gene expression and to reveal the native conformations of mitochondrial ribosomes at different translational stages and during translation inhibition by antibiotics.

This multidisciplinary study will yield valuable insights into how mitochondrial protein synthesis is regulated, how and why errors occur, and how this impinges upon cellular function and disease.

Identification of novel genes and pathways involved in this fundamental process will ultimately lead to advanced pre-clinical diagnostics and open new avenues for therapy.