Functional mechanism of novel mitochondrial protein import chaperones

Mitochondrion is an essential organelle playing a central role in many biological processes, from ATP generation to cell growth and cell death (apoptosis). Not surprisingly therefore, mitochondrial dysfunction leads to life threatening diseases, including diabetes, stroke, Alzheimer’s, and cancer. Protein import is essential for the biogenesis of mitochondria, since the majority of mitochondrial proteins is synthesized in the cytosol on cytosolic ribosomes and thus has to be imported into mitochondria for their function.

Tim9 and Tim10 are members of an evolutionary conserved ‘small Tim’ family, which are located in the mitochondrial intermembrane space. It has been suggested that the Tmi9-Tim10 complex play an essential, chaperone-like role during import of mitochondrial membrane proteins. In the absence of Tim9 and Tim10, many mitochondrial membranes cannot be correctly inserted into mitochondrial membrane, and cells die. The importance of the small Tim proteins is also illustrated by the observation that a single Cys mutation in the human deafness-dystonia peptide 1 (DDP1, a member of small Tim protein family) causes Mohr-Tranebjaerg syndrome. Despite the important function of Tim9 and Tim10, their import and functional mechanisms are not fully understood. This PhD project will elucidate the essential function of these proteins. How some conserved residues affect the mitochondrial import, folding, and function of Tim9 and Tim10 will be studied. A wide range of biological, biochemical, and biophysical methods will be used to address the issues comprehensively. The methods including molecular biology, mitochondrial import analysis, protein purification and characterization using biochemical assays and biophysical techniques. The project will be carried out in a multidisciplinary environment of the Manchester Institute of Biotechnology (MIB).