Many neurodegenerative diseases have a devastating impact on the quality of life for patients and constitute a significant burden for families and the healthcare system. Although a large and diverse group of diseases, symptoms can include memory loss, cognitive impairment and a decline in motor control. Currently there are limited treatment options and in many cases there is only a rudimentary understanding of the primary cause of these diseases and the molecular events that lead to disease.
It is very apparent that mitochondrial dysfunction is associated with a significant number of neurodegenerative diseases. Many genes mutated in patients with a neurological disease are required for mitochondrial biogenesis, function or maintenance. Research in our laboratory aims to understand, at a molecular level, the function of mitochondrial proteins involved in the biogenesis and maintenance of mitochondria. It is anticipated that new knowledge in this area will aid in the development of effective ways to treat neurodegenerative diseases.
Research areas
Biogenesis and proteostasis of mitochondrial complex II
This research aims to determine the interplay between molecular components of the mitochondrial proteostasis (mitostasis) network and subunits of mitochondrial respiratory complex II in the biogenesis of complex II. Complex II, also known as succinate dehydrogenase (SDH), is a key respiratory enzyme that participates in both the tricarboxylic acid cycle and the electron transport chain. It is a relatively simple respiratory enzyme as it is composed of only four protein subunits (SDHA, SDHB, SDHC and SDHD). In eukaryotes, the ~ 140 kDa complex is located in the mitochondrion and is composed of a single copy of each subunit and several cofactors. The four subunits, all of which are nuclear-encoded, couple the oxidation of succinate to fumarate with electron transfer, resulting in the reduction of the electron carrier ubiquinone to ubiquinol.
Disruptions to this pathway arising from inherited mutations cause tumour syndromes including hereditary paraganglioma-pheochromocytomas (PGL-PCC), gastrointestinal stroma tumours and renal cell carcinomas. Disease causing mutations have been reported in all four genes coding for complex II subunits although mutations in SDHA are more commonly associated with the neurodegenerative disorder Leigh syndrome. Specifically, this study examines the molecular mechanism of complex II assembly mediated by assembly factors and the interplay with proteases of the AAA+ superfamily.
Mitochondrial protein processing and degradation by proteases
This research examines the contribution of the mitochondrial protein quality control machinery, particularly proteases to the biogenesis and clearance of normal and mutant mitochondrial proteins. It is anticipated that a thorough understanding of the kinetic partitioning of proteins (both normal and mutant) between their normal functional partners, chaperones and proteases will help in the successful development of small molecules for therapeutic intervention of some mitochondrial diseases.
