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.