We plan to identify genetic determinants of the mitochondrial proteome in relation to important complex disease traits in the rat and thereby improve understanding of the pathogenetic role of mitochondria in common clinical disorders.
Mitochondria, the powerhouses of mammalian cells, accommodate a number of key metabolic pathways. Mitochondrial dysfunction is recognised as an important determinant of a variety of human pathologies, ranging from oxidative phosphorylation (OXPHOS) disorders to common complex diseases. The mitochondrial proteome is uniquely encoded by two genomes – nuclear and mitochondrial (mtDNA). While mtDNA encodes only 13 proteins, it is estimated that another ~1,500 nuclear (mitonuclear) genes code for mitochondrial proteins. So far only ~1,100 proteins have clearly ascribed mitochondrial localisation but ~300 of them have no known function and the functions of another ~300 are based only on domain annotations and sequence similarity. Our research is focused to genetically dissect the role of mitochondrial proteins in the pathogenesis of mitochondrial dysfunction and cardiometabolic disorders in the most widely used animal model of hypertension, insulin resistance and dyslipidemia, the spontaneously hypertensive rat (SHR). This will be accomplished by large scale genetic and network analyses of the mitochondrial proteome and the mitonuclear and mtDNA transcriptomes together with mitochondrial function phenotypes (structure and biogenesis of key mitochondrial pathways, including OXPHOS machinery, cellular energetic state and generation of reactive oxygen species) and cardiometabolic traits in recombinant inbred (RI) strains derived from the SHR and the normotensive Brown Norway (BN-Lx) rat. These studies will identify high priority candidate gene variants involved in the regulation of both mitochondrial function and disease related phenotypes. Variants of mitonuclear genes prioritised by the above mentioned analyses will be directly tested by in vivo functional studies.