The novel associations demonstrated in this study provide insight into the genetic basis of complex traits and variation in disease susceptibility. The missense variant in Fh1 is a case in point. A variant in Fh1 is linked to the UPRmt, a protective stress pathway specific to mitochondria, and we confirmed that downregulation of fum-1, the C. elegans homolog of Fh1, activates the UPRmt. Various disturbances have been shown to induce the UPRmt, including treatment with paraquat, a pesticide that strongly induces reactive oxygen species30, activation of mitochondrial biogenesis31, overexpression of aggregation-prone mitochondrial proteins32 and interference with electron transport chain protein expression and assembly1933. Here, we show that a purely metabolic perturbation, such as induced by loss of function of the TCA cycle component, fumarate hydratase, can activate the UPRmt. While we have detected a single missense variant in Fh1, the molecular cascade that links Fh1 to other TCA cycle genes (that is, Dlst, Sdha and Sdhb) and a UPRmt proteostasis regulatory loop requires additional analysis.
