Mitochondrial electron transport chain (ETC) dysfunction is a common cause of metabolic disease in humans, but the mechanisms underlying tissue specific phenotypes are not understood. Complex I (cI) is classically considered the entry point for electrons into the ETC, and in vitro experiments indicate that cI is required for maintenance of the NAD+/NADH ratio, an indicator of cellular redox status. This finding has largely not been tested in vivo. Here, we report that mitochondrial complex I (cI) is dispensable for homeostasis of the adult mouse liver; animals with hepatocyte-specific loss of cI function display no overt phenotypes or signs of liver damage, and maintain liver function and redox status. Further analysis of cI-deficient livers did not reveal significant proteomic or metabolic changes, indicating little to no compensation is required in the setting of complex I loss. In contrast, complex IV (cIV) dysfunction in adult hepatocytes results in decreased liver function, steatosis, and liver damage, accompanied by significant metabolomic and proteomic perturbations. Correspondingly, we find that complex I-deficient livers are reliant on an alternative pathway, whereby electrons are donated to the ETC via dihydroorotate dehydrogenase, to maintain redox status. Our results support a model whereby complex I loss is tolerated in the mouse liver because hepatocytes make use of alternative electron donors to fuel the mitochondrial ETC.
Chromophore-Assisted Light Inactivation of Mitochondrial Electron Transport Chain Complex II in Caenorhabditis elegans