Hepatic mitochondrial respiration is crucial for euthermia in complex III-deficient mice with impaired brown adipose tissue thermogenesis

Liver is the key hub of systemic energy metabolism and growth regulation, yet its roles in mitochondrial disease pathophysiology remain relatively understudied. Bcs1l ^p.S78G knock-in mice, carrying a patient mutation causing respiratory complex III (CIII)-deficiency, present juvenile-onset liver and kidney disease, growth restriction, lipodystrophy, and early death. We restored CIII function in the hepatocytes of these mice using recombinant adeno-associated viral vectors (rAAVs) expressing wild-type Bcs1l . A single intraperitoneal injection of rAAVs into presymptomatic juvenile mice prevented liver disease, improved hypoglycemia and growth, normalized hepatic fuel utilization, and doubled the survival. The mutant mice showed hypothermia and brown adipose tissue (BAT) inflammation, and lacked BAT activation basally and upon acute cold challenge. Disrupted foot pad innervation suggested sensory neuropathy and impaired thermosensation as a contributor to the BAT inactivity. Surprisingly, the rAAV-treated mice maintained near-normal body temperature without significant effect on BAT. Increasing cellular respiration via transgenic alternative oxidase (AOX) was sufficient to prevent the hypothermia. The CIII-deficient mice did not reach euthermia until at an ambient temperature of 35°C, housing at which relieved metabolic stress and ameliorated hepatocyte senescence. We conclude that mitochondrial respiration in hepatocytes is essential for euthermia in mice. Our findings highlight the crucial role of the liver in thermoregulation, hypothermia as a consequence of mitochondrial dysfunction, and the therapeutic potential of rAAV-based gene delivery in a preclinical model of a multiorgan mitochondrial disease.