UCLA

Mitochondrial architecture has long been associated with metabolic flexibility, although the precise causalities and the underlying mechanisms are still enigmatic. We showed that mitochondrial fragmentation is highly associated with fatty acid oxidation (FAO) rates. Furthermore, forced mitochondrial elongation using Mfn2 over-expression or Drp1 depletion significantly decreased FAO rates, while Mfn2 knockout lead to enhanced FAO rates, suggesting that mitochondrial fragmentation is functionally coupled with fatty acid utilization. Notably, the increased FAO rates upon mitochondrial fragmentation is attributed to decreased CPT1 sensitivity to malonyl-CoA, the endogenous CPT1 inhibitor, consistent with the observation that mitochondrial fragmentation specifically facilitates long chain-fatty acid oxidation (LCFAO), but not short chain fatty acid oxidation. Furthermore, we show pharmacological activators of CPT1 enhance FAO of elongate dmitochondria but not in the presence of malonyl-CoA binding. Suggesting mitochondrial morphology influences CPT1’s binding to a CoA moiety. Taken together, our study provides a biochemical and mechanistic explanation of how mitochondrial architecture links cellular metabolic needs to differential fuel utilization, such as LCFAO, which may be implicated in a myriad of human physiologies and pathologies. In non-alcoholic steatohepatitis (NASH), increased Drp1 mediated mitochondrial fragmentation has been observed in hepatocytes. NASH is characterized by liver inflammation, increased hepatocyte swelling, and some degree of fibrosis. Hepatic steatosis can occur when glucose and fatty acid availability exceeds the energy demand of the liver. This presents the question, is increased fission in NASH a compensatory or a pathogenic mechanism? To address this question, we decreased Drp1 function in liver from adult mice with established NASH (26 week-GAN diet) using GalNAc-siRNA mediated delivery. While NASH alone only elevated circulating AST and ALT levels, markers of hepatic injury, Drp1KD in the NASH liver engaged the mitochondrial integrated stress response (ISR) by OMA1 activation and ER stress. The fibrosis and hepatocyte necrosis observed only in Drp1KD of NASH mice can be explained by reduced metabolic adaptability as a result of inhibiting fission-mediated fragmentation, reducing FAO capacity, and enhancing accumulation of NEFA. Overall, our data suggests Drp1-mediated mitochondrial fragmentation is an adaptive mechanism in NASH that prevents lipotoxicity, overactivation of the integrated stress response, and ER stress to limit fibrosis, inflammation, and necrosis.