Mitochondrial fatty acid synthesis is essential for coordinated energy transformation

Abstract Mitochondria warrant cellular energy demands by generating energy equivalents in central carbon metabolism. They are also able to newly synthesize fatty acids via mitochondrial fatty acid synthesis (mtFAS), however, the role of mtFAS for systemic metabolism has been poorly investigated. Here we show that mitochondrial Trans-2-Enoyl-CoA Reductase (MECR), a key enzyme of mtFAS, critically regulates cellular and systemic glucose and lipid homeostasis. In mice, liver or adipose tissue-specific deletion of Mecr reduces the capacity for aerobic glycolytic catabolism and lipogenesis and causes severe mitochondrial as well as fatal parenchymal organ dysfunction. Mechanistically, mtFAS is essential for pyruvate dehydrogenase activity, resulting in low NAD(P)H synthesis and reduced non-mitochondrial lipogenesis. In different human mitochondriopathies we further identify a dysregulation of mtFAS-associated lipid species, thus linking inherited mitochondrial disease to mtFAS. In summary, we introduce mtFAS as an important player in metabolic health via facilitating cellular glycolysis-derived metabolite transformation ultimately linking mtFAS to mitochondrial function and diseases.