Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolism

Cells harbor two systems for the synthesis of fatty acids, one in the cytoplasm (FASN or fatty acid synthase) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, with the major product(s), metabolic roles, and cellular function(s) essentially unknown. Here we show that hypomorphic mtFAS mutants display a profound loss of electron transport chain (ETC) complexes and exhibit compensatory reductive carboxylation. This effect on ETC complexes is independent of the synthesis of lipoic acid, the best characterized function of mtFAS, as mutants lacking lipoic acid synthesis have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. These data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels. Overall design: 44 total samples from C2C12 immortalized mouse skeletal myoblasts (ATCC CRL-1772). Samples include GFP (control), Mcat, Oxsm, and Mecr mutant cell lines grown and harvested at days -1, 0, and 1 of a muscle differentiation time course. Three or four biological replicates of each line at each day are included.