Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Abstract

Cells harbor two systems for fatty acid synthesis, one in the cytoplasm (catalyzed by fatty acid synthase, FASN) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, especially in higher eukaryotes, with the major product(s), metabolic roles, and cellular function(s) being essentially unknown. Here we show that hypomorphic mtFAS mutant mouse skeletal myoblast cell lines display a severe loss of electron transport chain (ETC) complexes and exhibit compensatory metabolic activities including reductive carboxylation. This effect on ETC complexes appears to be independent of protein lipoylation, the best characterized function of mtFAS, as mutants lacking lipoylation have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. Together, 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.

The diversity and breadth of cancer cell fatty acid metabolism

“…The synthesis of new long-chain fatty acids from non-lipid substrates is another input to the intracellular free fatty acid pool. We will focus on the cytosolic pathway but acknowledge that mitochondria are capable of synthesizing predominantly short- and medium-chain fatty acids that can act as precursors for lipoic acid synthesis and protein lipoylation [ 72 , 73 ]. The cytosolic synthesis of fatty acids starts with the export of mitochondrial citrate into the cytosol via the mitochondrial tricarboxylate transporter (encoded by SLC25A1) where it is converted into acetyl-CoA by ATP-citrate lyase (encoded by ACLY; Fig.…”

Divergent Acyl Carrier Protein Decouples Mitochondrial Fe-S Cluster Biogenesis from Fatty Acid Synthesis in Malaria Parasites

“…We became interested to unravel what this essential function might be. Recent studies in yeast and human cells have identified an expanding network of mitochondrial ACP interactions beyond FASII that includes roles in respiratory chain assembly, Fe-S cluster biogenesis, and mitochondrial ribosomal translation (19)(20)(21)(22)(23). However, in all cases these critical interactions in yeast and/or humans are linked to mitochondrial FASII function and the Ppant group of ACP (22,(24)(25)(26).…”

Altered Metabolic Flexibility in Inherited Metabolic Diseases of Mitochondrial Fatty Acid Metabolism

“…Lipoic acid is found in all kingdoms of life and is an essential cofactor for several cellular redox reactions [ 49 ]. Several inborn errors of metabolism also characterized by defective lipoylation have been described [ 49 ], such as lipoic acid synthetase (LIAS) [ 93 , 94 ] and lipoyltransferase 1 (LIPT1) deficiencies [ 95 ]. As in most of the identified patients the onset of clinical manifestations appeared later in life [ 50 ], and pre-symptomatic patient management may have contributed to reduce the initial risk of symptoms development [ 52 ], we hypothesize that compensatory mechanisms in mitochondrial energetics may specifically address the required energy need.…”