Mitochondrial fatty acid synthesis is essential for coordinated energy transformation

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement C.S. was supported by the Werner-Otto-foundation, by the DFG (SCHL2276/2-1), the Muehlbauer foundation and by the University Medical Center Hamburg Eppendorf medical faculty (TDM-21/06). A.W. is supported by the University Medical Center Hamburg Eppendorf medical faculty (TDM-21/06; NWF-20/07) and the Muehlbauer-foundation. F.H. is supported by the Werner- Otto-foundation. J.H. (P05), K.A.D. (S02), C.S. (P15), L.B. (P07) and A.W. (P07) are supported by a grant funded by the DFG (450149205-TRR333/1). A.B. is supported by the Deutsche Forschungsgemeinschaft Sonderforschungsbereich 1123 (B10), the Deutsches Zentrum fuer Herz-Kreislauf-Forschung Junior Research Group Grant, the European Research Council Starting Grant PROTEOFIT, and the DFG Priority Programme on ferroptosis SPP2306. In addition, A.W.,L.B. J.H., L.S. and H.S. are supported by the State of Hamburg (LFF-FV75). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Medical Association Hamburg gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.