Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Sara M. Nowinski, Ashley Solmonson, Scott F. Rusin, J. Alan Maschek, Claire L. Bensard, Sarah Fogarty, Mi Young Jeong, Sandra Lettlova, Jordan A. Berg, Jeffrey T. Morgan, Yeyun Ouyang, Bradley C. Naylor, Joao A. Paulo, Katsuhiko Funai, James E. Cox, Steven P. Gygi, Dennis R. Winge, Ralph J. Deberardinis, Jared Rutter

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Article numbere58041
Pages (from-to)1-35
Number of pages35
JournaleLife
Volume9
DOIs
StatePublished - Aug 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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