Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria
- University of Utah, United States
- UT Southwestern Medical Center, United States
- Harvard Medical School, United States
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.
Data availability
The data have been deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al., 2019) partner repository. The code used to process these data is available at Github https://github.com/j-berg/nowinski_2020.Sequencing data have been deposited at the Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo) under accession number GSE148617
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Mitochondrial fatty acid synthesis coordinates mitochondrial oxidative metabolismNCBI Gene Expression Omnibus, GSE148617.
Article and author information
Author details
Funding
National Institute of General Medical Sciences (GM115174)
- Jared Rutter
National Cancer Institute (R35CA22044901)
- Ralph J DeBerardinis
The Once Upon a Time Foundation
- Ralph J DeBerardinis
Eunice Kennedy Shriver National Institute of Child Health and Human Development (F32HD096786)
- Ashley Solmonson
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK107397)
- Katsuhiko Funai
National Institute of Diabetes and Digestive and Kidney Diseases (R21AG063077)
- Katsuhiko Funai
Office of the Director (S10OD016232)
- James E Cox
Office of the Director (S10OD021505)
- James E Cox
National Institute of Diabetes and Digestive and Kidney Diseases (U54DK110858)
- James E Cox
National Institute of General Medical Sciences (R01GM132129)
- Joao A Paulo
National Institute of General Medical Sciences (GM97645)
- Steven P Gygi
National Institute of General Medical Sciences (GM115129)
- Jared Rutter
National Institute of General Medical Sciences (GM110755)
- Dennis R Winge
The Nora Eccles Treadwell Foundation
- Jared Rutter
Howard Hughes Medical Institute (Investigator)
- Jared Rutter
United Mitochondrial Disease Foundation (PF-15-046)
- Sara M Nowinski
American Cancer Society (PF-18-106-01)
- Sara M Nowinski
National Heart, Lung, and Blood Institute (T32HL007576)
- Sara M Nowinski
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK11096601)
- Jordan A Berg
Howard Hughes Medical Institute (Investigator)
- Ralph J DeBerardinis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2020, Nowinski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria
eLife 9:e58041.
https://doi.org/10.7554/eLife.58041
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