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
Further reading
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- Biochemistry and Chemical Biology
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
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- Biochemistry and Chemical Biology
- Microbiology and Infectious Disease
Teichoic acids (TA) are linear phospho-saccharidic polymers and important constituents of the cell envelope of Gram-positive bacteria, either bound to the peptidoglycan as wall teichoic acids (WTA) or to the membrane as lipoteichoic acids (LTA). The composition of TA varies greatly but the presence of both WTA and LTA is highly conserved, hinting at an underlying fundamental function that is distinct from their specific roles in diverse organisms. We report the observation of a periplasmic space in Streptococcus pneumoniae by cryo-electron microscopy of vitreous sections. The thickness and appearance of this region change upon deletion of genes involved in the attachment of TA, supporting their role in the maintenance of a periplasmic space in Gram-positive bacteria as a possible universal function. Consequences of these mutations were further examined by super-resolved microscopy, following metabolic labeling and fluorophore coupling by click chemistry. This novel labeling method also enabled in-gel analysis of cell fractions. With this approach, we were able to titrate the actual amount of TA per cell and to determine the ratio of WTA to LTA. In addition, we followed the change of TA length during growth phases, and discovered that a mutant devoid of LTA accumulates the membrane-bound polymerized TA precursor.
