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

The following data sets were generated

Article and author information

Author details

  1. Sara M Nowinski

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  2. Ashley Solmonson

    Children's Research Institute, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8863-4558
  3. Scott F Rusin

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  4. J Alan Maschek

    Nutrition and Integrative Physiology, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  5. Claire L Bensard

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  6. Sarah Fogarty

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  7. Mi-Young Jeong

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  8. Sandra Lettlova

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  9. Jordan A Berg

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  10. Jeffrey T Morgan

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  11. Yeyun Ouyang

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  12. Bradley C Naylor

    Metabolomics, Proteomics, and Mass Spectrometry Core, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  13. Joao A Paulo

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  14. Katsuhiko Funai

    Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  15. James E Cox

    Biochemistry, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
  16. Steven P Gygi

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  17. Dennis R Winge

    Department of Medicine, University of Utah, Salt Lake City, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1160-1189
  18. Ralph J DeBerardinis

    Children's Research Institute, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    Ralph J DeBerardinis, Reviewing editor, eLife.
  19. Jared Rutter

    Biochemistry, University of Utah, Salt Lake City, United States
    For correspondence
    rutter@biochem.utah.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2710-9765

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.

Reviewing Editor

  1. Peter Tontonoz, University of California, Los Angeles, United States

Version history

  1. Received: April 20, 2020
  2. Accepted: August 15, 2020
  3. Accepted Manuscript published: August 17, 2020 (version 1)
  4. Version of Record published: September 3, 2020 (version 2)

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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  1. Sara M Nowinski
  2. Ashley Solmonson
  3. Scott F Rusin
  4. J Alan Maschek
  5. Claire L Bensard
  6. Sarah Fogarty
  7. Mi-Young Jeong
  8. Sandra Lettlova
  9. Jordan A Berg
  10. Jeffrey T Morgan
  11. Yeyun Ouyang
  12. Bradley C Naylor
  13. Joao A Paulo
  14. Katsuhiko Funai
  15. James E Cox
  16. Steven P Gygi
  17. Dennis R Winge
  18. Ralph J DeBerardinis
  19. Jared Rutter
(2020)
Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria
eLife 9:e58041.
https://doi.org/10.7554/eLife.58041

Share this article

https://doi.org/10.7554/eLife.58041

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