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

doi:10.7554/ELIFE.58041

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 journal › Article › peer-review

51 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 language	English (US)
Article number	e58041
Pages (from-to)	1-35
Number of pages	35
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/ELIFE.58041
State	Published - Aug 2020

ASJC Scopus subject areas

General Neuroscience
General Biochemistry, Genetics and Molecular Biology
General Immunology and Microbiology

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10.7554/ELIFE.58041

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Nowinski, S. M., Solmonson, A., Rusin, S. F., Maschek, J. A., Bensard, C. L., Fogarty, S., Jeong, M. Y., Lettlova, S., Berg, J. A., Morgan, J. T., Ouyang, Y., Naylor, B. C., Paulo, J. A., Funai, K., Cox, J. E., Gygi, S. P., Winge, D. R., Deberardinis, R. J., & Rutter, J. (2020). Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria. eLife, 9, 1-35. Article e58041. https://doi.org/10.7554/ELIFE.58041

Nowinski, SM, Solmonson, A, Rusin, SF, Maschek, JA, Bensard, CL, Fogarty, S, Jeong, MY, Lettlova, S, Berg, JA, Morgan, JT, Ouyang, Y, Naylor, BC, Paulo, JA, Funai, K, Cox, JE, Gygi, SP, Winge, DR, Deberardinis, RJ & Rutter, J 2020, 'Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria', eLife, vol. 9, e58041, pp. 1-35. https://doi.org/10.7554/ELIFE.58041

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title = "Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria",

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.",

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

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year = "2020",

month = aug,

doi = "10.7554/ELIFE.58041",

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AU - Nowinski, Sara M.

AU - Solmonson, Ashley

AU - Rusin, Scott F.

AU - Maschek, J. Alan

AU - Bensard, Claire L.

AU - Fogarty, Sarah

AU - Jeong, Mi Young

AU - Lettlova, Sandra

AU - Berg, Jordan A.

AU - Morgan, Jeffrey T.

AU - Ouyang, Yeyun

AU - Naylor, Bradley C.

AU - Paulo, Joao A.

AU - Funai, Katsuhiko

AU - Cox, James E.

AU - Gygi, Steven P.

AU - Winge, Dennis R.

AU - Deberardinis, Ralph J.

AU - Rutter, Jared

PY - 2020/8

Y1 - 2020/8

N2 - 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.

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Mitochondrial fatty acid synthesis coordinates oxidative metabolism in mammalian mitochondria

Abstract

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