Mitochondrial dysfunction remodels one-carbon metabolism in human cells
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REgev_Mitochondrial dysfunction.pdf
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Author(s)
Bao, Xiaoyan Robert
Ong, Shao-En
Goldberger, Olga
Peng, Jun
Sharma, Rohit
Thompson, Dawn A
Vafai, Scott B
Cox, Andrew G
Marutani, Eizo
Ichinose, Fumito
Date Issued
June 2016
Journal
eLife
Publisher
eLife Sciences Publications, Ltd.
Citation
Bao, Xiaoyan Robert et al. “Mitochondrial Dysfunction Remodels One-Carbon Metabolism in Human Cells.” eLife 5 (2016): n. pag.
Version
Final published version
Abstract
Mitochondrial dysfunction is associated with a spectrum of human disorders, ranging from rare, inborn errors of metabolism to common, age-associated diseases such as neurodegeneration. How these lesions give rise to diverse pathology is not well understood, partly because their proximal consequences have not been well-studied in mammalian cells. Here we provide two lines of evidence that mitochondrial respiratory chain dysfunction leads to alterations in one-carbon metabolism pathways. First, using hypothesis-generating metabolic, proteomic, and transcriptional profiling, followed by confirmatory experiments, we report that mitochondrial DNA depletion leads to an ATF4-mediated increase in serine biosynthesis and transsulfuration. Second, we show that lesioning the respiratory chain impairs mitochondrial production of formate from serine, and that in some cells, respiratory chain inhibition leads to growth defects upon serine
withdrawal that are rescuable with purine or formate supplementation. Our work underscores the connection between the respiratory chain and one-carbon metabolism with implications for understanding mitochondrial pathogenesis.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Terms of Use
Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.7554/eLife.10575
