MassIVE MSV000079791

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Mitochondrial dysfunction remodels one-carbon metabolism in human cells

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Description

Bao XR, Ong SE, Goldberger O, Peng J, Sharma R, Thompson DA, Vafai SB, Cox A, Marutani E, Ichinose F, Goessling W, Regev A, Carr SA, Clish CB, Mootha VK. eLife 2016. 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 mtDNA 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. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: SILAC ; mitochondria

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Principal Investigators:
(in alphabetical order) 		Steven A. Carr
Submitting User: clauser
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