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Elife DOI:10.7554/eLife.10575

Mitochondrial dysfunction remodels one-carbon metabolism in human cells.

Publication TypeJournal Article
Year of Publication2016
AuthorsBao, XRobert, Ong, S-E, Goldberger, O, Peng, J, Sharma, R, Thompson, DA, Vafai, SB, Cox, AG, Marutani, E, Ichinose, F, Goessling, W, Regev, A, Carr, SA, Clish, CB, Mootha, VK
JournalElife
Volume5
Date Published2016 Jun 16
ISSN2050-084X
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.

DOI10.7554/eLife.10575
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27307216?dopt=Abstract

Alternate JournalElife
PubMed ID27307216
PubMed Central IDPMC4911214
Grant ListR01 DK081457 / DK / NIDDK NIH HHS / United States