Mitochondrial dysfunction remodels one-carbon metabolism in human cells.
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.
Department of Molecular Biology, Howard Hughes Medical Institute , Massachusetts General Hospital, Boston, United States.|Department of Systems Biology, Harvard Medical School, Boston, United States.|Broad Institute of MIT and Harvard, Cambridge, United States.
Xiaoyan Robert
0000-0001-7931-2944
XR
Bao
Broad Institute of MIT and Harvard, Cambridge, United States.
Shao-En
SE
Ong
Department of Molecular Biology, Howard Hughes Medical Institute , Massachusetts General Hospital, Boston, United States.
Olga
O
Goldberger
Department of Molecular Biology, Howard Hughes Medical Institute , Massachusetts General Hospital, Boston, United States.|Broad Institute of MIT and Harvard, Cambridge, United States.
Jun
J
Peng
Department of Molecular Biology, Howard Hughes Medical Institute , Massachusetts General Hospital, Boston, United States.
Rohit
R
Sharma
Broad Institute of MIT and Harvard, Cambridge, United States.
Dawn A
DA
Thompson
Department of Molecular Biology, Howard Hughes Medical Institute , Massachusetts General Hospital, Boston, United States.|Broad Institute of MIT and Harvard, Cambridge, United States.
Scott B
SB
Vafai
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
Andrew G
AG
Cox
Department of Anesthesia, Critical Care, and Pain Medicine, Masaschusetts General Hospital, Boston, United States.
Eizo
E
Marutani
Department of Anesthesia, Critical Care, and Pain Medicine, Masaschusetts General Hospital, Boston, United States.
Fumito
F
Ichinose
Broad Institute of MIT and Harvard, Cambridge, United States.|Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, United States.
Wolfram
W
Goessling
Broad Institute of MIT and Harvard, Cambridge, United States.|Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, United States.
Aviv
A
Regev
Broad Institute of MIT and Harvard, Cambridge, United States.
Steven A
SA
Carr
Broad Institute of MIT and Harvard, Cambridge, United States.
Clary B
CB
Clish
Department of Molecular Biology, Howard Hughes Medical Institute , Massachusetts General Hospital, Boston, United States.|Department of Systems Biology, Harvard Medical School, Boston, United States.|Broad Institute of MIT and Harvard, Cambridge, United States.
Vamsi K
0000-0001-9924-642X
VK
Mootha
D002244:Carbon / Q000378:metabolism*; D002460:Cell Line; D020869:Gene Expression Profiling; D006801:Humans; D055442:Metabolome; D010085:Oxidative Phosphorylation; D020543:Proteome / Q000032:analysis
D020543:Proteome; D002244:Carbon
computational biology; folate metabolism; human; human biology; medicine; metabolite profiling; mitochondrial disease; mouse; proteomics; sulfur metabolism; systems biology; transcriptional profiling