Mitochondrial dysfunction remodels one-carbon metabolism in human cells.
Xiaoyan Robert BaoShao-En OngOlga GoldbergerJun PengRohit SharmaDawn A ThompsonScott B VafaiAndrew G CoxEizo MarutaniFumito IchinoseWolfram GoesslingAviv RegevSteven A CarrClary B ClishVamsi K MoothaPublished in: 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 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.
Keyphrases
- mitochondrial dna
- oxidative stress
- copy number
- induced apoptosis
- respiratory tract
- transcription factor
- protein kinase
- gene expression
- endoplasmic reticulum stress
- cell cycle arrest
- cell proliferation
- patient safety
- signaling pathway
- dna methylation
- cell death
- quality improvement
- electronic health record
- heat stress
- drug induced