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Mitochondrial dysfunction remodels one-carbon metabolism in human cells
Xiaoyan Robert Bao1,2,3, Shao-En Ong3, Olga Goldberger1
1Department of Molecular Biology, Howard Hughes Medical Institute , Massachusetts General Hospital, Boston, United States.
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.
Insights
Mitochondrial dysfunction impacts one-carbon metabolism, increasing serine synthesis and altering formate production. This link is crucial for understanding diseases linked to mitochondrial defects.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Disorders
Background:
- Mitochondrial dysfunction underlies various human diseases, from metabolic disorders to neurodegeneration.
- The precise mechanisms linking mitochondrial lesions to cellular pathology remain unclear.
- Proximal consequences of mitochondrial dysfunction in mammalian cells require further investigation.
Purpose of the Study:
- To investigate the link between mitochondrial respiratory chain dysfunction and one-carbon metabolism pathways.
- To elucidate how mitochondrial defects influence metabolic alterations in mammalian cells.
Main Methods:
- Metabolic, proteomic, and transcriptional profiling for hypothesis generation.
- Confirmatory experiments following mitochondrial DNA depletion.
- Assessment of respiratory chain function and formate production from serine.
- Cell growth assays under serine withdrawal with purine or formate supplementation.
Main Results:
- Mitochondrial DNA depletion induced an ATF4-mediated increase in serine biosynthesis and transsulfuration.
- Respiratory chain dysfunction impaired mitochondrial formate production from serine.
- Serine withdrawal caused growth defects in respiratory chain-inhibited cells, rescuable by purine or formate.
Conclusions:
- Mitochondrial respiratory chain function is directly connected to one-carbon metabolism.
- Alterations in serine biosynthesis and formate production are key consequences of mitochondrial dysfunction.
- Findings offer insights into the pathogenesis of mitochondrial disorders.
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