Serine one-carbon catabolism with formate overflow
Johannes Meiser1, Sergey Tumanov2, Oliver Maddocks3
1Cancer Research UK Beatson Institute, Glasgow, UK.
Science Advances
|November 8, 2016
Summary
Most cellular serine is converted to formate, a one-carbon unit, supporting cell growth. Formate release relies on mitochondrial enzymes and complex I activity, impacting cancer and diabetes treatments.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Pathways
Background:
- Serine catabolism is traditionally linked to anabolic needs in proliferating cells.
- Genome-scale modeling suggests a catabolic role for serine with formate release.
- Understanding one-carbon metabolism is crucial for cellular processes and disease.
Purpose of the Study:
- To experimentally determine the fate of serine-derived one-carbon units in mammalian cells.
- To investigate the enzymatic and mitochondrial dependencies of formate release.
- To assess the in vivo significance of serine-derived formate and its regulation.
Main Methods:
- Cell culture experiments with cultured cancer cells and fibroblasts.
- Isotopic tracing to track serine-derived one-carbon units.
- Mitochondrial complex I activity assays and inhibition studies.
- In vivo studies in mice to measure plasma formate levels.
Main Results:
- The majority of serine-derived one-carbon units are released as formate from cultured cells.
- Formate release is dependent on mitochondrial 10-formyltetrahydrofolate synthetase activity.
- In cancer cells, formate release is linked to mitochondrial complex I; in fibroblasts, it's partially independent.
- In mice, approximately 50% of plasma formate originates from serine, and its synthesis is reduced by serine starvation or complex I inhibition.
Conclusions:
- Serine catabolism primarily releases one-carbon units as formate, challenging previous assumptions.
- Mitochondrial complex I activity plays a significant role in formate production, particularly in cancer cells.
- These findings offer new insights into one-carbon metabolism with potential therapeutic implications for diabetes and cancer.
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