Study reveals IDH1 enzyme's role in cardiac metabolic adaptation during cancer-related stress
Researchers have discovered that the enzyme isocitrate dehydrogenase 1 (IDH1) plays an unexpected role in protecting the heart when exposed to the cancer-derived oncometabolite D-2-hydroxyglutarate (D2-HG). Using stable isotope tracing and computational modeling in rat hearts and mouse cardiomyocytes, the team found that IDH1 redirects carbon metabolism from oxidative to reductive pathways, increasing glutamine uptake and citrate formation. The findings suggest a novel link between cancer metabolism and cardiac function, with potential implications for patients who carry IDH mutations.
Cardiovascular disease and cancer are the two leading causes of death worldwide, and emerging evidence suggests that cancer metabolism can directly harm the heart. Mutations in IDH1 and IDH2 are common in certain cancers and cause production of the oncometabolite D-2-hydroxyglutarate (D2-HG), which inhibits mitochondrial metabolism and has been associated with reduced cardiac contractile function. Using stable isotope tracer studies combined with computational modeling in perfused working rat hearts and isolated adult mouse ventricular cardiomyocytes, the researchers found that when mitochondrial metabolism is impaired by D2-HG, carbon flux is redirected from oxidative toward reductive pathways. Specifically, IDH1—not IDH2 or IDH3—was identified as the isoform responsible for driving reductive carboxylation of alpha-ketoglutarate, boosting glutamine uptake and glutamine-derived citrate formation. Knockout models confirmed that loss of IDH1 impaired reductive citrate formation and caused measurable functional defects in cardiomyocytes. Additionally, epigenetic analyses revealed that IDH1 activity induces widespread changes in histone acetylation and tri-methylation, suggesting it also influences transcriptional regulation of metabolic genes. These findings expand the known role of IDH1 in the heart and may open new avenues for protecting cardiac function in cancer patients with IDH mutations.
What's missing
The study was conducted entirely in rat and mouse models; whether these metabolic adaptations occur in human hearts under IDH-mutant cancer conditions remains undemonstrated. The functional significance of the observed epigenetic changes (histone acetylation and tri-methylation) on downstream gene expression and long-term cardiac outcomes is not fully characterized. It is also unclear whether therapeutic targeting of IDH1 in this context would be beneficial or harmful, given IDH1's dual roles in tumor biology and cardiac protection.
What different sources said
- bioRxivCenter
Reductive carboxylation via isocitrate dehydrogenase 1 supports cardiac metabolic adaptation during oncometabolic stress.
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