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Updated: Mar 15, 2026
Analysis of Cardiac Contractile Dysfunction and Ca2+ Transients in Rodent Myocytes
Published on: May 25, 2022
Oncometabolite d-2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart
Anja Karlstaedt1, Xiaotian Zhang2, Heidi Vitrac3
1Department of Internal Medicine, Division of Cardiology, McGovern Medical School, The University of Texas Health Science Center, Houston, TX 77030;
Insights
Mutant isocitrate dehydrogenase (IDH) leukemia cells produce d-2-hydroxyglutarate (D2-HG), an oncometabolite that impairs heart function. This cancer metabolite disrupts cardiac metabolism and leads to heart contractile dysfunction.
Area of Science:
- Cardiovascular Biology
- Cancer Metabolism
- Hematologic Malignancies
Background:
- Hematologic malignancies often involve cardiac pathologies.
- Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in acute myeloid leukemia cause metabolic and epigenetic changes.
- Leukemic cell metabolism can significantly impact cardiac function.
Purpose of the Study:
- To investigate the effect of IDH-mutant leukemic cell metabolism on cardiac function.
- To elucidate the role of the oncometabolite d-2-hydroxyglutarate (D2-HG) in cardiac pathology.
- To understand the molecular mechanisms linking cancer metabolism to heart dysfunction.
Main Methods:
- Mathematical modeling
- In vivo studies
- Ex vivo studies
- Analysis of cardiac metabolism and epigenetic modifications
Main Results:
- Increased D2-HG from IDH2-mutant leukemic cells induces cardiac contractile dysfunction.
- Cardiac dysfunction is linked to impaired α-ketoglutarate metabolism and increased ATP citrate lyase (ACL) activity.
- D2-HG alters cardiac histone methylation and acetylation, suggesting epigenetic reprogramming.
Conclusions:
- D2-HG produced by IDH-mutant leukemia cells directly impairs heart function.
- The mechanism involves disruption of α-ketoglutarate dehydrogenase and ACL-dependent histone modifications.
- Cancer cell metabolism critically influences cardiac metabolism and function, highlighting a potential therapeutic target.
Abstract:
Hematologic malignancies are frequently associated with cardiac pathologies. Mutations of isocitrate dehydrogenase 1 and 2 (IDH1/2) occur in a subset of acute myeloid leukemia patients, causing metabolic and epigenetic derangements. We have now discovered that altered metabolism in leukemic cells has a profound effect on cardiac metabolism. Combining mathematical modeling and in vivo as well as ex vivo studies, we found that increased amounts of the oncometabolite d-2-hydroxyglutarate (D2-HG), produced by IDH2 mutant leukemic cells, cause contractile dysfunction in the heart. This contractile dysfunction is associated with impaired oxidative decarboxylation of α-ketoglutarate, a redirection of Krebs cycle intermediates, and increased ATP citrate lyase (ACL) activity. Increased availability of D2-HG also leads to altered histone methylation and acetylation in the heart. We propose that D2-HG promotes cardiac dysfunction by impairing α-ketoglutarate dehydrogenase and induces histone modifications in an ACL-dependent manner. Collectively, our results highlight the impact of cancer cell metabolism on function and metabolism of the heart.
