Oncometabolite d -2-hydroxyglutarate impairs α-ketoglutarate dehydrogenase and contractile function in rodent heart

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. D-2-hydroxyglutarate | IDH2 | metabolism | cardiomyopathy | flux rate analysis M etabolic dysregulation in cancer cells changes the way nutrients are consumed and macromolecules are produced to meet the increased demands for cell growth. Somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are common and are described in several cancer types (i.e., gliomas and acute myeloid leukemia). IDH mutations lead to increased production and accumulation of the oncometabolite D-2-hydroxyglutarate (D2-HG) through a neomorphic enzymatic function (1). WT IDH1/2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), while reducing NADP + to NADPH either in the cytosol and peroxisome (IDH1), or in mitochondria (IDH2). In this reaction, D2-HG is produced in small amounts but converted back to its structural homolog α-KG by D2-HG dehydrogenase. Common features of tumors with IDH1/2 mutations are abnormal histone and DNA methylation, connecting metabolic changes with epigenetic control of gene expression (2). In hematologic malignancies, IDH1/2 are often co-mutated with epigenetic regulatory genes encoding enzymes that are important in DNA hydroxymethylation (i.e., tet methylcytosine dioxygenase 2, TET2) and methylation (i.e., DNA methyltransferase 3 A, DNMT3A) (3). Accumulation of D2-HG contributes to leukemogenesis, likely due to inhibition of α-KG-dependent dioxygenases, including histone lysine demethylases (KDMs) and TET2 (4). This hypothesis has been supported by recent reports linking the hypermethylation phenotype in cancer cells to IDH, fumarate hydratase, and succinate dehydrogenase mutations (5, 6).The starting point for the present work were reports that myeloid malignancies are associated with cardiac pathologies, which are commonly considered a side effect of chemotherapy (7). Other recent reports suggest that systemically produced D2-HG by neomorphic ...

Oncometabolic Tracks in the Heart

“…We recently showed that D-2-hydroxyglutarate mediates cardiac dysfunction by inhibiting α-ketoglutarate dehydrogenase, which, in turn, leads to redirection of Krebs cycle intermediates and epigenetic modifications. 8 Our findings provide evidence that the heart in isocitrate dehydrogenase 1/2-mutant leukemia is at risk for contractile dysfunction because of the tumor biology. In other words, metabolic dysregulation in cancer cells causes metabolic reprogramming in the heart, which may put cancer patients and survivors at risk for developing heart diseases.…”

Potential mechanisms linking SIRT activity and hypoxic 2-hydroxyglutarate generation: no role for direct enzyme (de)acetylation

“…Indeed, it was recently shown that SIRT1 can translocate from cytosol to mitochondria [47]. Furthermore, in the context of compartmentation it has also been reported that 2-HG can be transported into cardiomyocytes [46]. As such, it is intriguing that we found a small but non-significant increase in 2-HG levels in the serum of Sirt3 −/− mice (1.68 ± 0.29 fold vs. control, mean ± SEM, n=6, p=0.078, paired t-test).…”

“…Finally, the recent finding that 2-HG can inhibit α-ketoglutarate dehydrogenase (α-KGDH) activity [46] suggests that 2-HG and the TCA cycle may exhibit a complex cross-talk, wherein inhibition of α-KGDH would elevate α-KG levels, providing more substrate for 2-HG generation, resulting in a feed-forward activation for 2-HG generation. In conclusion, while direct enzyme acetylation does not appear to be an important 2-HG regulatory mechanism, the role of other protein post-translational modifications and signaling pathways that regulate this metabolite may be worthy of further investigation.…”

Recent advances in cardio‐oncology: a report from the ‘Heart Failure Association 2019 and World Congress on Acute Heart Failure 2019’

“…Cardiovascular events in cancer patients can be caused by three main factors: (i) concomitant CV risk factors and diseases; (ii) anti-cancer therapy (including chemotherapy, targeted therapy, immune checkpoint inhibitors, and radiation) through direct or indirect damage effects; (iii) cancer itself, through the direct invasion of CV structures or indirect release of metabolites and/or activation of adrenergic system [45][46][47] (Figure 1).…”