Mitochondrial energy metabolism is markedly impaired by d-2-hydroxyglutaric acid in rat tissues

Latini, Alexandra; Silva, Cleide Goncalves da; Ferreira, Gustavo C.; Schuck, Patrícia Fernanda; Scussiato, Karina; Sarkis, João José de Freitas; Dutra-Filho, Carlos Severo; Wyse, Ângela T. S.; Wannmacher, Clóvis Milton Duval; Wajner, Moaçir

doi:10.1016/j.ymgme.2005.05.002

Cited by 85 publications

(47 citation statements)

References 71 publications

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“…S2D). The results are consistent with prior reports that an increased supply of D2-HG leads to impaired ATP provision through inhibition of ATP synthase by D2-HG both in vivo and in vitro (18,20). To assess whether D2-HG differentially affects energy substrate metabolism in the heart, we perfused rat hearts (n = 4 animals per group) with or without D2-HG (1 mM) in presence of glucose (5 mM) and oleate (0.4 mM) (Fig.…”

Section: Significancesupporting

confidence: 92%

“…1F). This decreased susceptibility suggests that D2-HG binds to and stabilizes both α-KGDH and ATP5B, affecting their activity, as evidenced by the reduced ATP levels and consistent with previous reports (18,20). We measured the level of α-KGDH activity and production rate of hydrogen peroxide (H 2 O 2 ) fluorometrically in the ex vivo perfused rat hearts.…”

Section: Significancesupporting

confidence: 87%

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

Karlstaedt

Zhang

Vitrac

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

101

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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 ...

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Section: Significancesupporting

confidence: 92%

Section: Significancesupporting

confidence: 87%

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

Karlstaedt

Zhang

Vitrac

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

107

101

View full text Add to dashboard Cite

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“…This effect has been reported in cells with cytochrome C reductase dysfunction, in cells with disrupted hypoxia signaling pathways, and in cells cultured under hypoxia, all of which have been identified as etiologies for altered mitochondrial function (15)(16)(17)(18). A plausible explanation for the similarity between metabolic alterations caused by IDH1 mutation knock-in and by mitochondrial dysfunction is that the D-2HG produced by mutant IDH1 can cause mitochondrial dysfunction by inhibiting complexes I, IV, and V of the electron transport chain (27,28). Indeed, our JC-1 dye data indicate that electron transport chain function is altered in IDH1-mutated cells.…”

Section: Discussionmentioning

confidence: 63%

Cancer-associated Isocitrate Dehydrogenase 1 (IDH1) R132H Mutation and d-2-Hydroxyglutarate Stimulate Glutamine Metabolism under Hypoxia

Reitman

Duncan²,

Poteet

et al. 2014

Journal of Biological Chemistry

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“…Oxidative stress itself can deregulate many epigenetic enzymes through both direct and indirect means; these include deregulation of the labile iron pool (LIP), derangement of glutathione (GSH) metabolism, and alteration of the NAD þ =NADH ratios, each of which will be discussed in greater detail below. This same group later demonstrated that 2-HG impairs mitochondrial energy metabolism, potentially through an uncoupling mechanism (166). Mitochondrial uncoupling would promote rapid electron flux through the electron transport complexes of the inner mitochondrial membrane, potentially speeding up the rate at which the CAC turns through a cycle due to rapid recycling of the electron shuttles NADH and NADPH.…”

Section: Cyr and Domannmentioning

confidence: 98%

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

Cyr

Domann

2011

Antioxidants & Redox Signaling

236

165

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Epigenetic modifications represent mechanisms by which cells may effectively translate multiple signaling inputs into phenotypic outputs. Recent research is revealing that redox metabolism is an increasingly important determinant of epigenetic control that may have significant ramifications in both human health and disease. Numerous characterized epigenetic marks, including histone methylation, acetylation, and ADP-ribosylation, as well as DNA methylation, have direct linkages to central metabolism through critical redox intermediates such as NAD + , S-adenosyl methionine, and 2-oxoglutarate. Fluctuations in these intermediates caused by both normal and pathologic stimuli may thus have direct effects on epigenetic signaling that lead to measurable changes in gene expression. In this comprehensive review, we present surveys of both metabolism-sensitive epigenetic enzymes and the metabolic processes that may play a role in their regulation. To close, we provide a series of clinically relevant illustrations of the communication between metabolism and epigenetics in the pathogenesis of cardiovascular disease, Alzheimer disease, cancer, and environmental toxicity. We anticipate that the regulatory mechanisms described herein will play an increasingly large role in our understanding of human health and disease as epigenetics research progresses. Antioxid. Redox Signal. 15, 551-589.

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Mitochondrial energy metabolism is markedly impaired by d-2-hydroxyglutaric acid in rat tissues

Cited by 85 publications

References 71 publications

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

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

Cancer-associated Isocitrate Dehydrogenase 1 (IDH1) R132H Mutation and d-2-Hydroxyglutarate Stimulate Glutamine Metabolism under Hypoxia

The Redox Basis of Epigenetic Modifications: From Mechanisms to Functional Consequences

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