2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling

Fu, Xudong; Chin, Robert; Vergnes, Laurent; Hwang, Heejun; Deng, Gang; Xing, Yanpeng; Pai, Melody Y.; Li, Sichen; Ta, Lisa; Fazlollahi, Farbod; Chen, Chuo; Prins, Robert M.; Teitell, Michael A.; Nathanson, David; Lai, Albert; Faull, Kym F.; Jiang, Meisheng; Clarke, Steven; Cloughesy, Timothy F.; Graeber, Thomas G.; Braas, Daniel; Christofk, Heather R.; Jung, Michael E.; Reue, Karen; Huang, Jing

doi:10.1016/j.cmet.2015.06.009

Cited by 201 publications

(181 citation statements)

References 38 publications

(50 reference statements)

Supporting

Mentioning

162

Contrasting

Order By: Relevance

“…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: 88%

“…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.…”

supporting

confidence: 92%

See 1 more Smart Citation

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

112

View full text Add to dashboard Cite

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 ...

show abstract

Section: Significancesupporting

confidence: 88%

supporting

confidence: 92%

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

112

View full text Add to dashboard Cite

show abstract

“…Although some mechanisms have been proposed by which D-2HG could stimulate tumor progression (activation of the prolyl 4-hydroxylase EGLN that acts on HIF (75) and inhibition of DNA and histone demethylation (76,77)), the better outcome of glioma patients with IDH mutations compared with glioma patients without IDH mutations indicates that the connection between D-2HG and cancer is more complex than what is currently understood. Very recently, D-2HG has been shown to inhibit ATP synthase and signaling through the serine/threonine-protein kinase mTOR in U87 glioblastoma cells, suggesting a growth-suppressive function of this metabolite (78). Except for these latter observations, most of the cellular D-2HG effects identified so far involve activity modulation of ␣-ketoglutarate-dependent dioxygenases such as prolyl 4-hydroxylase, Jmj histone demethylases, and ten-eleven translocation (TET) 5-methylcytosine hydroxylases (75)(76)(77)79).…”

Section: Identification Of a New Type Of Enzymatic Activity For Degramentioning

confidence: 99%

Saccharomyces cerevisiae Forms d-2-Hydroxyglutarate and Couples Its Degradation to d-Lactate Formation via a Cytosolic Transhydrogenase

Becker-Kettern

Paczia

Conrotte

et al. 2016

Journal of Biological Chemistry

122

View full text Add to dashboard Cite

The D or L form of 2-hydroxyglutarate (2HG) accumulates in certain rare neurometabolic disorders, and high D-2-hydroxyglutarate (D-2HG) levels are also found in several types of cancer. Although 2HG has been detected in Saccharomyces cerevisiae, its metabolism in yeast has remained largely unexplored. Here, we show that S. cerevisiae actively forms the D enantiomer of 2HG. Accordingly, the S. cerevisiae genome encodes two homologs of the human D-2HG dehydrogenase: Dld2, which, as its human homolog, is a mitochondrial protein, and the cytosolic protein Dld3. Intriguingly, we found that a dld3⌬ knock-out strain accumulates millimolar levels of D-2HG, whereas a dld2⌬ knock-out strain displayed only very moderate increases in D-2HG. Recombinant Dld2 and Dld3, both currently annotated as D-lactate dehydrogenases, efficiently oxidized D-2HG to ␣-ketoglutarate. Depletion of D-lactate levels in the dld3⌬, but not in the dld2⌬ mutant, led to the discovery of a new type of enzymatic activity, carried by Dld3, to convert D-2HG to ␣-ketoglutarate, namely an FAD-dependent transhydrogenase activity using pyruvate as a hydrogen acceptor. We also provide evidence that Ser3 and Ser33, which are primarily known for oxidizing 3-phosphoglycerate in the main serine biosynthesis pathway, in addition reduce ␣-ketoglutarate to D-2HG using NADH and represent major intracellular sources of D-2HG in yeast. Based on our observations, we propose that D-2HG is mainly formed and degraded in the cytosol of S. cerevisiae cells in a process that couples D-2HG metabolism to the shuttling of reducing equivalents from cytosolic NADH to the mitochondrial respiratory chain via the D-lactate dehydrogenase Dld1. 2-Hydroxyglutarate (2HG)3 is a 5-carbon dicarboxylic acid that was first detected in human urine in the late 1970s (1).Because of the hydroxyl group on the second carbon, 2HG exists under two enantiomeric configurations (L or D) that can be separated by gas or liquid chromatography after derivatization with another chiral compound and that can therefore be differentially assayed in biological samples using GC-MS or LC-MS methods (2, 3). The interest in 2HG increased when it was found to accumulate in urine of patients with suspected inborn errors of metabolism (4, 5). Most 2-hydroxyglutaric aciduria patients present elevations of either L-2HG or D-2HG in their extracellular fluids, and the clinical phenotype depends on the configuration of the accumulated organic acid. More recently, cases of "combined D,L-hydroxyglutaric aciduria" have been reported (6).2-Hydroxyglutaric acidurias remained enigmatic diseases because neither L-2HG nor D-2HG are intermediates of any known metabolic pathway, and the causal gene deficiencies were only discovered many years after the first patient case reports. It is now established that L-2-hydroxyglutaric aciduria is caused by loss-of-function mutations in the L2HGDH gene, encoding a specific L-2HG dehydrogenase, whereas in many cases D-2-hydroxyglutaric aciduria results from loss-of-function mutations in the D2H...

show abstract

“…Recently, 2-HG has been reported to impair the activities of two enzymes in OXPHOS, including cytochrome c oxidase and ATP synthase (11,12), but whether the pathogenesis of 2-HGA is associated with impairment of OXPHOS remains unknown. Furthermore, 2-HG is now considered an oncometabolite (13)(14)(15)(16), and numerous studies indicate that altered epigenetic regulation is a major mechanism underlying its oncogenic activity.…”

mentioning

confidence: 99%

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Ma¹,

Sun²,

Jiang³

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

L-2-Hydroxyglutarate aciduria (L-2-HGA) is an autosomal recessive neurometabolic disorder caused by a mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene. In this study, we generated L2hgdh knockout (KO) mice and observed a robust increase of L-2-hydroxyglutarate (L-2-HG) levels in multiple tissues. The highest levels of L-2-HG were observed in the brain and testis, with a corresponding increase in histone methylation in these tissues. L2hgdh KO mice exhibit white matter abnormalities, extensive gliosis, microglia-mediated neuroinflammation, and an expansion of oligodendrocyte progenitor cells (OPCs). Moreover, L2hgdh deficiency leads to impaired adult hippocampal neurogenesis and late-onset neurodegeneration in mouse brains. Our data provide in vivo evidence that L2hgdh mutation leads to L-2-HG accumulation, leukoencephalopathy, and neurodegeneration in mice, thereby offering new insights into the pathophysiology of L-2-HGA in humans.KEYWORDS L2HGDH, 2-HG, leukoencephalopathy, gliosis, neurodegeneration T he rare, autosomal recessive neurometabolic disorders D-2-hydroxyglutaric aciduria (D-2-HGA) and L-2-hydroxyglutaric aciduria (L-2-HGA) are characterized by the accumulation of D-2-hydroxyglutarate (D-2-HG) and L-2-hydroxyglutarate (L-2-HG), respectively, in body fluids. Genetic characterization has shown that 50% of the D-2-HGA population and the majority of L-2-HGA patients harbor pathogenic mutations in D2HGDH and L2HGDH genes, respectively (1-3). The other half of D-2-HGA patients have a gain-of-function mutation in isocitrate dehydrogenase 2 (IDH2) at the residue of R140 (R140Q), which leads to abnormally high accumulation of D-2-HG (4). Based on phenotypic severity in patients, D-2-HGA is classified as mild type I (D2HGDH mutation) and severe type II (IDH2 mutation) (4, 5). Of note, 2-HG concentrations are 2-to 8-fold higher for type II D-2-HGA than type I D-2-HGA patients (4, 6, 7), suggesting that

show abstract

2-Hydroxyglutarate Inhibits ATP Synthase and mTOR Signaling

Cited by 201 publications

References 38 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

Saccharomyces cerevisiae Forms d-2-Hydroxyglutarate and Couples Its Degradation to d-Lactate Formation via a Cytosolic Transhydrogenase

L2hgdh Deficiency Accumulates l-2-Hydroxyglutarate with Progressive Leukoencephalopathy and Neurodegeneration

Contact Info

Product

Resources

About