Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A

Dodo, Mina; Kitamura, Hiroshi; Shima, Hiroki; Saigusa, Daisuke; Wati, Sisca Meida; Ota, Nao; Katsuoka, Fumiki; Chiba, Hayato; Okae, Hiroaki; Arima, Takahiro; Igarashi, Kazuhiko; Koseki, Takeyoshi; Sekine, Hiroshi; Motohashi, Hozumi

doi:10.1093/jb/mvy108

Cited by 16 publications

(23 citation statements)

References 36 publications

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“…Our results are in accordance with this previous data as malignant testicular tissues tend to resemble the hypoxic and undifferentiated embryonic tissues (54, 55), therefore showing higher expression of GLUT1 but lower expression of HKII when compared to normal tissues. Regarding LDHV expression, Dodo and collaborators (56) found that LDHV was co-expressed with LDHX, the major LDH isoform present in testis, which has been found in different animals, including humans (57, 58). Curiously, LDHX mice knock-out presented an ablation of LDHV expression, not demonstrated by wild type mice, resulting in reduced energy production through glycolysis and impaired fertilization (56).…”

Section: Discussionmentioning

confidence: 99%

“…Regarding LDHV expression, Dodo and collaborators (56) found that LDHV was co-expressed with LDHX, the major LDH isoform present in testis, which has been found in different animals, including humans (57, 58). Curiously, LDHX mice knock-out presented an ablation of LDHV expression, not demonstrated by wild type mice, resulting in reduced energy production through glycolysis and impaired fertilization (56). Also, another study described that LDHV human transgene expression was able to restore LDHX expression in testis and sperm of LDHX knock-out mice, also restoring sperm motility and fertilization capacity (59).…”

Section: Discussionmentioning

confidence: 99%

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The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors

et al. 2019

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Testicular Germ Cell Tumors (TGCTs) are a rare group of neoplasms and the most common solid malignancy arising in young male adults. Despite the good response of these tumors to platinum-based chemotherapy, some patients are refractory to treatment and present poor clinical outcomes. During carcinogenesis and tumor development, cancer cells reprogram energy metabolism toward a hyper-glycolytic phenotype, an emerging hallmark of cancer. This phenomenon, known as the Warburg effect or aerobic glycolysis, involves overexpression of metabolism-related proteins, like glucose and monocarboxylate transporters, pH regulators and intracellular glycolytic enzymes. The metabolic profile of TGCTs is very little explored and, recently, this metabolic rewiring of cancer cells has been associated with aggressive clinicopathological characteristics of these tumors. The overexpression of monocarboxylate transporter 4 (MCT4) in TGCTs has been pointed out as a poor prognostic factor, as well as a promising therapeutic target. As a result, the main aim of the present study was to evaluate the prognostic value of key metabolism-related proteins in TGCTs. The immunohistochemical expressions of CD44 (as a monocarboxylate transporter chaperone), glucose transporter 1 (GLUT1), carbonic anhydrase IX (CAIX), hexokinase II (HKII) and lactate dehydrogenase V (LDHV) were evaluated in a series of 148 adult male patients with TGCTs and associated with clinicopathological parameters. In addition, paired normal tissues were also evaluated. The sample included 75 seminoma and 73 non-seminoma tumors. GLUT1 and CD44 expression was significantly increased in malignant samples when compared to paired normal samples. Conversely, HKII and LDHV expressions were significantly decreased in malignant samples. Concerning the clinicopathological values, CAIX expression was significantly associated with disease recurrence, while HKII expression was significantly associated with aggressive characteristics of TGCTs, including higher staging and non-seminoma histology. In conclusion, this study brings new insights on the metabolic characteristics of TGCTs, showing alterations in the expression of proteins related with the Warburg effect, as well as associations of the hyper-glycolytic and acid-resistant phenotype with aggressive clinicopathological parameters.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors

et al. 2019

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“…Previous studies showed that whole testis extract harbors a high content of 2HG, yet the specific cell stages that generate this metabolite were not defined (Dodo et al, 2019;Teng et al, 2016).…”

Section: L-2hg Is Produced In Pachytene/diplotene/diakinesis Cells By...mentioning

confidence: 99%

2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline

Mayorek¹,

Schlossberg²,

Mansour³

et al. 2022

Preprint

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2-hydroxyglutarate (2HG) is recognized as an epigenetic regulator in cancer and in a few physiological states. Of all organs, the testis harbors the highest levels of 2HG, yet it's putative functions in germ cell biology are unknown. Here we show that 2HG is generated in specific stages of the mouse germ cell lineage by the testis specific lactate dehydrogenase C (LDHC). LDHC is expressed in pachytene, diplotene and diakinesis (PDD) cells and unexpectedly enters nuclei where it localizes along chromosomes and centromeres. LDHC-generated L-2HG controls centromere compaction and pericentromeric heterochromatin organization through multiple effects including clustering of chromocenters, centromere and chromocenter condensation and expression of satellite RNAs. The involvement of L-2HG in the above functions was shown both in isolated PDD cells and in vivo and is specific to the L but not D enantiomer. Our findings reveal that 2HG can rapidly change the conformation of these multisubunit structures and is necessary for the proper progression of the cell cycle.

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“…1 ). Interestingly, a specific isoform C of LDH (LDHC) is a significant producer of s -2HG in the testis, where levels of up to 200 nmol/g s -2HG are found, compared with much lower levels in the liver (∼20 nmol/g) ( 41 ).…”

Section: Metabolism Of 2hgmentioning

confidence: 99%

2-Hydroxyglutarate in Cancer Cells

Ježek

2020

Antioxidants & Redox Signaling

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Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

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Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A

Cited by 16 publications

References 36 publications

The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors

The Warburg Effect Is Associated With Tumor Aggressiveness in Testicular Germ Cell Tumors

2-hydroxyglutarate controls centromere and heterochromatin conformation and function in the male germline

2-Hydroxyglutarate in Cancer Cells

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