Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A
Lactate dehydrogenase C is required for the protein expression of a sperm-specific isoform of lactate dehydrogenase A
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DOI：
10.1093/jb/mvy108
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发表时间：
2019-04-01
影响因子：
2.7
通讯作者：
Motohashi, Hozumi
中科院分区：
文献类型：
--
作者：
Dodo, Mina;Kitamura, Hiroshi;Motohashi, Hozumi
代谢产物是细胞状态和活性的敏感指标。期望组织特异性代谢特征揭示组织的独特功能，我们检查了小鼠肝脏和睾丸的代谢组，发现一种不寻常的代谢物2-羟基戊二酸（2-HG）在睾丸中大量积累。2-HG可以作为D-或L-对映体存在，并且两种对映体都干扰2-酮戊二酸（2-OG）依赖性双加氧酶的活性，例如组蛋白脱甲基酶的Jumonji家族。D-2-HG是由异柠檬酸脱氢酶（IDH）的致癌突变体产生的，被称为癌代谢物，而L-2-HG是睾丸中检测到的主要对映体，表明睾丸产生这种代谢物的独特机制。我们澄清，乳酸脱氢酶C（LDHC），睾丸特异性乳酸脱氢酶，是负责L-2-HG积累的生产和分析Ldhc缺陷小鼠。虽然在睾丸中几乎没有观察到2-HG对2-OG依赖性双加氧酶的抑制作用，但在Ldhc缺陷的精子中LDHA蛋白水平显著降低，表明LDHC是精子中LDHA表达所必需的。LDH家族成员之间的这种独特的功能相互作用支持精子中的乳酸脱氢酶活性。Ldhc缺陷精子的运动性严重受损，表明糖酵解对精子运动性的能量产生有重大贡献。
Metabolites are sensitive indicators of moment-to-moment cellular status and activity. Expecting that tissue-specific metabolic signatures unveil a unique function of the tissue, we examined metabolomes of mouse liver and testis and found that an unusual metabolite, 2-hydroxyglutarate (2-HG), was abundantly accumulated in the testis. 2-HG can exist as D- or L-enantiomer, and both enantiomers interfere with the activities of 2-oxoglutarate (2-OG)-dependent dioxygenases, such as the Jumonji family of histone demethylases. Whereas D-2-HG is produced by oncogenic mutants of isocitrate dehydrogenases (IDH) and known as an oncometabolite, L-2-HG was the major enantiomer detected in the testis, suggesting that a distinct mechanism underlies the testicular production of this metabolite. We clarified that lactate dehydrogenase C (LDHC), a testis-specific lactate dehydrogenase, is responsible for L-2-HG accumulation by generating and analysing Ldhc-deficient mice. Although the inhibitory effects of 2-HG on 2-OG-dependent dioxygenases were barely observed in the testis, the LDHA protein level was remarkably decreased in Ldhc-deficient sperm, indicating that LDHC is required for LDHA expression in the sperm. This unique functional interaction between LDH family members supports lactate dehydrogenase activity in the sperm. The severely impaired motility of Ldhc-deficient sperm suggests a substantial contribution of glycolysis to energy production for sperm motility.