State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China; Graduate School, University of Chinese Academy of Sciences, Beijing 100093, China.
State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
Cell Rep. 2023 Feb 28;42(2):112067. doi: 10.1016/j.celrep.2023.112067. Epub 2023 Jan 31.
The generation of neurons from quiescent radial-glia-like neural stem cells (RGLs) in adult brain goes hand in hand with the modulation of cellular metabolism. However, it is still unclear how the exact metabolic program governs the balance between quiescent and activated RGLs. Here, we find that loss of mitochondrial D-2-hydroxyglutarate dehydrogenase (D2HGDH) leads to aberrant accumulation of D-2-hydroxyglutarate (D-2-HG) and impaired RGL activation. Mechanistically, accumulated D-2-HG bonds directly to ATP-citrate lyase and competitively inhibits its enzymatic activity, thereby reducing acetyl-CoA production and diminishing histone acetylation. However, administration of acetate restores the acetyl-CoA levels via acetyl-CoA synthetase-mediated catabolism and rescues the deficiencies in histone acetylation and RGL activation caused by loss of D2HGDH. Therefore, our findings define the role of cross talk between mitochondria and the nucleus via a mitochondrial metabolite, D-2-HG, the aberrant accumulation of which hinders the regulation of histone acetylation in RGL activation and attenuates continuous neurogenesis in adult mammalian brain.
从静息的放射状胶质样神经干细胞 (RGL) 中产生神经元与细胞代谢的调节密切相关。然而，目前尚不清楚确切的代谢程序如何控制静息和激活的 RGL 之间的平衡。在这里，我们发现线粒体 D-2-羟戊二酸脱氢酶 (D2HGDH) 的缺失导致 D-2-羟戊二酸 (D-2-HG) 的异常积累和 RGL 激活受损。在机制上，积累的 D-2-HG 直接与 ATP-柠檬酸裂解酶结合并竞争性抑制其酶活性，从而减少乙酰辅酶 A 的产生并降低组蛋白乙酰化。然而，通过乙酰辅酶 A 合酶介导的分解代谢，给予乙酸盐可恢复乙酰辅酶 A 水平，并挽救由 D2HGDH 缺失引起的组蛋白乙酰化和 RGL 激活缺陷。因此，我们的研究结果定义了通过线粒体代谢产物 D-2-HG 进行线粒体和核之间的串扰作用，其异常积累阻碍了 RGL 激活中组蛋白乙酰化的调节，并减弱了成年哺乳动物大脑中的持续神经发生。
