D-2-hydroxyglutarate dehydrogenase governs adult neural stem cell activation and promotes histone acetylation via ATP-citrate lyase

• Published in: Cell reports (Cambridge) Vol. 42; no. 2; p. 112067
• Main Authors: Liu, Yinghao, Wang, Min, Guo, Ye, Wang, Lei, Guo, Weixiang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28-02-2023; Elsevier
• Subjects: adult neurogenesis; ATP-citrate lyase; CP: Neuroscience; CP: Stem cell research; D-2-hydroxyglutarate; D-2-hydroxyglutarate dehydrogenase; histone acetylation; neural stem cells; adult neurogenesis; CP: Stem cell research; neural stem cells; CP: Neuroscience; D-2-hydroxyglutarate dehydrogenase; D-2-hydroxyglutarate; ATP-citrate lyase; histone acetylation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112067

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.
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•D2HGDH-mediated D-2-HG catabolism regulates adult neurogenesis•D-2-HG inhibits ACLY enzymatic activity, leading to reduced acetyl-CoA availability•D2HGDH-mediated D-2-HG catabolism promotes histone acetylation via ACLY•Acetate administration rescues defective adult neurogenesis in D2HGDH-deficient mice
In this study, Liu et al. show that D2HGDH deficiency leads to aberrant accumulation of D-2-HG and impaired NSC activation. Accumulated D-2-HG directly binds to ACLY and competitively inhibits its enzymatic activity, thereby reducing acetyl-CoA production and diminishing histone acetylation.