Loss of Echs1 in neural stem and progenitor cells impairs neurogenesis via ER stress activation and lipid metabolic reprogramming

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Abstract
Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare and severe encephalopathy linked to neurodevelopmental disorders, yet the connection between metabolic dysfunction and impaired neurogenesis remains unclear. In this study, we demonstrate that the loss of Echs1 in neural stem/progenitor cells (NSPCs) leads to fatty acid accumulation, which hinders proliferation and differentiation while promoting apoptosis. Mechanistically, Echs1 deficiency increases crotonyl-CoA levels, resulting in global histone crotonylation (Kcr) with an enrichment of H3K9cr. Neurodevelopmental gene promoters, such as the endoplasmic reticulum (ER) stress regulator Atf4, acquire H3K9cr. Atf4 then upregulates fatty acid synthase (Fasn), creating a feed-forward loop that exacerbates lipid accumulation. Inhibiting Fasn can rescue these defects. Alleviating ER stress through tauroursodeoxycholic acid (TUDCA) or Atf4 inhibition restores neurogenesis in vitro and enhances survival in vivo. This study uncovers an Echs1-H3K9cr-Atf4-Fasn axis that links metabolism to neurogenesis through epigenetic reprogramming and suggests TUDCA as a potential treatment for ECHS1D.
Funding Information
  • Ministry of Science and Technology of the People's Republic of China (2021YFA1101402)
  • Ministry of Science and Technology of the People's Republic of China (2024YFA1802600)
  • National Natural Science Foundation of China (82271428)
  • National Natural Science Foundation of China (82301346)
  • Institute of Zoology, Chinese Academy of Sciences (2023IOZ0101)
  • Institute of Zoology, Chinese Academy of Sciences (2024IOZ0104)
  • Initiative Scientific Research Program, Beijing Institute for Stem Cell and Regenerative Medicine

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