The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.
The mitochondrial unfolded protein response regulates hippocampal neural stem cell aging.
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DOI：
10.1016/j.cmet.2023.04.012
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发表时间：
2023-04
期刊：
影响因子：
29
通讯作者：
C. Wang;Rika Ohkubo;Wei‐Chieh Mu;Wei Chen;J. Fan;Zehan Song;Ayane Maruichi;Peter H. Sudmant;A. Pisco;D. Dubal;Na Ji;Danica Chen
中科院分区：
文献类型：
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作者：
C. Wang;Rika Ohkubo;Wei‐Chieh Mu;Wei Chen;J. Fan;Zehan Song;Ayane Maruichi;Peter H. Sudmant;A. Pisco;D. Dubal;Na Ji;Danica Chen
衰老导致神经干细胞（NSC）、神经发生和认知功能下降，有证据表明患有多种神经退行性疾病的患者海马中的成人神经发生受到破坏。在此，对年轻和老年小鼠齿状回的单细胞RNA测序表明，线粒体蛋白折叠应激在神经源性生态位中激活的神经干细胞/神经祖细胞（NPC）中表现突出，并且随着年龄的增长，线粒体蛋白折叠应激随着年龄的增长而增加，伴随着细胞周期和线粒体的失调。激活的神经干细胞/神经祖细胞（NPC）在齿状回中的活性。增加线粒体蛋白折叠应激导致NSC维持受损和齿状回神经发生减少、神经活动过度和认知功能受损。减少老年小鼠齿状回线粒体蛋白折叠应激可改善神经发生和认知功能。这些结果确立了线粒体蛋白折叠应激作为NSC衰老的驱动因素，并提出了改善衰老相关认知能力下降的方法。
Aging results in a decline in neural stem cells (NSCs), neurogenesis, and cognitive function, and evidence is emerging to demonstrate disrupted adult neurogenesis in the hippocampus of patients with several neurodegenerative disorders. Here, single-cell RNA sequencing of the dentate gyrus of young and old mice shows that the mitochondrial protein folding stress is prominent in activated NSCs/neural progenitors (NPCs) among the neurogenic niche, and it increases with aging accompanying dysregulated cell cycle and mitochondrial activity in activated NSCs/NPCs in the dentate gyrus. Increasing mitochondrial protein folding stress results in compromised NSC maintenance and reduced neurogenesis in the dentate gyrus, neural hyperactivity, and impaired cognitive function. Reducing mitochondrial protein folding stress in the dentate gyrus of old mice improves neurogenesis and cognitive function. These results establish the mitochondrial protein folding stress as a driver of NSC aging and suggest approaches to improve aging-associated cognitive decline.