Aβ-induced mitochondrial dysfunction in neural progenitors controls KDM5A to influence neuronal differentiation

Dong Kyu Kim, Hyobin Jeong, Jingi Bae, Moon Yong Cha, Moonkyung Kang, Dongjin Shin, Shinwon Ha, Seung Jae Hyeon, Hokeun Kim, Kyujin Suh, Mi Sun Choi, Hoon Ryu, Seong Woon Yu, Jong Il Kim, Yeon Soo Kim, Sang Won Lee, Daehee Hwang, Inhee Mook-Jung

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondria in neural progenitors play a crucial role in adult hippocampal neurogenesis by being involved in fate decisions for differentiation. However, the molecular mechanisms by which mitochondria are related to the genetic regulation of neuronal differentiation in neural progenitors are poorly understood. Here, we show that mitochondrial dysfunction induced by amyloid-beta (Aβ) in neural progenitors inhibits neuronal differentiation but has no effect on the neural progenitor stage. In line with the phenotypes shown in Alzheimer’s disease (AD) model mice, Aβ-induced mitochondrial damage in neural progenitors results in deficits in adult hippocampal neurogenesis and cognitive function. Based on hippocampal proteome changes after mitochondrial damage in neural progenitors identified through proteomic analysis, we found that lysine demethylase 5A (KDM5A) in neural progenitors epigenetically suppresses differentiation in response to mitochondrial damage. Mitochondrial damage characteristically causes KDM5A degradation in neural progenitors. Since KDM5A also binds to and activates neuronal genes involved in the early stage of differentiation, functional inhibition of KDM5A consequently inhibits adult hippocampal neurogenesis. We suggest that mitochondria in neural progenitors serve as the checkpoint for neuronal differentiation via KDM5A. Our findings not only reveal a cell-type-specific role of mitochondria but also suggest a new role of KDM5A in neural progenitors as a mediator of retrograde signaling from mitochondria to the nucleus, reflecting the mitochondrial status.

Original languageEnglish
Pages (from-to)1461-1471
Number of pages11
JournalExperimental and Molecular Medicine
Volume54
Issue number9
DOIs
StatePublished - Sep 2022

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