ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes

作者：Hyein Lee, Sukhee Cho, Mi-Jin Kim, Yeo Jin Park, Eunji Cho, Yeon Suk Jo, Yong‐Seok Kim, Jung Yi Lee, Themis Thoudam, Seung‐Hwa Woo, Se-In Lee, Juyeong Jeon, Young‐Sam Lee, Byung‐Chang Suh, Jong Hyuk Yoon, Younghoon Go, In-Kyu Lee, Jinsoo Seo · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.113183 · 被引用次数：85 · 研究领域：Mitochondrial Function and Pathology、Adipose Tissue and Metabolism、Autophagy in Disease and Therapy

Recent developments in genome sequencing have expanded the knowledge of genetic factors associated with late-onset Alzheimer's disease (AD). Among them, genetic variant ε4 of the APOE gene (APOE4) confers the greatest disease risk. Dysregulated glucose metabolism is an early pathological feature of AD. Using isogenic ApoE3 and ApoE4 astrocytes derived from human induced pluripotent stem cells, we find that ApoE4 increases glycolytic activity but impairs mitochondrial respiration in astrocytes. Ultrastructural and autophagy flux analyses show that ApoE4-induced cholesterol accumulation impairs lysosome-dependent removal of damaged mitochondria. Acute treatment with cholesterol-depleting agents restores autophagic activity, mitochondrial dynamics, and associated proteomes, and extended treatment rescues mitochondrial respiration in ApoE4 astrocytes. Taken together, our study provides a direct link between ApoE4-induced lysosomal cholesterol accumulation and abnormal oxidative phosphorylation.