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

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

doi:10.1016/j.celrep.2023.113183

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

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

Research output: Contribution to journal › Article › peer-review

21 Scopus citations

Abstract

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.

Original language	English
Article number	113183
Journal	Cell Reports
Volume	42
Issue number	10
DOIs	https://doi.org/10.1016/j.celrep.2023.113183
State	Published - 31 Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

ApoE4
CP: Cell biology
CP: Metabolism
glucose metabolism
human astrocytes
lysosomal cholesterol accumulation
mitophagy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.113183

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Lee, H., Cho, S., Kim, M. J., Park, Y. J., Cho, E., Jo, Y. S., Kim, Y. S., Lee, J. Y., Thoudam, T., Woo, S. H., Lee, S. I., Jeon, J., Lee, Y. S., Suh, B. C., Yoon, J. H., Go, Y., Lee, I. K., & Seo, J. (2023). ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes. Cell Reports, 42(10), Article 113183. https://doi.org/10.1016/j.celrep.2023.113183

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title = "ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes",

abstract = "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.",

keywords = "ApoE4, CP: Cell biology, CP: Metabolism, glucose metabolism, human astrocytes, lysosomal cholesterol accumulation, mitophagy",

author = "Hyein Lee and Sukhee Cho and Kim, {Mi Jin} and Park, {Yeo Jin} and Eunji Cho and Jo, {Yeon Suk} and Kim, {Yong Seok} and Lee, {Jung Yi} and Themis Thoudam and Woo, {Seung Hwa} and Lee, {Se In} and Juyeong Jeon and Lee, {Young Sam} and Suh, {Byung Chang} and Yoon, {Jong Hyuk} and Younghoon Go and Lee, {In Kyu} and Jinsoo Seo",

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Lee, H, Cho, S, Kim, MJ, Park, YJ, Cho, E, Jo, YS, Kim, YS, Lee, JY, Thoudam, T, Woo, SH, Lee, SI, Jeon, J, Lee, YS , Suh, BC, Yoon, JH, Go, Y, Lee, IK & Seo, J 2023, 'ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes', Cell Reports, vol. 42, no. 10, 113183. https://doi.org/10.1016/j.celrep.2023.113183

TY - JOUR

T1 - ApoE4-dependent lysosomal cholesterol accumulation impairs mitochondrial homeostasis and oxidative phosphorylation in human astrocytes

AU - Lee, Hyein

AU - Cho, Sukhee

AU - Kim, Mi Jin

AU - Park, Yeo Jin

AU - Cho, Eunji

AU - Jo, Yeon Suk

AU - Kim, Yong Seok

AU - Lee, Jung Yi

AU - Thoudam, Themis

AU - Woo, Seung Hwa

AU - Lee, Se In

AU - Jeon, Juyeong

AU - Lee, Young Sam

AU - Suh, Byung Chang

AU - Yoon, Jong Hyuk

AU - Go, Younghoon

AU - Lee, In Kyu

AU - Seo, Jinsoo

PY - 2023/10/31

Y1 - 2023/10/31

N2 - 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.

AB - 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.

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KW - CP: Cell biology

KW - CP: Metabolism

KW - glucose metabolism

KW - human astrocytes

KW - lysosomal cholesterol accumulation

KW - mitophagy

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M3 - Article

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AN - SCOPUS:85172483411

SN - 2639-1856

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 10

M1 - 113183

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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