Document Type
Article
Publication Date
3-14-2023
Abstract
Cholesterol is a key component of all mammalian cell membranes. Disruptions in cholesterol metabolism have been observed in the context of various diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). The genetic and pharmacological blockade of acyl-CoA:cholesterol acyltransferase 1/sterol O-acyltransferase 1 (ACAT1/SOAT1), a cholesterol storage enzyme found on the endoplasmic reticulum (ER) and enriched at the mitochondria-associated ER membrane (MAM), has been shown to reduce amyloid pathology and rescue cognitive deficits in mouse models of AD. Additionally, blocking ACAT1/SOAT1 activity stimulates autophagy and lysosomal biogenesis; however, the exact molecular connection between the ACAT1/SOAT1 blockade and these observed benefits remain unknown. Here, using biochemical fractionation techniques, we observe cholesterol accumulation at the MAM which leads to ACAT1/SOAT1 enrichment in this domain. MAM proteomics data suggests that ACAT1/SOAT1 inhibition strengthens the ER-mitochondria connection. Confocal and electron microscopy confirms that ACAT1/SOAT1 inhibition increases the number of ER-mitochondria contact sites and strengthens this connection by shortening the distance between these two organelles. This work demonstrates how directly manipulating local cholesterol levels at the MAM can alter inter-organellar contact sites and suggests that cholesterol buildup at the MAM is the impetus behind the therapeutic benefits of ACAT1/SOAT1 inhibition.
Recommended Citation
Harned, Taylor C; Stan, Radu V; Cao, Ze; Chakrabarti, Rajarshi; Higgs, Henry N; Chang, Catherine C Y; and Chang, Ta Yuan, "Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity." (2023). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 389.
https://jdc.jefferson.edu/pacbfp/389
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
36982602
Language
English
Included in
Medical Anatomy Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Pathology Commons
Comments
This article is the author's final published version in International Journal of Molecular Sciences, Volume 24, Issue 6, March 2023, Article number 5525.
The published version is available at https://doi.org/10.3390/ijms24065525.
Copyright © © 2023 by the authors. Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and
conditions of the Creative Commons Attribution (CC BY) license (https://
creativecommons.org/licenses/by/4.0/).