Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity.
Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity.
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DOI：
10.3390/ijms24065525
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发表时间：
2023-03-14
影响因子：
5.6
通讯作者：
Chang, Ta Yuan
中科院分区：
文献类型：
--
作者：
Harned, Taylor C.;Stan, Radu V.;Cao, Ze;Chakrabarti, Rajarshi;Higgs, Henry N.;Chang, Catherine C. Y.;Chang, Ta Yuan
关键词：
胆固醇是所有哺乳动物细胞膜的关键成分。在各种疾病的背景下观察到胆固醇代谢的中断，包括阿尔茨海默病(AD)等神经退行性疾病。乙酰辅酶A：胆固醇酰基转移酶1/固醇O-酰基转移酶1(ACAT1/SOAT1)是一种发现于内质网(ER)并富含在线粒体相关ER膜(MAM)上的胆固醇储存酶，已被证明可以减少淀粉样蛋白病理和挽救AD小鼠模型的认知功能障碍。此外，阻断ACAT1/SOAT1活性可刺激自噬和溶酶体的生物发生；然而，ACAT1/SOAT1阻断与这些观察到的益处之间的确切分子联系仍不清楚。在这里，使用生化分离技术，我们观察到胆固醇在MAM积累，导致ACAT1/SOAT1在该区域丰富。MAM蛋白质组学数据表明，ACAT1/SOAT1抑制增强了ER-线粒体的连接。共聚焦和电子显微镜证实，ACAT1/SOAT1抑制增加了ER-线粒体接触位点的数量，并通过缩短这两个细胞器之间的距离而加强了这种联系。这项工作证明了直接操纵MAM的局部胆固醇水平如何改变细胞器间的接触部位，并表明MAM的胆固醇积聚是ACAT1/SOAT1抑制治疗益处背后的动力。
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.
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影响因子：
4.8
作者：
Chan, Robin B.;Oliveira, Tiago G.;Di Paolo, Gilbert
通讯作者：
Di Paolo, Gilbert
影响因子：
11.4
作者：
Area-Gomez, Estela;Castillo, Maria Del Carmen Lara;Tambini, Marc D.;Guardia-Laguarta, Cristina;de Groof, Ad J. C.;Madra, Moneek;Ikenouchi, Junichi;Umeda, Masato;Bird, Thomas D.;Sturley, Stephen L.;Schon, Eric A.
通讯作者：
Schon, Eric A.
DOI：
10.1073/pnas.77.7.3957
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
ALBERTS, AW;CHEN, J;SPRINGER, J
通讯作者：
SPRINGER, J
影响因子：
1.7
作者：
Frears, ER;Stephens, DJ;Austen, BM
通讯作者：
Austen, BM
影响因子：
4.8
作者：
Fernández-Pérez EJ;Sepúlveda FJ;Peters C;Bascuñán D;Riffo-Lepe NO;González-Sanmiguel J;Sánchez SA;Peoples RW;Vicente B;Aguayo LG
通讯作者：
Aguayo LG