Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models.
Amyloid Β-Peptide Increases Mitochondria-Endoplasmic Reticulum Contact Altering Mitochondrial Function and Autophagosome Formation in Alzheimer's Disease-Related Models.
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淀粉样蛋白B-肽增加线粒体-内质网接触改变阿尔茨海默病相关模型中线粒体功能和自噬体形成。
DOI：
10.3390/cells9122552
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发表时间：
2020-11-28
期刊：
影响因子：
6
通讯作者：
Ankarcrona M
中科院分区：
文献类型：
--
作者：
Leal NS;Dentoni G;Schreiner B;Naia L;Piras A;Graff C;Cattaneo A;Meli G;Hamasaki M;Nilsson P;Ankarcrona M
最近的研究结果表明，在阿尔茨海默病（AD）和AD相关模型中，线粒体与内质网（ER）在线粒体-内质网接触点（MERCS）之间的连通性和串扰发生了改变。MERCS与自噬体形成的初始步骤以及线粒体功能的调节有关。本研究在Aβ水平升高的不同AD动物模型以及来源于这些动物的原代神经元中，评估了MERCS、线粒体超微结构和功能以及自噬之间的相互作用。我们首先发现，在家族性AD患者死后的脑组织中，Mitofusin 1、Mitofusin 2和线粒体输入受体亚基TOM70的水平降低。我们还发现，Aβ增加了不同AD小鼠成年脑模型以及来源于这些动物的原代培养物中内质网和线粒体之间的并置。此外，暴露于Aβ的野生型神经元内质网和线粒体之间的连通性也增加。饥饿时MERCS的改变影响自噬体的形成、线粒体功能和ATP的形成。有趣的是，er -线粒体连通性的增加与线粒体活性的增加同时发生，随后是自噬体形成的上调，这是一个明确的时间顺序。总之，我们报告了Aβ可以通过调节MERCS来影响细胞稳态，从而改变线粒体活性和自噬体的形成。我们的数据表明MERCS是阿尔茨海默病药物发现的潜在靶点。
Recent findings have shown that the connectivity and crosstalk between mitochondria and the endoplasmic reticulum (ER) at mitochondria–ER contact sites (MERCS) are altered in Alzheimer’s disease (AD) and in AD-related models. MERCS have been related to the initial steps of autophagosome formation as well as regulation of mitochondrial function. Here, the interplay between MERCS, mitochondria ultrastructure and function and autophagy were evaluated in different AD animal models with increased levels of Aβ as well as in primary neurons derived from these animals. We start by showing that the levels of Mitofusin 1, Mitofusin 2 and mitochondrial import receptor subunit TOM70 are decreased in post-mortem brain tissue derived from familial AD. We also show that Aβ increases the juxtaposition between ER and mitochondria both in adult brain of different AD mouse models as well as in primary cultures derived from these animals. In addition, the connectivity between ER and mitochondria are also increased in wild-type neurons exposed to Aβ. This alteration in MERCS affects autophagosome formation, mitochondrial function and ATP formation during starvation. Interestingly, the increment in ER–mitochondria connectivity occurs simultaneously with an increase in mitochondrial activity and is followed by upregulation of autophagosome formation in a clear chronological sequence of events. In summary, we report that Aβ can affect cell homeostasis by modulating MERCS and, consequently, altering mitochondrial activity and autophagosome formation. Our data suggests that MERCS is a potential target for drug discovery in AD.
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AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
64.5
作者：
Cárdenas C;Miller RA;Smith I;Bui T;Molgó J;Müller M;Vais H;Cheung KH;Yang J;Parker I;Thompson CB;Birnbaum MJ;Hallows KR;Foskett JK
通讯作者：
Foskett JK
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.
影响因子：
13.3
作者：
Gelmetti, Vania;De Rosa, Priscilla;Valente, Enza Maria
通讯作者：
Valente, Enza Maria
影响因子：
9
作者：
Area-Gomez E;de Groof A;Bonilla E;Montesinos J;Tanji K;Boldogh I;Pon L;Schon EA
通讯作者：
Schon EA