A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease.
A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease.
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DOI：
10.1038/s41419-017-0215-0
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发表时间：
2018-02-28
影响因子：
9
通讯作者：
Schon EA
中科院分区：
文献类型：
--
作者：
Area-Gomez E;de Groof A;Bonilla E;Montesinos J;Tanji K;Boldogh I;Pon L;Schon EA
在过去的几年中，越来越多的重点一直致力于了解的贡献，与内质网（ER）膜（MAM）的人类病理学一般，特别是神经退行性疾病。一个主要原因是ER的这个亚结构域在代谢调节和线粒体生物学中起着中心作用。因此，MAM功能异常可能有助于解释神经退行性变中常见的看似无关的代谢异常。在阿尔茨海默病（AD）的特定情况下，除了钙和脂质稳态的扰动之外，还有许多记录的线粒体行为和功能的改变，包括呼吸链活性和氧化磷酸化降低，自由基产生增加，以及细胞器形态、动力学和定位（特别是核周线粒体）改变。然而，这些改变是否是导致疾病的主要事件，或者是其他一些更根本的问题导致的次要下游事件，仍然不清楚。为了支持前一种可能性，我们最近报道了C99，淀粉样前体蛋白（APP）的C-末端加工产物，来源于β-分泌酶的切割，存在于MAM中，其水平在AD中增加，并且这种增加减少线粒体呼吸，可能通过C99诱导的细胞鞘脂稳态改变。因此，在AD中观察到的代谢紊乱可能是由MAM处C99水平增加驱动的ER-线粒体通讯增加引起的。
In the last few years, increased emphasis has been devoted to understanding the contribution of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) to human pathology in general, and neurodegenerative diseases in particular. A major reason for this is the central role that this subdomain of the ER plays in metabolic regulation and in mitochondrial biology. As such, aberrant MAM function may help explain the seemingly unrelated metabolic abnormalities often seen in neurodegeneration. In the specific case of Alzheimer disease (AD), besides perturbations in calcium and lipid homeostasis, there are numerous documented alterations in mitochondrial behavior and function, including reduced respiratory chain activity and oxidative phosphorylation, increased free radical production, and altered organellar morphology, dynamics, and positioning (especially perinuclear mitochondria). However, whether these alterations are primary events causative of the disease, or are secondary downstream events that are the result of some other, more fundamental problem, is still unclear. In support of the former possibility, we recently reported that C99, the C-terminal processing product of the amyloid precursor protein (APP) derived from its cleavage by β-secretase, is present in MAM, that its level is increased in AD, and that this increase reduces mitochondrial respiration, likely via a C99-induced alteration in cellular sphingolipid homeostasis. Thus, the metabolic disturbances seen in AD likely arise from increased ER-mitochondrial communication that is driven by an increase in the levels of C99 at the MAM.
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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：
4
作者：
Area-Gomez E;Schon EA
通讯作者：
Schon EA
影响因子：
2.1
作者：
Chen, Xi;Stern, David;Yan, Shi Du
通讯作者：
Yan, Shi Du
影响因子：
3
作者：
Coskun, Pinar;Wyrembak, Joanne;Schriner, Samual E.;Chen, Hsiao-Wen;Marciniack, Christine;LaFerla, Frank;Wallace, Douglas C.
通讯作者：
Wallace, Douglas C.
影响因子：
4.2
作者：
Bosetti, F;Brizzi, F;Solaini, G
通讯作者：
Solaini, G