Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.
Interactions of amyloidogenic proteins with mitochondrial protein import machinery in aging-related neurodegenerative diseases.
复制标题
DOI：
10.3389/fphys.2023.1263420
复制
发表时间：
2023
影响因子：
4
通讯作者：
中科院分区：
文献类型：
--
作者：
大多数线粒体蛋白质通过N-末端线粒体靶向序列(mTSS，或“前序列”)靶向细胞器，这些序列被进口机器识别，随后被切割以产生成熟蛋白质。MTSS没有保守的氨基酸组成，但具有共同的物理化学性质，包括能够在交替的面上形成富含碱性和疏水残基的两亲性α-螺旋结构。缺乏严格的序列保守意味着一些多肽可能被错误地定位到线粒体，特别是在细胞压力下。线粒体内蛋白质的病理性积聚与许多与衰老相关的神经退行性疾病有关，包括阿尔茨海默氏症、帕金森氏症和亨廷顿病。从机制上讲，这些疾病可能部分起源于线粒体分别与淀粉样蛋白前体蛋白(APP)或其裂解产物淀粉样蛋白(Aβ)，α-SYN)以及亨廷顿蛋白(α)的突变形式相互作用，部分是通过它们与线粒体蛋白输入机制的联系而介导的。新的证据表明，这些淀粉样蛋白可能提供隐蔽的靶向信号，作为MTS模拟物，可以被线粒体输入受体识别并运输到不同的线粒体区段。这些错误定位的蛋白质的积累可能会压倒进口机制及其相关的质量控制机制，从而促进神经疾病的进展。或者，淀粉样蛋白被线粒体摄取可能是清除细胞毒性蛋白的蛋白质质量控制机制的一部分。在这里，我们回顾了这些疾病的发病机制，因为它们与线粒体蛋白输入和对线粒体功能的影响有关，APP/Aβ，α-SYN和mHTT的哪些特征使它们适合于输入机制，以及如何利用这些信息开发治疗干预措施。
Most mitochondrial proteins are targeted to the organelle by N-terminal mitochondrial targeting sequences (MTSs, or “presequences”) that are recognized by the import machinery and subsequently cleaved to yield the mature protein. MTSs do not have conserved amino acid compositions, but share common physicochemical properties, including the ability to form amphipathic α-helical structures enriched with basic and hydrophobic residues on alternating faces. The lack of strict sequence conservation implies that some polypeptides can be mistargeted to mitochondria, especially under cellular stress. The pathogenic accumulation of proteins within mitochondria is implicated in many aging-related neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Mechanistically, these diseases may originate in part from mitochondrial interactions with amyloid-β precursor protein (APP) or its cleavage product amyloid-β (Aβ), α-synuclein (α-syn), and mutant forms of huntingtin (mHtt), respectively, that are mediated in part through their associations with the mitochondrial protein import machinery. Emerging evidence suggests that these amyloidogenic proteins may present cryptic targeting signals that act as MTS mimetics and can be recognized by mitochondrial import receptors and transported into different mitochondrial compartments. Accumulation of these mistargeted proteins could overwhelm the import machinery and its associated quality control mechanisms, thereby contributing to neurological disease progression. Alternatively, the uptake of amyloidogenic proteins into mitochondria may be part of a protein quality control mechanism for clearance of cytotoxic proteins. Here we review the pathomechanisms of these diseases as they relate to mitochondrial protein import and effects on mitochondrial function, what features of APP/Aβ, α-syn and mHtt make them suitable substrates for the import machinery, and how this information can be leveraged for the development of therapeutic interventions.
登录
查看更多内容
DOI：
10.3233/jad-2011-101716
发表时间：
2011
期刊：
Journal of Alzheimer's disease : JAD
影响因子：
--
作者：
Alikhani N;Guo L;Yan S;Du H;Pinho CM;Chen JX;Glaser E;Yan SS
通讯作者：
Yan SS
影响因子：
4
作者：
Genge MG;Mokranjac D
通讯作者：
Mokranjac D
影响因子：
4.1
作者：
Ahmad Z;Laughlin TF
通讯作者：
Laughlin TF
Sideroflexin 3是一种调节突触形态的α-突触核蛋白依赖性线粒体蛋白。
影响因子：
4
作者：
Amorim IS;Graham LC;Carter RN;Morton NM;Hammachi F;Kunath T;Pennetta G;Carpanini SM;Manson JC;Lamont DJ;Wishart TM;Gillingwater TH
通讯作者：
Gillingwater TH
影响因子：
6
作者：
通讯作者：
--