Poration of mitochondrial membranes by amyloidogenic peptides and other biological toxins.

IF 4.2 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Journal of Neurochemistry Pub Date : 2024-08-30 DOI:10.1111/jnc.16213
Neville Vassallo
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Abstract

Mitochondria are essential organelles known to serve broad functions, including in cellular metabolism, calcium buffering, signaling pathways and the regulation of apoptotic cell death. Maintaining the integrity of the outer (OMM) and inner mitochondrial membranes (IMM) is vital for mitochondrial health. Cardiolipin (CL), a unique dimeric glycerophospholipid, is the signature lipid of energy-converting membranes. It plays a significant role in maintaining mitochondrial architecture and function, stabilizing protein complexes and facilitating efficient oxidative phosphorylation (OXPHOS) whilst regulating cytochrome c release from mitochondria. CL is especially enriched in the IMM and at sites of contact between the OMM and IMM. Disorders of protein misfolding, such as Alzheimer's and Parkinson's diseases, involve amyloidogenic peptides like amyloid-β, tau and α-synuclein, which form metastable toxic oligomeric species that interact with biological membranes. Electrophysiological studies have shown that these oligomers form ion-conducting nanopores in membranes mimicking the IMM's phospholipid composition. Poration of mitochondrial membranes disrupts the ionic balance, causing osmotic swelling, loss of the voltage potential across the IMM, release of pro-apoptogenic factors, and leads to cell death. The interaction between CL and amyloid oligomers appears to favour their membrane insertion and pore formation, directly implicating CL in amyloid toxicity. Additionally, pore formation in mitochondrial membranes is not limited to amyloid proteins and peptides; other biological peptides, as diverse as the pro-apoptotic Bcl-2 family members, gasdermin proteins, cobra venom cardiotoxins and bacterial pathogenic toxins, have all been described to punch holes in mitochondria, contributing to cell death processes. Collectively, these findings underscore the vulnerability of mitochondria and the involvement of CL in various pathogenic mechanisms, emphasizing the need for further research on targeting CL-amyloid interactions to mitigate mitochondrial dysfunction.

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淀粉样肽和其他生物毒素对线粒体膜的分隔作用。
线粒体是重要的细胞器,具有广泛的功能,包括细胞代谢、钙缓冲、信号通路和细胞凋亡调控。保持线粒体外膜(OMM)和内膜(IMM)的完整性对线粒体的健康至关重要。心磷脂(CL)是一种独特的二聚甘油磷脂,是能量转换膜的标志性脂质。它在维持线粒体结构和功能、稳定蛋白质复合物、促进高效氧化磷酸化(OXPHOS)以及调节线粒体释放细胞色素 c 方面发挥着重要作用。CL尤其富集在线粒体内膜和线粒体外膜与线粒体内膜的接触部位。阿尔茨海默氏症和帕金森氏症等蛋白质错误折叠疾病涉及淀粉样蛋白-β、tau 和 α-突触核蛋白等淀粉样蛋白肽,这些肽会形成可转移的有毒低聚物,与生物膜相互作用。电生理学研究表明,这些低聚物会在模仿 IMM 磷脂成分的膜上形成离子传导纳米孔。线粒体膜上的孔破坏了离子平衡,导致渗透膨胀、跨线粒体膜的电压电位下降、促凋亡因子释放并导致细胞死亡。CL 与淀粉样蛋白寡聚体之间的相互作用似乎有利于它们的膜插入和孔隙形成,这直接表明 CL 与淀粉样蛋白的毒性有关。此外,线粒体膜孔隙的形成并不局限于淀粉样蛋白和肽,其他生物肽,如促凋亡的 Bcl-2 家族成员、gasdermin 蛋白、眼镜蛇毒心脏毒素和细菌致病毒素,都被描述为在线粒体上打孔,导致细胞死亡的过程。总之,这些发现强调了线粒体的脆弱性以及CL在各种致病机制中的参与,强调了进一步研究针对CL-淀粉样蛋白相互作用以缓解线粒体功能障碍的必要性。
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来源期刊
Journal of Neurochemistry
Journal of Neurochemistry 医学-神经科学
CiteScore
9.30
自引率
2.10%
发文量
181
审稿时长
2.2 months
期刊介绍: Journal of Neurochemistry focuses on molecular, cellular and biochemical aspects of the nervous system, the pathogenesis of neurological disorders and the development of disease specific biomarkers. It is devoted to the prompt publication of original findings of the highest scientific priority and value that provide novel mechanistic insights, represent a clear advance over previous studies and have the potential to generate exciting future research.
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