Vassallo Neville
Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Tal-Qroqq, Malta.
Centre for Molecular Medicine and Biobanking, University of Malta, Tal-Qroqq, Malta.
J Neurochem. 2025 Jan;169(1):e16213. doi: 10.1111/jnc.16213. Epub 2024 Aug 30.
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.
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、信号通路以及凋亡性细胞死亡的调控。维持线粒体外膜（OMM）和内膜（IMM）的完整性对于线粒体健康至关重要。心磷脂（CL）是一种独特的二聚体甘油磷脂，是能量转换膜的标志性脂质。它在维持线粒体结构和功能、稳定蛋白质复合物以及促进高效氧化磷酸化（OXPHOS）方面发挥着重要作用，同时调节细胞色素c从线粒体的释放。CL特别富集于IMM以及OMM和IMM之间的接触位点。蛋白质错误折叠疾病，如阿尔茨海默病和帕金森病，涉及淀粉样蛋白肽，如淀粉样β蛋白、tau蛋白和α-突触核蛋白，它们形成亚稳态的有毒寡聚体，与生物膜相互作用。电生理学研究表明，这些寡聚体在模拟IMM磷脂组成的膜中形成离子传导纳米孔。线粒体膜的穿孔破坏了离子平衡，导致渗透性肿胀、IMM跨膜电位丧失、促凋亡因子释放，并导致细胞死亡。CL与淀粉样寡聚体之间的相互作用似乎有利于它们插入膜并形成孔，直接表明CL参与淀粉样毒性。此外，线粒体膜上的孔形成并不局限于淀粉样蛋白和肽；其他生物肽，如促凋亡Bcl-2家族成员、gasdermin蛋白、眼镜蛇毒心脏毒素和细菌致病毒素，都被描述为能在线粒体上打孔，促进细胞死亡过程。总的来说，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作用，强调了进一步研究靶向CL-淀粉样相互作用以减轻线粒体功能障碍的必要性。
