Mitochondria possess a double-membrane envelope which is susceptible to insult by pathogenic intracellular aggregates of amyloid-forming peptides, such as the amyloid-beta (1-42) (Aβ42) peptide and the human islet amyloid polypeptide (hIAPP). The molecular composition of membranes plays a pivotal role in regulating peptide aggregation and cytotoxicity. Therefore, we hypothesized that modifying the physicochemical properties of mitochondrial model membranes with a small molecule might act as a countermeasure against the formation of, and damage by, membrane-active amyloid peptides. To investigate this, we inserted the natural ubiquinone Coenzyme Q10 (CoQ10) in model mito-mimetic lipid vesicles, and studied how they interacted with Aβ42 and hIAPP peptide monomers and oligomers. Our results demonstrate that the membrane incorporation of CoQ10 significantly attenuated fibrillization of the peptides, whilst also making the membranes more resilient against peptide-induced permeabilization. Furthermore, these protective effects were linked with the ability of CoQ10 to enhance membrane packing in the inner acyl chain region, which increased the mechanical stability of the vesicle membranes. Based on our collective observations, we propose that mitochondrial resilience against toxic biomolecules implicit in protein misfolding disorders such as Alzheimer's disease and type-2 diabetes, could potentially be enhanced by increasing CoQ10 levels within mitochondria.

Keywords: aggregation; amyloid peptides; coenzyme Q10; leakage; lipid vesicles; membranes; mitochondria.

线粒体具有双层膜结构，容易受到病理性细胞内淀粉样肽聚集体（如Aβ42肽和人胰岛淀粉样多肽hIAPP）的损伤。膜分子组成在调节肽聚集和细胞毒性方面起着关键作用。因此，我们假设通过小分子改变线粒体模型膜的理化性质可以作为针对膜活性淀粉样肽形成的及由此产生的损害的一种对策。为此，我们在模拟线粒体脂质囊泡中插入了天然辅酶Q10（CoQ10），并研究了它们与Aβ42和hIAPP单体及寡聚体的相互作用。我们的结果表明，膜中掺入CoQ10显著减弱了肽的纤维化，并使膜更加抵抗由肽诱导的渗透性损伤。此外，这些保护效果与CoQ10增强膜内部脂肪链区域堆积、从而提高囊泡膜机械稳定性的能力有关。根据我们的一系列观察结果，我们提出可以通过增加线粒体内辅酶Q10的水平来增强线粒体对包括阿尔茨海默病和2型糖尿病在内的蛋白质错误折叠疾病中毒性生物分子的耐受性。

关键词：聚集；淀粉样肽；辅酶Q10；泄漏；脂质囊泡；膜；线粒体。