Excessive accumulation of acylcarnitines (ACs), often caused by metabolic disorders, has been associated with obesity, arrhythmias, cardiac ischemia, insulin resistance, etc. Mechanisms whereby elevated ACs might contribute to pathophysiological effects remain largely unexplored. We have aimed to gain insight into AC interactions with the mitochondrial inner membrane. To model its outer leaflet, Langmuir monolayers and cushioned supported bilayers were employed. Their interactions with ACs were monitored with epifluorescence microscopy, which revealed a local leaflet expansion upon exposure to elevated concentrations of a long-chain AC, plausibly caused by its insertion. To assess the AC insertion parameters, constant-pressure insertion assays were performed. A value of 21 ± 3 Å2 was obtained for the AC insertion area, which is roughly the same as the cross-sectional area of an acyl chain. By contrast, the carnitine moiety was found to require an area of 37 ± 3 Å2. The AC insertion has thus been concluded to involve solely the AC acyl chain. This mode of insertion implies that the carnitine moiety, with its nontitratable positive charge, is left dangling at the membrane surface, which is likely to alter the surface electrostatics of the outer leaflet. The extrapolation of these findings has enabled us to hypothesize that, by altering the morphology and surface electrostatics of the outer leaflet, the insertion of ACs, in particular their long-chain counterparts, may trigger a nonspecific activation of signaling pathways in the inner mitochondrial membrane, thereby modulating its function and potentially leading to pathophysiological responses.

中文翻译：

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膜表面的酰基肉碱：线粒体传单模型的插入参数

通常由代谢紊乱引起的酰基肉碱 (AC) 的过度积累与肥胖、心律失常、心脏缺血、胰岛素抵抗等有关。 AC 升高可能导致病理生理效应的机制在很大程度上仍未得到探索。我们的目标是深入了解 AC 与线粒体内膜的相互作用。为了模拟它的外叶，Langmuir 单层和缓冲支撑的双层被采用。它们与 AC 的相互作用用落射荧光显微镜进行监测，这表明在暴露于高浓度的长链 AC 时，局部小叶扩张，这可能是由其插入引起的。为了评估交流插入参数，进行了恒压插入试验。AC 插入区域的值为 21 ± 3 Å2，这与酰基链的横截面积大致相同。相比之下，发现肉碱部分需要 37 ± 3 Å2 的面积。因此已经得出结论，AC 插入仅涉及 AC 酰基链。这种插入模式意味着带有不可滴定正电荷的肉碱部分悬在膜表面，这可能会改变外叶的表面静电。这些发现的推断使我们能够假设，通过改变外小叶的形态和表面静电，AC 的插入，特别是它们的长链对应物，可能会触发线粒体内膜中信号通路的非特异性激活，从而调节其功能并可能导致病理生理反应。