Rationale: Cardiac lipotoxicity, characterized by increased uptake, oxidation, and accumulation of lipid intermediates, contributes to cardiac dysfunction in obesity and diabetes mellitus. However, mechanisms linking lipid overload and mitochondrial dysfunction are incompletely understood.

Objective: To elucidate the mechanisms for mitochondrial adaptations to lipid overload in postnatal hearts in vivo.

Methods and Results: Using a transgenic mouse model of cardiac lipotoxicity overexpressing ACSL1 (long-chain acyl-CoA synthetase 1) in cardiomyocytes, we show that modestly increased myocardial fatty acid uptake leads to mitochondrial structural remodeling with significant reduction in minimum diameter. This is associated with increased palmitoyl-carnitine oxidation and increased reactive oxygen species (ROS) generation in isolated mitochondria. Mitochondrial morphological changes and elevated ROS generation are also observed in palmitate-treated neonatal rat ventricular cardiomyocytes. Palmitate exposure to neonatal rat ventricular cardiomyocytes initially activates mitochondrial respiration, coupled with increased mitochondrial polarization and ATP synthesis. However, long-term exposure to palmitate (>8 hours) enhances ROS generation, which is accompanied by loss of the mitochondrial reticulum and a pattern suggesting increased mitochondrial fission. Mechanistically, lipid-induced changes in mitochondrial redox status increased mitochondrial fission by increased ubiquitination of AKAP121 (A-kinase anchor protein 121) leading to reduced phosphorylation of DRP1 (dynamin-related protein 1) at Ser637 and altered proteolytic processing of OPA1 (optic atrophy 1). Scavenging mitochondrial ROS restored mitochondrial morphology in vivo and in vitro.

Conclusions: Our results reveal a molecular mechanism by which lipid overload-induced mitochondrial ROS generation causes mitochondrial dysfunction by inducing post-translational modifications of mitochondrial proteins that regulate mitochondrial dynamics. These findings provide a novel mechanism for mitochondrial dysfunction in lipotoxic cardiomyopathy.

基本原理：心脏脂毒性，以脂质中间体的摄取、氧化和积累增加为特征，导致肥胖和糖尿病患者的心脏功能障碍。然而，将脂质超载和线粒体功能障碍联系起来的机制尚不完全清楚。

目的：阐明体内线粒体适应产后心脏脂质过载的机制。

方法和结果：使用在心肌细胞中过表达 ACSL1（长链酰基辅酶 A 合成酶 1）的心脏脂毒性转基因小鼠模型，我们发现适度增加的心肌脂肪酸摄取导致线粒体结构重塑，最小直径显着减小。这与分离的线粒体中增加的棕榈酰肉碱氧化和增加的活性氧 (ROS) 生成有关。在棕榈酸酯处理的新生大鼠心室心肌细胞中也观察到线粒体形态学变化和升高的 ROS 生成。棕榈酸酯暴露于新生大鼠心室心肌细胞最初会激活线粒体呼吸，同时增加线粒体极化和 ATP 合成。然而，长期暴露于棕榈酸酯（>8 小时）会增强 ROS 的产生，这伴随着线粒体网的丧失和表明线粒体裂变增加的模式。机制上，脂质诱导的线粒体氧化还原状态变化通过增加 AKAP121（A 激酶锚定蛋白 121）的泛素化增加线粒体裂变，导致 Ser637 处 DRP1（动力相关蛋白 1）的磷酸化降低和 OPA1 的蛋白水解加工改变（视神经萎缩） 1）。清除线粒体 ROS 在体内和体外恢复了线粒体形态。脂质诱导的线粒体氧化还原状态变化通过增加 AKAP121（A 激酶锚定蛋白 121）的泛素化增加线粒体裂变，导致 Ser637 处 DRP1（动力相关蛋白 1）的磷酸化减少和 OPA1 的蛋白水解加工改变（视神经萎缩 1） . 清除线粒体 ROS 在体内和体外恢复了线粒体形态。脂质诱导的线粒体氧化还原状态变化通过增加 AKAP121（A 激酶锚定蛋白 121）的泛素化增加线粒体裂变，导致 Ser637 处 DRP1（动力相关蛋白 1）的磷酸化减少和 OPA1 的蛋白水解加工改变（视神经萎缩 1） . 清除线粒体 ROS 在体内和体外恢复了线粒体形态。

结论：我们的研究结果揭示了脂质超载诱导的线粒体 ROS 产生通过诱导调节线粒体动力学的线粒体蛋白的翻译后修饰导致线粒体功能障碍的分子机制。这些发现为脂毒性心肌病中的线粒体功能障碍提供了一种新的机制。