RATIONALE Lipid overload-induced heart dysfunction is characterized by cardiomyocyte death, myocardial remodeling, and compromised contractility, but the impact of excessive lipid supply on cardiac function remains poorly understood. OBJECTIVE To investigate the regulation and function of the mitochondrial fission protein Drp1 (dynamin-related protein 1) in lipid overload-induced cardiomyocyte death and heart dysfunction. METHODS AND RESULTS Mice fed a high-fat diet (HFD) developed signs of obesity and type II diabetes mellitus, including hyperlipidemia, hyperglycemia, hyperinsulinemia, and hypertension. HFD for 18 weeks also induced heart hypertrophy, fibrosis, myocardial insulin resistance, and cardiomyocyte death. HFD stimulated mitochondrial fission in mouse hearts. Furthermore, HFD increased the protein level, phosphorylation (at the activating serine 616 sites), oligomerization, mitochondrial translocation, and GTPase activity of Drp1 in mouse hearts, indicating that Drp1 was activated. Monkeys fed a diet high in fat and cholesterol for 2.5 years also exhibited myocardial damage and Drp1 activation in the heart. Interestingly, HFD decreased nicotinamide adenine dinucleotide (oxidized) levels and increased Drp1 acetylation in the heart. In adult cardiomyocytes, palmitate increased Drp1 acetylation, phosphorylation, and protein levels, and these increases were abolished by restoration of the decreased nicotinamide adenine dinucleotide (oxidized) level. Proteomics analysis and in vitro screening revealed that Drp1 acetylation at lysine 642 (K642) was increased by HFD in mouse hearts and by palmitate incubation in cardiomyocytes. The nonacetylated Drp1 mutation (K642R) attenuated palmitate-induced Drp1 activation, its interaction with voltage-dependent anion channel 1, mitochondrial fission, contractile dysfunction, and cardiomyocyte death. CONCLUSIONS These findings uncover a novel mechanism that contributes to lipid overload-induced heart hypertrophy and dysfunction. Excessive lipid supply created an intracellular environment that facilitated Drp1 acetylation, which, in turn, increased its activity and mitochondrial translocation, resulting in cardiomyocyte dysfunction and death. Thus, Drp1 may be a critical mediator of lipid overload-induced heart dysfunction as well as a potential target for therapy.

中文翻译：

---

脂质超载引起的Drp1乙酰化增加导致心肌细胞死亡和心脏功能障碍。

RATIONALE脂质超负荷引起的心脏功能障碍的特征是心肌细胞死亡，心肌重塑和收缩力下降，但对脂质供应过多对心脏功能的影响知之甚少。目的探讨线粒体裂变蛋白Drp1（动力相关蛋白1）在脂质超负荷引起的心肌细胞死亡和心脏功能障碍中的调控作用。方法和结果喂高脂饮食（HFD）的小鼠出现肥胖和II型糖尿病的体征，包括高脂血症，高血糖症，高胰岛素血症和高血压。HFD治疗18周还会诱发心脏肥大，纤维化，心肌胰岛素抵抗和心肌细胞死亡。HFD刺激小鼠心脏中的线粒体裂变。此外，HFD增加了蛋白质水平，磷酸化（在激活的丝氨酸616位），寡聚化，线粒体易位和Drp1在小鼠心脏中的GTPase活性，表明Drp1已激活。食用高脂肪和高胆固醇饮食2.5年的猴子也表现出心肌损害和心脏Drp1激活。有趣的是，HFD降低了心脏的烟酰胺腺嘌呤二核苷酸（氧化）水平并增加了Drp1乙酰化。在成年心肌细胞中，棕榈酸酯增加了Drp1的乙酰化，磷酸化和蛋白质水平，并且通过恢复降低的烟酰胺腺嘌呤二核苷酸（氧化）水平消除了这些增加。蛋白质组学分析和体外筛选显示，小鼠心脏中的HFD和心肌细胞中的棕榈酸酯孵育可增加赖氨酸642（K642）上的Drp1乙酰化。非乙酰化的Drp1突变（K642R）减弱了棕榈酸酯诱导的Drp1激活，其与电压依赖性阴离子通道1，线粒体裂变，收缩功能障碍和心肌细胞死亡的相互作用。结论这些发现揭示了一种新的机制，该机制有助于脂质超负荷引起的心脏肥大和功能障碍。过多的脂质供应创造了促进Drp1乙酰化的细胞内环境，进而增加了其活性和线粒体易位性，导致心肌细胞功能障碍和死亡。因此，Drp1可能是脂质超负荷引起的心脏功能障碍的关键介质，也是治疗的潜在靶标。和心肌细胞死亡。结论这些发现揭示了一种新的机制，该机制有助于脂质超负荷引起的心脏肥大和功能障碍。过多的脂质供应创造了促进Drp1乙酰化的细胞内环境，进而增加了其活性和线粒体易位性，导致心肌细胞功能障碍和死亡。因此，Drp1可能是脂质超负荷引起的心脏功能障碍的关键介质，也是治疗的潜在靶标。和心肌细胞死亡。结论这些发现揭示了一种新的机制，该机制有助于脂质超负荷引起的心脏肥大和功能障碍。过多的脂质供应创造了促进Drp1乙酰化的细胞内环境，进而增加了其活性和线粒体易位性，导致心肌细胞功能障碍和死亡。因此，Drp1可能是脂质超负荷引起的心脏功能障碍的关键介质，也是治疗的潜在靶标。导致心肌细胞功能障碍和死亡。因此，Drp1可能是脂质超负荷引起的心脏功能障碍的关键介质，也是治疗的潜在靶标。导致心肌细胞功能障碍和死亡。因此，Drp1可能是脂质超负荷引起的心脏功能障碍的关键介质，也是治疗的潜在靶标。