Increased Drp1 acetylation by lipid overload induces cardiomyocyte death and heart dysfunction

Metabolic syndrome is a cluster of abnormalities characterized by obesity and insulin resistance, which compromise energy metabolism, damage mitochondria, cause cardiomyocyte death, and eventually impair heart contraction and relaxation performance. Despite the increasing prevalence of heart complications in obese and diabetic patients, our knowledge on how obese and diabetes mellitus impair heart function is very limited. In this study, we used animal and cell culture models in rodents or monkeys and generated lipid overload models to mimic obesity conditions. We found that excessive lipid supply decreased nicotinamide adenine dinucleotide (oxidized) levels and increased the acetylation of a fission protein Drp1 at a specific lysine residue (K642). Drp1 acetylation at K642 activated Drp1 through phosphorylation, mitochondrial translocation, and oligomerization. The excessively activated Drp1 had higher GTPase activity, bound with VDAC1 on mitochondria, induced mitochondrial fission, and caused cardiomyocyte death. These findings provide new information regarding how lipid overload regulates redox environment, protein acetylation, and the function of mitochondrial fission protein Drp1 in the heart.

代谢综合征（Metabolic syndrome）是一类以肥胖与胰岛素抵抗为特征的异常症候群，该病症会损害能量代谢、损伤线粒体、引发心肌细胞死亡，最终损害心脏的收缩与舒张功能。尽管肥胖与糖尿病（diabetes mellitus）患者的心脏并发症发病率持续上升，但目前学界对肥胖与糖尿病如何损害心脏功能的认知仍十分有限。本研究采用啮齿类动物、非人灵长类动物的动物模型与细胞培养模型，并构建脂质过载模型以模拟肥胖状态。研究发现，过量脂质供给会降低烟酰胺腺嘌呤二核苷酸（氧化型）的水平，并使分裂蛋白Drp1在特定赖氨酸残基（K642）处的乙酰化水平升高。K642位点的Drp1乙酰化可通过磷酸化、线粒体易位与寡聚化激活Drp1。过度激活的Drp1具有更高的GTP酶活性，可与线粒体上的电压依赖性阴离子通道1（VDAC1）结合，诱导线粒体分裂并引发心肌细胞死亡。本研究结果为阐明脂质过载如何调控心脏内的氧化还原环境、蛋白质乙酰化以及线粒体分裂蛋白Drp1的功能提供了新的科学认知。