School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China; Department of Cardiology, The Sixth Medical Center of People's Liberation Army General Hospital, Beijing, China.
School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, China.
Metabolism. 2023 Mar;140:155383. doi: 10.1016/j.metabol.2022.155383. Epub 2023 Jan 2.
The regulatory mechanisms involved in mitochondrial quality control (MQC) dysfunction during septic cardiomyopathy (SCM) remain incompletely characterized. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) is an endoplasmic reticulum protein with Ca leak activity that modulates cellular responses to various cellular stressors.
In this study, we evaluated the role of TMBIM6 in SCM using cardiomyocyte-specific TMBIM6 knockout (TMBIM6) and TMBIM6 transgenic (TMBIM6) mice.
Myocardial TMBIM6 transcription and expression were significantly downregulated in wild-type mice upon LPS exposure, along with characteristic alterations in myocardial systolic/diastolic function, cardiac inflammation, and cardiomyocyte death. Notably, these alterations were further exacerbated in LPS-treated TMBIM6 mice, and largely absent in TMBIM6 mice. In LPS-treated primary cardiomyocytes, TMBIM6 deficiency further impaired mitochondrial respiration and ATP production, while defective MQC was suggested by enhanced mitochondrial fission, impaired mitophagy, and disrupted mitochondrial biogenesis. Structural protein analysis, Co-IP, mutant TMBIM6 plasmid transfection, and molecular docking assays subsequently indicated that TMBIM6 exerts cardioprotection against LPS-induced sepsis by interacting with and preventing the oligomerization of voltage-dependent anion channel-1 (VDAC1), the major route of mitochondrial Ca uptake.
We conclude that the TMBIM6-VDAC1 interaction prevents VDAC1 oligomerization and thus sustains mitochondrial Ca homeostasis as well as MQC, contributing to improved myocardial function in SCM.
脓毒症性心肌病（SCM）期间线粒体质量控制（MQC）功能障碍的调节机制仍不完全清楚。跨膜 BAX 抑制剂基序包含 6（TMBIM6）是一种内质网蛋白，具有 Ca 泄漏活性，可调节细胞对各种细胞应激源的反应。
在这项研究中，我们使用心肌细胞特异性 TMBIM6 敲除（TMBIM6）和 TMBIM6 转基因（TMBIM6）小鼠评估了 TMBIM6 在 SCM 中的作用。
在 LPS 暴露后，野生型小鼠的心肌 TMBIM6 转录和表达明显下调，同时伴有心肌收缩/舒张功能、心脏炎症和心肌细胞死亡的特征性改变。值得注意的是，这些改变在 LPS 处理的 TMBIM6 小鼠中进一步加重，而在 TMBIM6 小鼠中则基本不存在。在 LPS 处理的原代心肌细胞中，TMBIM6 缺失进一步损害了线粒体呼吸和 ATP 产生，而线粒体分裂增强、线粒体自噬受损和线粒体生物发生中断表明 MQC 受损。结构蛋白分析、Co-IP、突变 TMBIM6 质粒转染和分子对接实验随后表明，TMBIM6 通过与电压依赖性阴离子通道 1（VDAC1）相互作用并阻止其寡聚化来发挥对 LPS 诱导的败血症的心脏保护作用，VDAC1 是线粒体 Ca 摄取的主要途径。
我们得出结论，TMBIM6-VDAC1 相互作用可防止 VDAC1 寡聚化，从而维持线粒体 Ca 稳态和 MQC，有助于改善 SCM 中的心肌功能。
