TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury

VDAC1型 粒体自噬 内质网 线粒体生物发生 线粒体 细胞生物学 心肌保护 生物 化学 生物化学 细胞凋亡 内科学 医学 自噬 细菌外膜 缺血 大肠杆菌 基因
作者
Hao Zhou,Zhe Dai,Jialei Li,Jin Wang,Hang Zhu,Xing Chang,Wang Yi-jin
出处
期刊:Metabolism-clinical and Experimental [Elsevier]
卷期号:140: 155383-155383 被引量:42
标识
DOI:10.1016/j.metabol.2022.155383
摘要

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 Ca2+ 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 (TMBIM6CKO) and TMBIM6 transgenic (TMBIM6TG) 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 TMBIM6CKO mice, and largely absent in TMBIM6TG 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 Ca2+ uptake.We conclude that the TMBIM6-VDAC1 interaction prevents VDAC1 oligomerization and thus sustains mitochondrial Ca2+ homeostasis as well as MQC, contributing to improved myocardial function in SCM.
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