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

Zhou，Hao1,2; Dai，Zhe1; Li，Jialei1; Wang，Jin3; Zhu，Hang1; Chang，Xing4; Wang，Yijin1

2023-03-01

10.1016/j.metabol.2022.155383

METABOLISM-CLINICAL AND EXPERIMENTAL   Impact Factor & Quartile

0026-0495

1532-8600

Background: 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. Methods: In this study, we evaluated the role of TMBIM6 in SCM using cardiomyocyte-specific TMBIM6 knockout (TMBIM6) and TMBIM6 transgenic (TMBIM6) mice. Results: 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. Conclusion: 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.

Mitochondria Septic cardiomyopathy TMBIM6 VDAC1

SCI

English

First ; Corresponding

NSFC["82270279","82200296"] ; Natural Science Foundation of ShenZhen[JCYJ20210324103808023] ; Educational Committee of Guangdong for Specific Program of Key Scientific Research[2021ZDZX2016]

Endocrinology & Metabolism

Endocrinology & Metabolism

WOS:000989625900001

W B SAUNDERS CO-ELSEVIER INC

BIOLOGY & BIOCHEMISTRY

2-s2.0-85145718198

Scopus

1.School of Medicine,Southern University of Science and Technology,Shenzhen,Guangdong,China
2.Department of Cardiology,The Sixth Medical Center of People's Liberation Army General Hospital,Beijing,China
3.Department of Vascular Medicine,Peking University Shougang Hospital,Beijing,100144,China
4.Guang'anmen Hospital of Chinese Academy of Traditional Chinese Medicine,Beijing,China

Zhou，Hao,Dai，Zhe,Li，Jialei,et al. TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury[J]. METABOLISM-CLINICAL AND EXPERIMENTAL,2023,140.

Zhou，Hao.,Dai，Zhe.,Li，Jialei.,Wang，Jin.,Zhu，Hang.,...&Wang，Yijin.(2023).TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury.METABOLISM-CLINICAL AND EXPERIMENTAL,140.

Zhou，Hao,et al."TMBIM6 prevents VDAC1 multimerization and improves mitochondrial quality control to reduce sepsis-related myocardial injury".METABOLISM-CLINICAL AND EXPERIMENTAL 140(2023).