Highlights
- •TMBIM6 knockdown enhances LPS-induced cardiac inflammation and cardiomyocyte death
- •TMBIM6 knockdown enhances LPS-induced mitochondrial quality control (MQC) dysfunction in cardiomyocytes
- •TMBIM6 deficiency exacerbates LPS-mediated MQC dysfunction through interrupting VDAC1-dependent mitochondrial Ca2+ import
- •TMBIM6 binds to VDAC1 and prevents its oligomerization to increase [Ca2+]m
- •TMBIM6 overexpression improves MQC and restores mitochondrial function by repressing VDAC1 oligomerization
Abstract
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
Ca2+ 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 (TMBIM6CKO) and TMBIM6 transgenic (TMBIM6TG) 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 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.
Conclusion
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.
Abbreviations:
MQC (mitochondrial quality control), SCM (septic cardiomyopathy), TMBIM6 (Transmembrane BAX inhibitor motif containing 6), [Ca2+]m (mitochondrial Ca2+ concentration), VDAC2 (voltage dependent anion channel 2), MCU (mitochondrial Ca2+ uniporter)Keywords
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Article info
Publication history
Published online: January 02, 2023
Accepted:
December 18,
2022
Received:
October 13,
2022
Identification
Copyright
© 2023 Elsevier Inc. All rights reserved.
