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

Zhou, Hao; Dai, Zhe; Li, Jia‐Lei; Wang, Jin; Zhu, Hang; Chang, Xing; Wang, Yijin

doi:10.1016/j.metabol.2022.155383

Cited by 46 publications

(28 citation statements)

References 72 publications

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“…Previous studies have had similar findings regarding TMBIM6 [65]. Zhou et al reported that myocardial I/R injury suppressed TMBIM6 expression by upregulating the DNA-dependent protein kinase catalytic subunit, which recognizes double-stranded DNA damage in cardiomyocytes [34].…”

Section: Discussionmentioning

confidence: 63%

Transmembrane BAX inhibitor motif containing 6 suppresses presenilin-2 to preserve mitochondrial integrity after myocardial ischemia-reperfusion injury

Ma¹,

Liao²,

Zhou³

et al. 2023

Int. J. Biol. Sci.

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Myocardial ischemia-reperfusion (I/R) damage is characterized by mitochondrial damage in cardiomyocytes. Transmembrane BAX inhibitor motif containing 6 (TMBIM6) and presenilin-2 (PS2) participate in multiple mitochondrial pathways; thus, we investigated the impact of these proteins on mitochondrial homeostasis during an acute reperfusion injury. Myocardial post-ischemic reperfusion stress impaired myocardial function, induced structural abnormalities and promoted cardiomyocyte death by disrupting the mitochondrial integrity in wild-type mice, but not in TMBIM6 transgenic mice. We found that TMBIM6 bound directly to PS2 and promoted its post-transcriptional degradation. Knocking out PS2 in mice reduced I/R injury-induced cardiac dysfunction, inflammatory responses, myocardial swelling and cardiomyocyte death by improving the mitochondrial integrity. These findings demonstrate that sufficient TMBIM6 expression can prevent PS2 accumulation during cardiac I/R injury, thus suppressing reperfusion-induced mitochondrial damage. Therefore, TMBIM6 and PS2 are promising therapeutic targets for the treatment of cardiac reperfusion damage.

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Section: Discussionmentioning

confidence: 63%

Transmembrane BAX inhibitor motif containing 6 suppresses presenilin-2 to preserve mitochondrial integrity after myocardial ischemia-reperfusion injury

Ma¹,

Liao²,

Zhou³

et al. 2023

Int. J. Biol. Sci.

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“…Accordingly, mitochondriatargeted therapies have been found to improve liver function in rodent models of ALD [13][14][15]. Under stress conditions, mitochondrial damage is counteracted by activation of an endogenous repair mechanism, which coordinates mitochondrial division/fusion and biogenesis [16][17][18][19][20]. Another crucial process controlled by the MQC is mitochondrial autophagy (mitophagy), a PINK1/Parkin pathway-dependent process that serves to recycle the components of defective mitochondria to stabilize the mitochondrial network [21][22][23][24].…”

Section: Ivyspringmentioning

confidence: 99%

Interaction between dual specificity phosphatase-1 and cullin-1 attenuates alcohol-related liver disease by restoring p62-mediated mitophagy

Li¹,

Dai²,

Liu³

et al. 2023

Int. J. Biol. Sci.

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Besides abstinence, no effective treatment exists for alcohol-related liver disease (ALD), a dreaded consequence of alcohol abuse. In this study, we assessed the roles on ALD of dual specificity phosphatase-1 (DUSP1), an hepatoprotective enzyme, and Cullin-1 (CUL1), a member of the E3 ubiquitin ligase complex that exerts also transcriptional suppression of mitochondrial genes. Alcohol treatment downregulated hepatic DUSP1 expression in wild-type mice. Notably, DUSP1 transgenic ( Dusp1 Tg ) mice showed resistance to alcohol-mediated hepatic dysfunction, as evidenced by decreased AST/ALT activity, improved alcohol metabolism, and suppressed liver fibrosis, inflammation, and oxidative stress. Functional experiments demonstrated that DUSP1 overexpression prevents alcohol-mediated mitochondrial damage in hepatocytes through restoring mitophagy. Accordingly, pharmacological blockade of mitophagy abolished the hepatoprotective actions of DUSP1. Molecular assays showed that DUSP1 binds cytosolic CUL1 and prevents its translocation to the nucleus. Importantly, CUL1 silencing restored the transcription of p62 and Parkin, resulting in mitophagy activation, and sustained mitochondrial integrity and hepatocyte function upon alcohol stress. These results indicate that alcohol-mediated DUSP1 downregulation interrupts DUSP1/CUL1 interaction, leading to CUL1 nuclear translocation and mitophagy inhibition via transcriptional repression of p62 and Parkin. Thus, targeting the DUSP1/CUL1/p62 axis will be a key approach to restore hepatic mitophagy as well as alleviate symptoms of ALD.

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“…According to their important location in the outer membrane of mitochondria, channel proteins (voltage‐dependent anion‐selective channel proteins) are the superior targets for endogenous proteins placed at the interface between cytoplasm and mitochondria to control Ca 2+ transport into mitochondria. These types of regulator factor are the BCL‐2 family members 25,26 . For instance, BCL‐XL as an apoptosis regulator factor can interact with some channel proteins such as voltage‐dependent anion‐selective channel 1 and 3 proteins, but not voltage‐dependent anion‐selective channel 2, shaping mitochondrial Ca 2+ ions entries by favoring Ca 2+ transport across the outer mitochondrial membrane 27,28 .…”

Section: Mitochondrial Calcium Regulationmentioning

confidence: 99%

“…These types of regulator factor are the BCL-2 family members. 25,26 For instance, BCL-XL as an apoptosis regulator factor can interact with some channel proteins such as voltage-dependent anion-selective channel 1 and 3 proteins, but not voltage-dependent anionselective channel 2, shaping mitochondrial Ca 2+ ions entries by favoring Ca 2+ transport across the outer mitochondrial membrane. 27,28 Several investigations proposed BCL-XL can inhibit voltage-dependent anionselective channels mechanistically, which would improve its selectivity and also permeability for Ca 2+ ions.…”

Section: Mitochondrial Calcium Regulationmentioning

confidence: 99%

The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders

Bagheri‐Mohammadi

Farjami

Suha

et al. 2023

J of Cellular Biochemistry

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Mitochondrial calcium (Ca 2+ ) dynamics play critical roles in regulating vital physiological conditions in the brain. Importantly, Mitochondria-associated endoplasmic reticulum (ER) membranes serve different cellular functions including Ca 2+ signaling, bioenergetics, phospholipid biosynthesis, cholesterol esterification, programmed cell death, and communication between the two organelles. Several Ca 2+ -transport systems specialize at the mitochondria, ER, and their contact sites that provide tight control of mitochondrial Ca 2+ signaling at the molecular level. The biological function of Ca 2+ channels and transporters as well as the role of mitochondrial Ca 2+ signaling in cellular homeostasis can open new perspectives for investigation and molecular intervention. Emerging evidence suggests that abnormalities in ER/mitochondrial brain functions and dysregulation of Ca 2+ homeostasis are neuropathological hallmarks of neurological disorders like Alzheimer's disease, but little evidence is available to demonstrate their relationship to disease pathogenesis and therapeutic approaches. In recent years, the detection of the molecular mechanism regulating cellular Ca 2+ homeostasis and also mitochondrial functions have expanded the number of targeted treatments.The main experimental data identify beneficial effects, whereas some scientific trials did not meet the expectations. Together with an overview of the important function of mitochondria, this review paper introduced the possible tested therapeutic approaches that target mitochondria in the context of neurodegenerative diseases. Since these treatments in neurological disorders have shown different degrees of progress, it is essential to perform a detailed assessment of the significance of mitochondrial deterioration in neurodegenerative diseases and of a pharmacological treatment at this stage.

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

Cited by 46 publications

References 72 publications

Transmembrane BAX inhibitor motif containing 6 suppresses presenilin-2 to preserve mitochondrial integrity after myocardial ischemia-reperfusion injury

Transmembrane BAX inhibitor motif containing 6 suppresses presenilin-2 to preserve mitochondrial integrity after myocardial ischemia-reperfusion injury

Interaction between dual specificity phosphatase-1 and cullin-1 attenuates alcohol-related liver disease by restoring p62-mediated mitophagy

The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders

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