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Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury.

ABSTRACT: The mitochondrion serves many functions in the central nervous system (CNS) and other organs beyond the well-recognized role of adenosine triphosphate (ATP) production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequence of compromised mitochondrial function is induction of the mitochondrial permeability transition (mPT) state due to formation of the cyclosporine A sensitive permeability transition pore (mPTP). In this mini-review, we summarize evidence supporting the involvement of the mPTP as a mediator of mitochondrial and cellular demise following CNS traumatic injury and discuss the beneficial effects and limitations of the current ex-perimental strategies targeting the mPTP.

SUBMITTER: Springer JE

PROVIDER: S-EPMC6108215 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury.

Springer Joe E JE Prajapati Pareshkumar P Sullivan Patrick G PG

Neural regeneration research 20180801 8

The mitochondrion serves many functions in the central nervous system (CNS) and other organs beyond the well-recognized role of adenosine triphosphate (ATP) production. This includes calcium-dependent cell signaling, regulation of gene expression, synthesis and release of cytotoxic reactive oxygen species, and the release of cytochrome c and other apoptotic cell death factors. Traumatic injury to the CNS results in a rapid and, in some cases, sustained loss of mitochondrial function. One consequ ...[more]

PMID: 30106036

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Project description:Mitochondrial fission is critically involved in cardiomyocyte apoptosis, which has been considered as one of the leading causes of ischaemia/reperfusion (I/R)-induced myocardial injury. In our previous works, we demonstrate that aldehyde dehydrogenase-2 (ALDH2) deficiency aggravates cardiomyocyte apoptosis and cardiac dysfunction. The aim of this study was to elucidate whether ALDH2 deficiency promotes mitochondrial injury and cardiomyocyte death in response to I/R stress and the underlying mechanism. I/R injury was induced by aortic cross-clamping for 45 min. followed by unclamping for 24 hrs in ALDH2 knockout (ALDH2-/- ) and wild-type (WT) mice. Then myocardial infarct size, cell apoptosis and cardiac function were examined. The protein kinase C (PKC) isoform expressions and their mitochondrial translocation, the activity of dynamin-related protein 1 (Drp1), caspase9 and caspase3 were determined by Western blot. The effects of N-acetylcysteine (NAC) or PKC-? shRNA treatment on glycogen synthase kinase-3? (GSK-3?) activity and mitochondrial permeability transition pore (mPTP) opening were also detected. The results showed that ALDH2-/- mice exhibited increased myocardial infarct size and cardiomyocyte apoptosis, enhanced levels of cleaved caspase9, caspase3 and phosphorylated Drp1. Mitochondrial PKC-? translocation was lower in ALDH2-/- mice than in WT mice, and PKC-? was the opposite. Further data showed that mitochondrial PKC isoform ratio was regulated by cellular reactive oxygen species (ROS) level, which could be reversed by NAC pre-treatment under I/R injury. In addition, PKC-? inhibition caused activation of caspase9, caspase3 and Drp1Ser616 in response to I/R stress. Importantly, expression of phosphorylated GSK-3? (inactive form) was lower in ALDH2-/- mice than in WT mice, and both were increased by NAC pre-treatment. I/R-induced mitochondrial translocation of GSK-3? was inhibited by PKC-? shRNA or NAC pre-treatment. In addition, mitochondrial membrane potential (??m ) was reduced in ALDH2-/- mice after I/R, which was partly reversed by the GSK-3? inhibitor (SB216763) or PKC-? shRNA. Collectively, our data provide the evidence that abnormal PKC-?/PKC-? ratio promotes the activation of Drp1 signalling, caspase cascades and GSK-3?-dependent mPTP opening, which results in mitochondrial injury-triggered cardiomyocyte apoptosis and myocardial dysfuction in ALDH2-/- mice following I/R stress.

Dataset Information

Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury.

Publications

Targeting the mitochondrial permeability transition pore in traumatic central nervous system injury.

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