Second‐Generation Inhibitors of the Mitochondrial Permeability Transition Pore with Improved Plasma Stability

Šileikytė, Justina; Devereaux, Jordan; Jong, Jelle C.B.C. de; Schiavone, Marco; Jones, Kristen L.; Nilsen, Aaron; Bernardi, Paolo; Forte, Michael; Cohen, Michael S.

doi:10.1002/cmdc.201900376

Cited by 23 publications

(21 citation statements)

References 29 publications

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“…MPTP is an important channel protein across the mitochondrial inner and outer membranes (29)(30)(31). Previous studies have identified that MPTP opening is a key step to induce cell mitochondrial damage and activates the mitochondrial apoptotic pathway (32)(33)(34). The present study revealed that extracellular acidosis increased MPTP opening, while the overexpression of TRAP1 reversed this effect.…”

Section: Discussionsupporting

confidence: 54%

TRAP1 attenuates H9C2 myocardial cell injury induced by extracellular acidification via the inhibition of MPTP opening

Zhang

Liu

et al. 2020

Int J Mol Med

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Extracellular acidification leads to cardiac dysfunction in numerous diseases. Mitochondrial dysfunction plays an important role in this process. However, the mechanisms through which extracellular acidification induces mitochondrial dysfunction remain unclear. Tumor necrosis factor receptor-associated protein 1 (TRAP1) maintains mitochondrial function and cell viability in tumor and non-tumor cells. In the present study, extracellular acidification was found to induce H9C2 cell apoptosis, mitochondrial dysfunction and TRAP1 expression. The overexpression of TRAP1 attenuated H9C2 cell injury, while the silencing of TRAP1 exacerbated it. Moreover, mitochondrial permeability transition pore (MPTP) opening, which is associated with the mitochondrial apoptotic pathway and cell death, was also increased in acidic medium. The overexpression of TRAP1 inhibited MPTP opening, while the silencing of TRAP1 promoted it. The protective effect of TRAP1 on cardiomyocytes was abolished by the addition of a specific MPTP opening promoter. Similarly, a specific MPTP opening inhibitor reversed cell injury by silencing TRAP1. Taken together, the findings of the present study demonstrate that TRAP1 attenuates H9C2 cell injury induced by extracellular acidification by inhibiting MPTP opening.

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Section: Discussionsupporting

confidence: 54%

TRAP1 attenuates H9C2 myocardial cell injury induced by extracellular acidification via the inhibition of MPTP opening

Zhang

Liu

et al. 2020

Int J Mol Med

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“…Several compounds have been identified which appear to directly inhibit the MPTP through its (putative) components [ [34] , [35] , [36] ]. Since they act as repressors, they may be more useful in other contexts in which the MPTP plays a role, e.g.…”

Section: Mitochondrial Ion Channels and Their Pharmacological Targeting By Small Moleculesmentioning

confidence: 99%

Targeting mitochondrial ion channels for cancer therapy

2021

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Pharmacological targeting of mitochondrial ion channels is emerging as a promising approach to eliminate cancer cells; as most of these channels are differentially expressed and/or regulated in cancer cells in comparison to healthy ones, this strategy may selectively eliminate the former. Perturbation of ion fluxes across the outer and inner membranes is linked to alterations of redox state, membrane potential and bioenergetic efficiency. This leads to indirect modulation of oxidative phosphorylation, which is/may be fundamental for both cancer and cancer stem cell survival. Furthermore, given the crucial contribution of mitochondria to intrinsic apoptosis, modulation of their ion channels leading to cytochrome c release may be of great advantage in case of resistance to drugs triggering apoptotic events upstream of the mitochondrial phase. In the present review, we give an overview of the known mitochondrial ion channels and of their modulators capable of killing cancer cells. In addition, we discuss state-of-the-art strategies using mitochondriotropic drugs or peptide-based approaches allowing a more efficient and selective targeting of mitochondrial ion channel-linked events.

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“…The further exploration of potent and selective cyclophilin D-independent MPTP inhibitors performed by screening the small-molecule libraries identified an isoxazole compound that possessed the inhibitory activity for MPTP [ 81 ]. Further optimization work was focused on improving the pharmacokinetic properties of the identified compound, resulting in a second-generation MPTP inhibitor with improved plasma stability—TR001 [ 82 ]. Animal studies using the zebrafish model of DMD and myoblasts and myotubes from DMD patients proved the efficiency of TR001 in the restoration of mitochondrial dysfunction regulated by MPTP [ 83 ].…”

Section: Mitochondrial Dysfunction In Specific Neuromuscular Disordersmentioning

confidence: 99%

Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype

Ignatieva

Smolina

Kostareva

et al. 2021

IJMS

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Mitochondrial dysfunction is considered the major contributor to skeletal muscle wasting in different conditions. Genetically determined neuromuscular disorders occur as a result of mutations in the structural proteins of striated muscle cells and therefore are often combined with cardiac phenotype, which most often manifests as a cardiomyopathy. The specific roles played by mitochondria and mitochondrial energetic metabolism in skeletal muscle under muscle-wasting conditions in cardiomyopathies have not yet been investigated in detail, and this aspect of genetic muscle diseases remains poorly characterized. This review will highlight dysregulation of mitochondrial representation and bioenergetics in specific skeletal muscle disorders caused by mutations that disrupt the structural and functional integrity of muscle cells.

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Second‐Generation Inhibitors of the Mitochondrial Permeability Transition Pore with Improved Plasma Stability

Cited by 23 publications

References 29 publications

TRAP1 attenuates H9C2 myocardial cell injury induced by extracellular acidification via the inhibition of MPTP opening

TRAP1 attenuates H9C2 myocardial cell injury induced by extracellular acidification via the inhibition of MPTP opening

Targeting mitochondrial ion channels for cancer therapy

Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype

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