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, 330 (3), 670-8

Mitochondrial Permeability Transition Pore Opening as a Promising Therapeutic Target in Cardiac Diseases

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Mitochondrial Permeability Transition Pore Opening as a Promising Therapeutic Target in Cardiac Diseases

Sabzali Javadov et al. J Pharmacol Exp Ther.

Abstract

In addition to their central role in ATP synthesis, mitochondria play a critical role in cell death. Oxidative stress accompanied by calcium overload, ATP depletion, and elevated phosphate levels induces mitochondrial permeability transition (MPT) with formation of nonspecific MPT pores (MPTP) in the inner mitochondrial membrane. Pore opening results in mitochondrial dysfunction with uncoupled oxidative phosphorylation and ATP hydrolysis, ultimately leading to cell death. For the past 20 years, three proteins have been accepted as key structural components of the MPTP: adenine nucleotide translocase (ANT) in the inner membrane, cyclophilin D (CyP-D) in the matrix, and the voltage-dependent anion channel (VDAC) in the outer membrane. However, most recent studies have questioned the molecular identity of the pores. Genetic studies have eliminated the VDAC as an essential component of MPTP and attributed a regulatory (rather than structural) role to ANT. Currently, the phosphate carrier appears to play a crucial role in MPTP formation. MPTP opening has been examined extensively in cardiac pathological conditions, including ischemia/reperfusion as well as heart failure. Accordingly, MPTP is accepted as a therapeutic target for both pharmacological and conditional strategies to block pore formation by direct interaction with MPTP components or indirectly by decreasing MPTP inducers. Inhibition of MPTP opening by reduction of CyP-D activity by nonimmunosuppressive analogs of cyclosporine A or sanglifehrin A, as well as attenuation of reactive oxygen species accumulation through mitochondria-targeted antioxidants, is the most promising. This review outlines our current knowledge of the structure and function of the MPTP and describes possible approaches for cardioprotection.

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