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

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. Mitochondria play an important role as ATP producers and as regulators of cell death, which make them essential for cell survival. In the heart, mitochondria occupy approximately 30% of cardiomyocyte volume and provide more than 90% ATP necessary for cardiac function. One of the key factors regulating mitochondrial function and ATP synthesis is the mitochondrial Ca concentration. Cardiomyocyte Ca homeostasis is altered under pathological conditions, such as ischemia and heart failure (HF), due to decreased ATP levels resulting from inadequate oxygen consumption. Furthermore, dysfunction of the electron transport chain, particularly during reperfusion, results in increased generation of ROS. Calcium overload and oxidative stress combine with other factors, including high phosphate and low adenine nucleotide concentrations to induce the formation of nonspecific mitochondrial permeability transition pores (MPTP) in the inner mitochondrial membrane (Bernardi et al., 1992; Crompton, 1999; Halestrap et al., 2004). Opening of MPTP causes uncoupling of the mitochondria and swelling of the matrix leading to rupture of the outer mitochondrial membrane and ultimately cell death. In recent years, MPTP openThis work was supported by the Canadian Institutes of Health Research (to M.K.) and the School of Medicine, University of Puerto Rico (to S.J.). Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.109.153213. ABBREVIATIONS: HF, heart failure; ANT, adenine nucleotide translocase; BKA, bongkrekic acid; CsA, cyclosporine A; CyP-D, cyclophilin D; IR, ischemia/reperfusion; MPT, mitochondrial permeability transition; MPTP, mitochondrial permeability transition pore; NHE-1, Na /H exchanger 1; PiC, phosphate carrier; PPIase, peptidyl-prolyl cis-trans-isomerase; ROS, reactive oxygen species; SfA, sanglifehrin A; VDAC, voltage-dependent anion channel; Pi, phosphate; NIM811, N-Me-4-Ile-CsA; Debio-025, D-3-MeAla-4-EtVal-CsA; DOG, [ H]2-deoxy-glucose; LDH, lactate dehydrogenase; FK506, tacrolimus; Ro 68-3400, spiro[cyclopentane-1,5 -[5H]dibenzo[a,d]cyclohepten]-2-one,10 ,11 -dihydro-3-methylene; UQ0, ubiquinone 0; BNIP3, Bcl2/E1B 19-kDa interacting protein 3; MCI-186, 3-methyl-1-phenyl-2-pyrazolin-5-one; Ru360, oxygen-bridged dinuclear ruthenium amine complex; EMD87580, N-[2-methyl-4,5-bis(methylsulphonyl)-benzoyl]-guanidine, hydrochloride. 0022-3565/09/3303-670–678$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 330, No. 3 Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics 153213/3503150 JPET 330:670–678, 2009 Printed in U.S.A. 670 at A PE T Jornals on Jne 0, 2017 jpet.asjournals.org D ow nladed from ing has been considered a therapeutic target for cardioprotection during cardiac diseases, especially those associated with ischemia/reperfusion (IR) primarily to the central role of the MPTP in cell death (Di Lisa and Bernardi, 2006; Javadov and Karmazyn, 2007; Halestrap and Pasdois, 2009). In this review, we discuss the current understanding of the molecular structure and function of the MPTP, mechanisms of MPTP opening, and its consequences during IR and HF, and MPTP opening as a therapeutic target for cardioprotection. Molecular Composition of the MPTP and Consequences of Pore Opening