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

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.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 2ϩ concentration. Cardiomyocyte Ca 2ϩ 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 Ins...

African eggplant (Solanum anguivi Lam.) fruit with bioactive polyphenolic compounds exerts in vitro antioxidant properties and inhibits Ca2+-induced mitochondrial swelling

“…The mitochondrial permeability transition (MPT) is considered to contribute substantially to the regulation of normal mitochondrial metabolism and it is regarded as an important mediator of cell death through the opening of a membrane structure known as the mitochondrial permeability transition pore (MPTP) [40,41] . The opening of this pore is accompanied by membrane potential (ΔΨ) collapse, calcium release, uptake of electrolytes and water, matrix swelling and ruptures of the mitochondrial outer membrane [42] .…”

“…Then, 0.2 mL of 10 % Folin-Ciocalteu reagent (diluted 1:1 with water) and 0.4 mL of sodium carbonate solution (7.5 %) were added sequentially to the test tube. The tubes were then incubated for 40 min at 45 °C and the absorbance was measured at 725 nm in a spectrophotometer (SP-2000UV, Biospectro, Brazil). The standard curve was prepared using 0, 1, 2.5, 5, 10 and 15 mg/mL solutions of gallic acid (0.1 mg/mL).…”

Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca2+ Uniporter

“…With sustained elevations in [Ca 2+ ] mt , mROS generation and DJ mt depolarization trigger the mPTP opening that leads to apoptosis (7,35). Thus, [Ca 2+ ] mt is commonly regarded as an important determinant in cell sensitivity to apoptotic stimuli in various cell types (64).…”

Mitochondrial Dysfunction in the Aging Heart Is Accompanied by Constitutive No-Synthases Uncoupling on the Background of Oxidative and Nitrosative Stress

“…Усі ці порушення характеризу-ються дисфункцією мітохондрій, одним із проявів якої є відкривання неселективної циклоспоринчутливої мітохондріальної пори (МП), індукторами якої є оксидативний стрес і навантаження Са 2+ [8]. Відомо, що відкри-вання високопровідної МП між зовнішньою і внутрішньою мембранами органел викликає колапс мітохондріального потенціалу, що призводить до втрати енергоутворювальної функції органел (синтезу АТФ) і індукції клітинної смерті -апоптозу [8,9]. Тим не менше існує МП, яка характеризується низькою провідністю і оборотністю, відіграє фізіологічну роль, вивільняючи кальцій і АФК з органел, тим самим регулюючи каль-цієвий і енергетичний гомеостаз клітини.…”