Mitochondrial Permeability Transition Pore and Number of Openings

Abstract

Mitochondria are double membrane intracellular organelles that provide the ATP to meet the energy demands of the cell. Mitochondrial dysfunction has been implicated in diverse disease including neurodegenerative pathologies, heart diseases and many more. In rat cardiac ventricular myocytes, due to the large energy demand of a beating heart, mitochondria comprise 30-40% of cell volume and number approximately 20,000 per cell. Within each mitochondrion, the inner mitochondrial membrane (IMM) provide a base for electron transport chain (ETC) and ATP Synthase proteins. The ETC establishes an electrical and pH gradient with the matrix potential of approximately −180 mV. However, depolarizations of the IMM can occur following elevations of reactive oxygen species (ROS) and/or elevations of matrix [Ca2+]m and under other conditions. These depolarizations are largely attributed to the opening of a putative mitochondrial permeability transition pore (mPTP). The exact molecular composition of the mPTP is controversial and over the years has been attributed to many inner and outer membrane protein components as well as other proteins. Recently, the ATP synthase dimers have been implicated as key components of the mPTP as well. Contributions of mPTP to the regulation of matrix Ca2+, mitochondrial volume and programmed cell death (apoptosis) have been suggested. The model suggests that in order to simulate experimental data the ion fluxes that pass through mPTP are mainly Na+ and K+ as these are the most abundant ions present. Furthermore, it takes the opening of only one mPTP for a transient depolarization or sustained depolarization with a current of 30 pA and 26 pA respectively. Constraints on the protein identities and their behaviors are suggested by these models. Importantly, this work suggests that specific experiments be carried out to test candidate proteins and protein-combinations for possible involvement in mPTP.