The Mitochondrial Permeability Transition Pore—Current Knowledge of Its Structure, Function, and Regulation, and Optimized Methods for Evaluating Its Functional State

Abstract

The mitochondrial permeability transition pore (MPTP) is a calcium-dependent, ion non-selective membrane pore with a wide range of functions. Although the MPTP has been studied for more than 50 years, its molecular structure remains unclear. Short-term (reversible) opening of the MPTP protects cells from oxidative damage and enables the efflux of Ca2+ ions from the mitochondrial matrix and cell signaling. However, long-term (irreversible) opening induces processes leading to cell death. Ca2+ ions, reactive oxygen species, and changes in mitochondrial membrane potential regulate pore opening. The sensitivity of the pore to Ca2+ ions changes as an organism ages, and MPTP opening plays a key role in the pathogenesis of many diseases. Most studies of the MPTP have focused on elucidating its molecular structure. However, understanding the mechanisms that will inhibit the MPTP may improve the treatment of diseases associated with its opening. To evaluate the functional state of the MPTP and its inhibitors, it is therefore necessary to use appropriate methods that provide reproducible results across laboratories. This review summarizes our current knowledge of the function and regulation of the MPTP. The latter part of the review introduces two optimized methods for evaluating the functional state of the pore under standardized conditions.

Formulation of Carnosic-Acid-Loaded Polymeric Nanoparticles: An Attempt to Endorse the Bioavailability and Anticancer Efficacy of Carnosic Acid against Triple-Negative Breast Cancer

“…Cancer cells generally have constantly hyperpolarized mitochondria to account for elevated and altered metabolic levels and MMP being positive upon treatment indicates lesser metabolism and impending apoptotic death . This result could also be correlated to the increased intracellular ROS in CA-PLGA NPs treated cells, as mitochondrial membrane damage could lead to enhanced and uncontrolled bursts of elevated mitochondrial ROS into the cytosol, by increased sequestration of calcium ions and opening of mitochondrial permeability transition pores. − All results obtained in this regard point toward the superior therapeutic efficiency of CA-PLGA NPs over free CA.…”

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“…While it is established beyond reasonable doubt that mitochondrial PTP openings are associated with mitochondrial depolarizations and eventually the initiation of cell death programs (64), the physical identity of PTPs and their signaling roles in normal cell physiology remain controversial (65,66).…”

“…While it is firmly established that mitochondrial PTP openings are associated with mitochondrial depolarization, and eventually the initiation of cell death programs (71), the physical identity of PTPs and their signaling roles in normal cell physiology remain controversial (72,73). That PTPs can open transiently in a so-called 'flickering' mode during normal cell physiology is well established, and such openings are in general thought to have a low conductance that is adequate for depolarization, release of calcium, and generation of 'flashes' of mitochondrial ROS.…”

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