The mitochondrial permeability transition pore: an evolving concept critical for cell life and death

Abstract

In this review, we summarize current knowledge of perhaps one of the most intriguing phenomena in cell biology: the mitochondrial permeability transition pore (mPTP). This phenomenon, which was initially observed as a sudden loss of inner mitochondrial membrane impermeability caused by excessive calcium, has been studied for almost 50 years, and still no definitive answer has been provided regarding its mechanisms. From its initial consideration as an in vitro artifact to the current notion that the mPTP is a phenomenon with physiological and pathological implications, a long road has been travelled. We here summarize the role of mitochondria in cytosolic calcium control and the evolving concepts regarding the mitochondrial permeability transition (mPT) and the mPTP. We show how the evolving mPTP models and mechanisms, which involve many proposed mitochondrial protein components, have arisen from methodological advances and more complex biological models. We describe how scientific progress and methodological advances have allowed milestone discoveries on mPTP regulation and composition and its recognition as a valid target for drug development and a critical component of mitochondrial biology.

Mitochondria as the Target of Hepatotoxicity and Drug-Induced Liver Injury: Molecular Mechanisms and Detection Methods

“…MPTP opening, known to be involved in drug-induced mitochondrial toxicity, can be determined experimentally using the mitochondrial swelling assay [ 215 , 292 ]. This method is based on measuring spectrophotometrically mitochondrial swelling and conformational changes, direct consequences of MPTP opening, which are reflected in a decrease in absorbance at optical density in the presence of Ca 2+ [ 214 ].…”

The Interplay of Hypoxia Signaling on Mitochondrial Dysfunction and Inflammation in Cardiovascular Diseases and Cancer: From Molecular Mechanisms to Therapeutic Approaches

“…Uncontrolled ROS and RNS production, generate oxidative stress with consequent mtDNA damage and oxidation of proteins and lipids of membranes. In the first case, ROS and RNS directly react with pyrimidine and purine bases, especially in the D-loop region [ 112 ]; here, this damage led to a significant decrease in mtDNA copies and of ETC function [ 113 ]. Otherwise, peroxidation of mitochondrial lipids and proteins alters the mitochondrial membrane potential (MMP), their energy production and triggers the opening of mPTP [ 105 , 109 , 110 ].…”

Ca2+ Sensors Assemble: Function of the MCU Complex in the Pancreatic Beta Cell

“…Mitochondrial membrane permeability transition pore (PTP) opening allows for rapid Ca 2+ release from the mitochondria into the cytosol. When the PTP is constitutively open mitochondrial metabolism decreases, the mitochondrial membrane ruptures, and apoptogenic proteins are released from the mitochondria [26,27]. During apoptosis, apoptogenic proteins facilitate rough endoplasmic reticulum (RER) Ca 2+ release into the cytosol.…”