Mitochondrial Ca2+ and regulation of the permeability transition pore

Abstract

The mitochondrial permeability transition pore was originally described in the 1970’s as a Ca2+ activated pore and has since been attributed to the pathogenesis of many diseases. Here we evaluate how each of the current models of the pore complex fit to what is known about how Ca2+ regulates the pore, and any insight that provides into the molecular identity of the pore complex. We also discuss the central role of Ca2+ in modulating the pore’s open probability by directly regulating processes, such as ATP/ADP balance through the tricarboxylic acid cycle, electron transport chain, and mitochondrial membrane potential. We review how Ca2+ influences second messengers such as reactive oxygen/nitrogen species production and polyphosphate formation. We discuss the evidence for how Ca2+ regulates post-translational modification of cyclophilin D including phosphorylation by glycogen synthase kinase 3 beta, deacetylation by sirtuins, and oxidation/nitrosylation of key residues. Lastly we introduce a novel view into how Ca2+ activated proteolysis through calpains in the mitochondria may be a driver of sustained pore opening during pathologies such as ischemia reperfusion injury.

Contribution of Mitophagy to Cell‐Mediated Mineralization: Revisiting a 50‐Year‐Old Conundrum

“…Concomitantly, increasing amount of matrix Ca 2+ triggers mitophagy of the mitochondria 23. These organelles respond to stressful stimuli such as Ca 2+ overloading in a hierarchical manner such as mitophagy, apoptosis, or necrosis 23, 24. In the present context, it appears that mitophagy is the most logical strategy for maintaining hDPSCs in a healthy, viable state during osteogenesis.…”

“…As mentioned previously, liquid‐like ACP precursors accumulated within the mitochondria during osteogenic differentiation of hDPSCs. Concomitantly, increasing amount of matrix Ca 2+ triggers mitophagy of the mitochondria 23. These organelles respond to stressful stimuli such as Ca 2+ overloading in a hierarchical manner such as mitophagy, apoptosis, or necrosis 23, 24.…”

Role of Mitochondria-Associated Endoplasmic Reticulum Membrane in Inflammation-Mediated Metabolic Diseases

“…At a physiological concentration of matrix calcium, aerobic metabolism and ATP synthesis are stimulated by activation of calcium-sensitive mitochondrial metabolic enzymes [77]. During the extreme rise in matrix calcium that can occur in pathological conditions, enhanced ROS generation occurs, which eventually leads to a collapse in mitochondrial function and apoptosis, via opening of mitochondrial permeability transition pores (mPTPs) [17, 78, 79]. Taken together, it is likely that accumulation of mitochondrial calcium, occurring because of an abnormal induction of MAM, leads to apoptosis via mPTP opening.…”

Interactions of Mitochondria/Metabolism and Calcium Regulation in Alzheimer’s Disease: A Calcinist Point of View

“…The inner mitochondrial membrane potential is regulated by the calcium uniporter which removes calcium from the mitochondria. Calcium transport into the mitochondria is regulated by the mitochondrial membrane potential [38]. …”