Abstract
Mitochondria represent the fundamental system for cellular energy metabolism, by not only supplying energy in the form of ATP, but also by affecting physiology and cell death via the regulation of calcium homeostasis and the activity of Bcl-2 proteins. A lot of research has recently been devoted to understanding the interplay between Bcl-2 proteins, the regulation of these interactions within the cell, and how these interactions lead to the changes in calcium homeostasis. However, the role of Bcl-2 proteins in the mediation of mitochondrial calcium homeostasis, and therefore the induction of cell death pathways, remain underestimated and are still not well understood. In this review, we first summarize our knowledge about calcium transport systems in mitochondria, which, when miss-regulated, can induce necrosis. We continue by reviewing and analyzing the functions of Bcl-2 proteins in apoptosis. Finally, we link these two regulatory mechanisms together, exploring the interactions between the mitochondrial Ca2+ transport systems and Bcl-2 proteins, both capable of inducing cell death, with the potential to determine the cell death pathway—either the apoptotic or the necrotic one.
Highlights
Calcium (Ca2+ ) is a divalent cation and a universal second messenger that regulates the most important functions and facets of all eukaryotic cells, including gene expression, proliferation, regulation of bioenergetics, contraction of muscles, mediation of fertilization, and many other cellular functions [1,2,3,4,5]
VDAC1 consists of 19 transmembrane β-strands that are organized into the membrane-incorporated β-barrel and a amphipathic 26-residue-long N-terminal domain, which can translocate from the pore interior to the channel surface [56]
That mitochondrial permeability transition pore (mPTP) could be stimulated by Ca2+ in combination with an increase in the concentration of reactive oxygen species (ROS) and phosphate; that it could be inhibited by divalent cations, adenine nucleotides, low pH, or CypD
Summary
Calcium (Ca2+ ) is a divalent cation and a universal second messenger that regulates the most important functions and facets of all eukaryotic cells, including gene expression, proliferation, regulation of bioenergetics, contraction of muscles, mediation of fertilization, and many other cellular functions [1,2,3,4,5]. Ca2+ uptake by mitochondria participates in the regulation of cytosolic Ca2+ concentration ([Ca2+ ]), and stimulates mitochondrial respiration and ATP production [18,19] These properties make these organelles the major cellular components in the regulation of the fate of a cell [9,12,17,20,21]. Production of ATP involves activation of the Ca2+ -dependent dehydrogenases in the citric acid cycle, F0F1-ATP-synthase and metabolite transporters; all of them being supplied by basal oscillating increases in the concentration of Ca2+ in the mitochondrial matrix [6,28,29,30] In addition to these normal physiological oscillations, large Ca2+ spikes in mitochondria can cause an opening of the mitochondrial permeability transition pore (mPTP) [9,28,29].
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