Regulation of Cell Death by Mitochondrial Transport Systems of Calcium and Bcl-2 Proteins

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.

The Interplay between Dysregulated Ion Transport and Mitochondrial Architecture as a Dangerous Liaison in Cancer

“…Other pathways for Ca 2+ entry into the matrix, albeit less extensively characterized, are mitochondrial ryanodine receptors (mRyR, [ 60 , 61 ], transient receptor potential canonical type 3 (TRPC3) channels [ 62 ], and possibly Leucine-zipper and EF-hand-containing transmembrane protein 1 (LETM1) (see Section 2.2 ). A fourth rapid Ca 2+ uptake mechanism (RaM) with unknown molecular substrate operates at low Ca 2+ concentrations and could correspond to a different mode of operation of MCU since MCU knockout abolishes this pathway (reviewed in [ 63 , 64 ]) ( Figure 3 ).…”

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

“…Due to these multiple functions, microtubule system has become an attractive target for cancer chemotherapy 11 , 12 . Disruption of MTs or tubulin dynamics exposes the cell to mitotic arrest of the cell cycle at G 2 /M phase, and consequently induction of cellular apoptosis 13 , 14 . Several microtubule-interfering agents (MIAs) have been identified, e.g.…”

A Walk in the Memory, from the First Functional Approach up to Its Regulatory Role of Mitochondrial Bioenergetic Flow in Health and Disease: Focus on the Adenine Nucleotide Translocator

“…Originally, only regulatory components were identified. The first unambiguously established component was CypD (in the matrix), which remains the only protein whose involvement in mPTP pore formation and activity regulation is undisputed [ 77 ]. The identity of other proteins comprising the PTP is to date debated; however, mPTP is usually described as a polyprotein complex located at the mitochondrial contact site formed from the voltage-gated anion channel (VDAC, in the OMM), members of the Bax/Bcl2 pro and antiapoptotic protein family [ 78 ], and additional proteins such as HK (in the cytosol), creatine kinase, peripheral benzodiazepine receptor (PBR, in the OMM) [ 79 ], and the phosphate carrier [ 80 ].…”

“…It seems that despite its role as the main energy-producing enzyme, it is precisely the ATP synthase that plays a role in the IMM depolarization caused by the channel activity of the mPTP. However, this aspect of the question concerning PTP, although of considerable importance, is a problem beyond our competence and therefore we refer the interested reader to specific readings [ 77 , 78 , 83 , 84 , 88 ].…”