Bcl-2 family proteins, beyond the veil

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

“…The Bcl-2 (B-cell lymphoma-2) family of proteins represents a collection of pro- and anti-apoptotic proteins, functioning in a delicate balance during homeostasis ( Figure 2 ). The main role of this group of proteins is the regulation of caspase activity and the execution of cells as a consequence of different intracellular and extracellular stimuli, and thereby dictating the fate of a cell [ 185 , 186 , 187 , 188 , 189 ]. They work as regulators of cell cycle progression, or autophagy, as well as the mediators of Ca 2+ concentration, unfolded protein response and metabolism of the lipids and carbohydrates [ 169 , 185 , 190 , 191 ].…”

“…The main role of this group of proteins is the regulation of caspase activity and the execution of cells as a consequence of different intracellular and extracellular stimuli, and thereby dictating the fate of a cell [ 185 , 186 , 187 , 188 , 189 ]. They work as regulators of cell cycle progression, or autophagy, as well as the mediators of Ca 2+ concentration, unfolded protein response and metabolism of the lipids and carbohydrates [ 169 , 185 , 190 , 191 ]. Importantly, Bcl-2 proteins are crucial regulators of Ca 2+ homeostasis and dynamics due to their ability to directly target and regulate the intracellular Ca 2+ -transport systems, in particular IP3 receptors and mitochondrial Ca 2+ transport systems [ 192 , 193 , 194 ].…”

“…The BH3 activator cBID sequestered by Bcl-XL complexes only changes from an inactive to an active form while bound to a Bcl-XL complex (and when Bad is also bound). Bcl-XL complexes enable Bad to function as a non-competitive inhibitor of Bcl-XL and allosterically activate BID, dramatically enhancing the pro-apoptotic potency of BAD [ 185 , 189 , 241 ]. Both the activators and sensitizers could be activated via specific mechanisms, leading to the transfer of the apoptotic stimuli to Bax and Bak, as well as to the pro-survival Bcl-2 proteins [ 3 , 242 ].…”

“…Apart from the ability to influence mitochondrial permeability directly, Bcl-2 proteins are also involved in the mediation of apoptotic signaling by regulating Ca 2+ homeostasis [ 29 , 185 , 193 , 254 ]. This regulation can occur through direct interactions between the intracellular Ca 2+ -transport systems and anti-apoptotic Bcl-2 members; in particular Bcl-2, Bcl-XL, Mcl-1, Bax, and Bak [ 255 , 256 , 257 , 258 , 259 , 260 , 261 ].…”

“…Those involving regulation of mitochondrial dynamics and morphology have already been mentioned in chapter 3.4. Other processes are responsible for Ca 2+ homeostasis and include regulation of the metabolism and functioning of the electron transport chain, permeability transition, and mPTP opening [ 185 , 193 , 194 , 254 , 255 , 263 ]. A substantial part of these processes is summarized in Table 1 for clarity.…”