Non-canonical functions of BCL-2 family members in energy metabolism and necrotic cell death regulation

Abstract

The large family of BCL-2 proteins plays a well-established role in the regulation of mitochondrial apoptosis pathway, and the crosstalk between death receptor signaling and mitochondrial apoptosis. Accumulating evidence suggests, however, that various BCL-2 family members are also involved in the regulation of apoptosis-unrelated necrotic forms of cell death, and even non-cell death processes. In this review, we discuss the emerging role of BCL-2 family members, and in particular BIM, in the regulation of mitochondrial dynamics, morphology and energy metabolism, and associated consequences for drug-inuced necrotic cell death.

Keywords: BCL-2; apoptosis; electron transport chain; glycolysis; mitochondria; mitotoxicants.

Figure 1.

Canonical functions of the BCL-2 family. The canonical BCL-2 protein function, i.e. apoptosis, is triggered by extracellular and/or intracellular stimuli, which disturb the balance between pro- and anti-apoptotic BCL-2 proteins. Extracellular stimuli start with death receptor activation (such as TNF-R1, FAS and TRAIL-Rs), leading to DISC assembly and caspase 8 activation. Activated caspase 8 either directly activates the effector caspases 3 and 7, or triggers the intrinsic apoptosis pathway by inducing BID cleavage and the release of truncated BID (tBID). Intracellular stress stimuli affect the balance between BCL-2 proteins by transcriptional induction or posttranslational activation of BCL-2 proteins. There are two modes how the pore-forming members BAX and BAK become activated, the direct and indirect way. In the indirect way, anti-apoptotic proteins are neutralized by activated or overexpressed BH3-only proteins, which triggers BAX/BAK oligomerization and MOMP induction. The direct mode requires direct activation of BAX/BAK by certain BH3-only proteins to induce MOMP, which is antagonized by anti-apoptotic BCL-2 proteins. MOMP induction leads to the release of different mitochondrial proteins into the cytoplasm, such as cytochrome c and SMAC/DIABLO. Cytochrome c release induces apoptosome assembly, which triggers caspase 9 activation, subsequent activation of the effector caspases 3 and 7, and apoptosis induction.

Figure 2.

Non-canonical functions of BCL-2 homologs in mitochondrial metabolism and morphology. (a). In addition to their canonical functions, BCL-2 proteins excert non-canonical functions at the mitochondrial cristae by regulating mitochondrial respiration through interaction with complexes of the electron transport chain (ETC). Anti-apoptotic BCL-2 homologs positively regulate the ETC, via interaction with complex IV (cIV), complex V (cV) or by promoting the formation of supercomplexes (cIII₂cIV, cIcIII₂cIV). The pore-forming BCL-2 protein BAX is a negative regulator of the ETC by inhibiting complex I (cI). (b). BCL-2 proteins regulate mitochondrial morphology and function through fission and fusion. BID and BIM can inhibit DRP1 oligomerization-mediated fission, while BCL-x_L can enhance it. BAX and BAK interact with MFN2 and promote mitochondrial fusion. Yet to be confirmed is the exact molecular role of interactions of BCL-2 proteins with regulators of mitochondrial morphology, such as that of MCL-1 with DRP1 and OPA1, or BCL-2 and BCL-x_L with MFN2. The role of BID and BIM in mitochondrial fusion processes remains unknown.

Figure 3.

Summary of canonical and non-canonical functions of BCL-2 homologs. Cellular functions of BCL-2 proteins are divided into canonical and non-canonical functions. Canonical functions are related to MOMP induction and subsequent execution of apoptotic cell death, which is considered immunologically silent. Non-canonical functions include the role of BCL-2 proteins in energy metabolism, regulation of mitochondrial fission/fusion and ROS production. Mitotoxicants damage the mitochondria, inhibit the ETC, promote ROS production and induce expression of BH3-only proteins. BCL-2 family members regulate mitochondrial energy metabolism and fission/fusion. Since the apoptosome activation requires ATP, and ROS inhibits caspase activation, BCL-2 family members also regulate necrotic cell death and associated inflammation.