Balancing life and death: BCL‐2 family members at diverse ER–mitochondrial contact sites

Abstract

The outer mitochondrial membrane is a busy place. One essential activity for cellular survival is the regulation of membrane integrity by the BCL‐2 family of proteins. Another critical facet of the outer mitochondrial membrane is its close approximation with the endoplasmic reticulum. These mitochondrial‐associated membranes (MAMs) occupy a significant fraction of the mitochondrial surface and serve as key signaling hubs for multiple cellular processes. Each of these pathways may be considered as forming their own specialized MAM subtype. Interestingly, like membrane permeabilization, most of these pathways play critical roles in regulating cellular survival and death. Recently, the pro‐apoptotic BCL‐2 family member BOK has been found within MAMs where it plays important roles in their structure and function. This has led to a greater appreciation that multiple BCL‐2 family proteins, which are known to participate in numerous functions throughout the cell, also have roles within MAMs. In this review, we evaluate several MAM subsets, their role in cellular homeostasis, and the contribution of BCL‐2 family members to their functions.

Visualization of BOK pores independent of BAX and BAK reveals a similar mechanism with differing regulation

“…Previous studies reported that BOK, in contrast to BAX and BAK, mainly localizes to the ER and Golgi [19] and that it accumulates at the contact sites between the ER and mitochondria, where it plays a role in regulating calcium fluxes between the two organelles [38,39]. This is in agreement with our data in Fig.…”

Bcl-2 Family Members and the Mitochondrial Import Machineries: The Roads to Death

“…Of note, since the mitochondrial localization of Bax and Bak is required but not sufficient to the MOMP, the functional consequences of the interactions between anti-apoptotic Bcl-2s and TOMs are certainly highly dependent on the cellular context, governing the completion of Bax and Bak full activation. The role played by MAM in this regulation is currently under investigation and will certainly improve our understanding of this highly complex regulation network ([ 134 ], for an exhaustive review).…”

Cell death regulation by MAMs: from molecular mechanisms to therapeutic implications in cardiovascular diseases

“…In addition, B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-X L ), two Bcl-2 family members on MAMs, connect with central modulatory domain of IP 3 Rs to suppress Ca 2+ release or indirectly inhibit IP 3 Rs through regulating its phosphorylation. Besides, both Bcl-2 and Bcl-X L can conjugate with VDAC1 to suppress mitochondrial Ca 2+ intake [ 63 ]. Moreover, myeloid cell leukemia factor-1 (Mcl-1), another anti-apoptotic protein of Bcl-2 family, not only restrains IP 3 R-mediated Ca 2+ release but also binds with VDACs to modulate mitochondrial Ca 2+ uptake.…”