Figure 3.

Regulation of ER calcium homeostasis by the BCL-2 family. Different pro- and anti-apoptotic proteins of the BCL-2 family localize to the ER membrane where they regulate ER calcium homeostasis mainly through the modulation of the IP₃Rs. Left panel: under physiological conditions, anti-apoptotic proteins of the BCL-2 family interact with the IP₃R decreasing its calcium leak activity or promoting the release of oscillatory calcium bursts. This calcium signaling is transduced to the mitochondrial matrix through the VDAC and MCU1 channels at the mitochondria outer and inner membranes, respectively, where it promotes the activity of several metabolic enzymes, increasing ATP production and mitochondrial bioenergetics. The regulation of the IP₃R by BCL-2 proteins may be antagonized by BH3-only proteins and BAX. BI-1, a protein of the TMBIM family, also interacts with IP₃R, diminishing ER-to-mitochondria calcium transfer. Right panel: under some apoptotic conditions, IP₃Rs are activated, leading to sustained calcium release from the ER. Massive calcium uptake by the mitochondria leads to the opening of the mPTP, resulting in mitochondrial swelling, MOMP and decrease in ATP production. This leads to necrotic cell death. Additionally, the ER membrane becomes permeabilized, leading to the release of calcium- and ER-resident proteins. This process is regulated by the proteins of the BCL-2 family. IP₃R, inositol 1,4,5-trisphosphate receptor; MCU, mitochondrial calcium uniporter; VDAC, voltage-dependent anion channel