BAX and BAK Regulation of Endoplasmic Reticulum Ca ²⁺ : A Control Point for Apoptosis

Abstract

BAX and BAK are "multidomain" proapoptotic proteins that initiate mitochondrial dysfunction but also localize to the endoplasmic reticulum (ER). Mouse embryonic fibroblasts deficient for BAX and BAK (DKO cells) were found to have a reduced resting concentration of calcium in the ER ([Ca2+]er) that results in decreased uptake of Ca2+ by mitochondria after Ca2+ release from the ER. Expression of SERCA (sarcoplasmic-endoplasmic reticulum Ca2+ adenosine triphosphatase) corrected [Ca2+]er and mitochondrial Ca2+ uptake in DKO cells, restoring apoptotic death in response to agents that release Ca2+ from intracellular stores (such as arachidonic acid, C2-ceramide, and oxidative stress). In contrast, targeting of BAX to mitochondria selectively restored apoptosis to "BH3-only" signals. A third set of stimuli, including many intrinsic signals, required both ER-released Ca2+ and the presence of mitochondrial BAX or BAK to fully restore apoptosis. Thus, BAX and BAK operate in both the ER and mitochondria as an essential gateway for selected apoptotic signals.

Advanced oxidation protein products induce pre‐osteoblast apoptosis through a nicotinamide adenine dinucleotide phosphate oxidase‐dependent, mitogen‐activated protein kinases‐mediated intrinsic apoptosis pathway

“…In our study, AOPP stimulation significantly decreased ▵Ψm of osteoblastic cell and induced a marked expression of pro‐apoptosis protein such as cytochrome c, BAX, and cleaved caspase‐9, which activated the intrinsic pathway. Endoplasmic reticulum (ER) is the primary storage site for intracellular Ca 2+ , which can release Ca 2+ from the ER Ca 2+ channel (Scorrano et al., 2003). ER stress acts as a decider in cell life and death, which can be marked by BiP/GRP78.…”

hsp70-DnaJ chaperone pair prevents nitric oxide- and CHOP-induced apoptosis by inhibiting translocation of Bax to mitochondria

“…The precise mechanism of CHOP-induced Bax translocation remains to be clarified. Recently, Scorrano et al 47 reported that Bax and Bak operate at ER as well as mitochondria to maintain homeostasis of ER Ca 2 þ . We reported that excess NO increases Ca 2 þ in cytosol, presumably due to the release from ER.…”

Gangliosides as apoptotic signals in ER stress response

“…95 The ER-localized proapoptotic Bax and Bak undergo conformational changes and oligomerization upon Ca 2 þ -induced ER stress. 96 In turn, the proteins promote proteolytic processing of the ER-resident caspase-12 leading to cell death. In fact, targeted overexpression of Bak in the ER depletes its Ca 2 þ levels, activates caspase-12, and ultimately causes cell death.…”