Abstract
Cells under stress activate cell survival and cell death signaling pathways. Cell death signaling frequently converges on mitochondria, a process that is controlled by the activities of pro- and anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins. In this review, we summarize current knowledge on the control of neuronal survival, development and injury by anti-apoptotic BCL-2 family proteins. We discuss overlapping and differential effects of the individual family members BCL-2, BCL-extra long (BCL-XL), myeloid cell leukemia 1 (MCL-1), and BCL2-like 2 (BCL-W) in the control of survival during development and pathophysiological processes such as trophic factor withdrawal, ischemic injury, excitotoxicity, oxidative stress and energy stress. Finally we discuss recent evidence that several anti-apoptotic BCL-2 proteins influence mitochondrial bioenergetics and control neuronal Ca2+ homeostasis independent of their classical role in cell death signaling.
Highlights
Cells under stress activate cell survival and cell death signaling pathways
Two models have been proposed for the activation of BAX and BAK during apoptosis: (a) the direct activation model where BAX and BAK activation occurs directly through conformational changes induced by BH3-only proteins (Letai et al, 2002) and (b) indirect activation model where cell death signals induce the binding of BH3-only pro-apoptotic initiators to anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins, facilitating the release and activation of BAX and BAK (Uren et al, 2007; Willis et al, 2007)
In this review we focus on recent advancements in describing the role of individual anti-apoptotic BCL-2 family proteins during neuronal development, injury and neurodegeneration
Summary
Cell death signaling frequently converges on mitochondria, a process that is controlled by the activities of pro- and anti-apoptotic B-cell lymphoma 2 (BCL-2) proteins. We summarize current knowledge on the control of neuronal survival, development and injury by anti-apoptotic BCL-2 family proteins. Activation of the mitochondrial apoptosis pathway through pro-apoptotic BCL-2 proteins is able to activate different cell death pathways including apoptosis (Kilbride and Prehn, 2013). The key upstream event that leads to the activation of these different pathways is mitochondrial outer membrane permeabilization (MOMP) This process is triggered by the membrane insertion and oligomerization of the pro-apoptotic members BAX and BAK, with subsequent release of apoptosis-activating factors such as cytochrome c (cyt c) from the mitochondrial intermembrane space to the cytosol.
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