Control of mitochondrial physiology and cell death by the Bcl-2 family proteins Bax and Bok. (October 2017)

• Record Type: Journal Article
• Authors: D'Orsi, Beatrice; Mateyka, Julia; Prehn, Jochen H.M.
• Is Part Of: Neurochemistry international. Volume 109(2017)
• Page Start: 162
• Page End: 170
• Publication Date: 2017-10
• Subjects: Bcl-2 proteins -- Mitochondria -- Calcium -- Excitotoxicity -- Bax -- Bok; Δψm mitochondrial membrane potential -- Bcl-2 B cell lymphoma gene 2 -- BH Bcl-2 homology region -- Bax Bcl-2-associated protein x -- Bak Bcl-2-antagonist/killer -- Mcl-1 myeloid cell leukemia gene 1 -- A1 Bcl-2-related protein A1 -- Bim Bcl-2 interacting mediator of cell death -- Puma p53 upregulated modulator of apoptosis -- Bid BH3 interacting-domain death agonist -- Bad Bcl-2-associated death promoter -- Bik Bcl-2-interacting killer -- Hrk Harakiri -- Bmf Bcl-2-modifying factor -- tBid Truncated Bid -- Bok Bcl-2-related ovarian killer -- CNS central nervous system -- ER endoplasmic reticulum -- IMS intermembrane space -- MEF mouse embryonic fibroblast -- MOM mitochondrial outer membrane -- MOMP mitochondrial outer membrane permeabilization -- mPTP mitochondrial permeability transition pore -- NMDA N-Methyl-d-aspartic acid -- ROS Reactive oxygen species -- SERCA sarcoplasmic/endoplasmic reticulum Ca2 +ATPase -- WT wild-type; Neurochemistry -- Periodicals; Neurochemistry -- Periodicals; Neurochimie -- Périodiques; Neurochemistry; Periodicals; 612.804205
• DOI: 10.1016/j.neuint.2017.03.010
• Languages: English
• ISSNs: 0197-0186

Abstract

Abstract: Neuronal cell death is often triggered by events that involve intracellular increases in Ca 2+ . Under resting conditions, the intracellular Ca 2+ concentration is tightly controlled by a number of extrusion and sequestering mechanisms involving the plasma membrane, mitochondria, and ER. These mechanisms act to prevent a disruption of neuronal ion homeostasis. As these processes require ATP, excessive Ca 2+ overloading may cause energy depletion, mitochondrial dysfunction, and may eventually lead to Ca 2+ -dependent cell death. Excessive Ca 2+ entry though glutamate receptors (excitotoxicity) has been implicated in several neurologic and chronic neurodegenerative diseases, including ischemic stroke, epilepsy, and Alzheimer's disease. Recent evidence has revealed that excitotoxic cell death is regulated by the B-cell lymphoma-2 (Bcl-2) family of proteins. Bcl-2 proteins, comprising of both pro-apoptotic and anti-apoptotic members, have been shown to not only mediate the intrinsic apoptosis pathway by controlling mitochondrial outer membrane (MOM) integrity, but to also control neuronal Ca 2+ homeostasis and energetics. In this review, the role of Bcl-2 family proteins in the regulation of apoptosis, their expression in the central nervous system and how they control Ca 2+ -dependent neuronal injury are summarized. We review the current knowledge on Bcl-2 family proteins in the regulation of mitochondrial function and bioenergetics, including the fusion and fission machinery, and their role in Ca 2+ homeostasis regulation at the mitochondria and ER. Specifically, we discuss how the 'pro-apoptotic' Bcl-2 family proteins, Bax and Bok, physiologically expressed in the nervous system, regulate such 'non-apoptotic/daytime' functions. Highlights: Bcl-2 family proteins are essential regulators of the mitochondrial apoptosis pathway. It is emerging that Bcl-2 proteins also have non-apoptotic, 'daytime' activities. Bcl-2 proteins Bax and Bok play a key role in the regulation of mitochondrial function and Ca 2+ homeostasis in neurons.