Redox regulation of the intrinsic pathway in neuronal apoptosis

• Published in: Antioxidants & redox signaling Vol. 14; no. 8; p. 1437
• Main Author: Franklin, James L
• Format: Journal Article
• Language: English
• Published: United States 15.04.2011
• Subjects: Animals; Apoptosis; bcl-2-Associated X Protein - metabolism; Cytochromes c - metabolism; Humans; Nerve Growth Factors - metabolism; Neurons - metabolism; Neurons - pathology; Oxidation-Reduction; Reactive Oxygen Species - metabolism
• ISSN: 1557-7716
• DOI: 10.1089/ars.2010.3596

Two principal pathways exist by which cells can undergo apoptotic death, known as the extrinsic and the intrinsic pathways. Binding of a ligand to a death receptor activates the extrinsic pathway. In the intrinsic pathway, an apoptotic stimulus, such as neurotrophin withdrawal or exposure to a toxin, causes a proapoptotic member of the Bcl-2 family of proteins, such as Bax, to permeabilize the outer mitochondrial membrane. This allows redistribution of cytochrome c from the mitochondrial intermembrane space into the cytoplasm, where it causes activation of caspase proteases and, subsequently, cell death. A dramatic increase occurs in mitochondria-derived reactive oxygen species (ROS) during the apoptotic death of sympathetic, cerebellar granule, and cortical neurons. These ROS lie downstream of Bax in each cell type. Here I review possible mechanisms by which Bax causes increased ROS during neuronal apoptosis. I also discuss evidence that these ROS are an important part of the apoptotic cascade in these cells. Finally, I discuss evidence that suggests that neurotrophins prevent release of cytochrome c in neurons through activation of an antioxidant pathway.