Figure 8.

Proposed events that account for the protective effect of oligomycin and CsA in neurons subsequent to cytochrome c release by the “mitochondrial hit.” In NGF-maintained sympathetic neurons (A), electron transport generates ΔΨm, which is used by the ΔΨm ATPase to generate ATP. In NGF-deprived, BAF-saved cells (B), mitochondrial cytochrome c (Cc) is lost by permeabilization of the outer mitochondrial membrane, possibly by a channel that includes the proapoptotic Bcl-2 family member BAX. Despite this, electron transport continues, at least through complexes I and III, contributing to ΔΨm. Oxidation of electron transport intermediates could be mediated by residual mitochondrial cytochrome c, or by the generation of reactive oxygen species (ROS), which could themselves be detrimental. Reverse operation of F₀F₁ also contributes to ΔΨm by hydrolyzing ATP. The importance of the permeability transition pore (PTP), which is composed of the voltage-dependent anion channel (VDAC), adenine nucleotide translocase (ANT), and cyclophilin D (CyD), is evidenced by the ability of CsA to inhibit caspase-independent death (Chang and Johnson, 2002; Fig. 4). Although precisely how PTP opening contributes to caspase-independent cell death is not known, it is possible, but purely speculative, that the opening of the PTP could allow the F₀F₁ to hydrolyze cytosolic ATP generated by glycolysis, on which the cell depends for survival. Although this model can account for inhibition of caspase-independent death by both oligomycin and CsA, it supposes that mechanisms to equilibrate adenine nucleotides are compromised in NGF-deprived, BAF-saved cells.