Molecular participants in mitochondrial cell death channel formation during neuronal ischemia

Abstract

Mitochondrial ion channels are involved in numerous cellular processes. Membrane pores and transporters regulate the influx and efflux of calcium, sodium, potassium, zinc and determine the membrane compartmentalization of numerous cytosolic metabolites. The permeability of the inner membrane to ions and solutes helps determine the membrane potential of the inner membrane, but the permeability of the outer membrane, controlled in part by VDAC and the BCL-2 family proteins, regulates the release of important signaling molecules that determine the onset of programmed cell death. BCL-2 family proteins have properties of ion channels and perform specialized physiological functions, for example, regulating the strength and pattern of synaptic transmission, in addition to their well known role in cell death. The ion channels of the inner and outer membranes may come together in a complex of proteins during programmed cell death, particularly during neuronal ischemia, where elevated levels of the divalents calcium and zinc activate inner membrane ion channel conductances. The variety of possible molecular participants within the ion channel complex may be matched only by the variety of different types of programmed cell death.

Figure 1

Interaction of inner and outer mitochondrial membrane ion channels in different scenarios. From left to right: 1. During physiological functioning of mitochondria VDAC opens to allow the release of ATP. This action is assisted by full length BCL-xL protein during the prevention of cell death or during synaptic transmission. 2. During cell death, cytochrome c is released through an outer membrane channel formed by BAX or ΔN BCL-xL working in conjunction with VDAC. 3. In certain types of neuronal death such as occur during ischemia, both inner and outer membrane channels participate. Ca²⁺ binds to Cyclophilin to activate the inner membrane permeability transition pore, which then either a) sends a messenger to the outer membrane to cause the opening of VDAC or b) contacts the outer membrane directly, forming a two-membrane spanning pore. 4. In certain types of brain ischemia, BAD participates in the formation of the outer membrane component of the death channel.

Figure 2

The inner membrane forms a barrier to ions and solutes that can be breached by transporters and channel pores. When cytosolic calcium levels are low, calcium cycles into and out of the matrix using channels and transporters (1–4). When calcium levels rise, mitochondria buffer calcium through the exchange of H+ ions for calcium, compromising the ability of mitochondria to make ATP (6). The buffering of calcium is aided by the formation of a calcium-phosphate complex in the matrix (7). Calcium can be re-released from the matrix by transporters (2–4), or through a calcium activated pore (5).