Examination of mitochondrial ion conductance by patch clamp in intact neurons and mitochondrial membrane preparations

Abstract

Mitochondrial ion channels are involved in numerous cellular processes. Membrane pores and transporters regulate the influx and efflux of H+, calcium, sodium, potassium, zinc and determine the membrane compartmentalization of numerous cytosolic metabolites. The permeability of the inner membrane to the various ions determines the membrane potential of the inner membrane. The recently described mitochondrial calcium uniporter (MCU) plays a major role in inner membrane calcium uptake into the matrix. The permeability of the outer membrane, controlled in part by VDAC and by BCL-2 family proteins, regulates the trafficking of metabolites into and out of mitochondria and the release of important signaling molecules that determine the onset of programmed cell death. Very recently discovered is that the membrane portion of the F1FOATP synthase contains a highly regulated ion channel that participates in formation of the death channel known as the mitochondrial permeability transition pore (mPTP). mPTP opening in response to pro-death stimuli compromises the osmotic barrier of the inner membrane. The ion channels of the mitochondrial inner and outer membranes may come together in a complex of proteins during programmed cell death, particularly during neuronal ischemia, where elevated levels of calcium and zinc activate inner membrane ion channel conductances. The variety of possible molecular participants within the mPTP ion channel complex may be matched only by the variety of different types of programmed cell death. Perhaps equally interesting, however, is the potential role of the ion channel activity of the FOof the ATP synthase as a metabolic regulator, since a relative decrease in channel activity enhances inner mitochondrial membrane coupling, producing salubrious effects on cell metabolism including the ability of synaptic mitochondria to enhance the efficiency of ATP production and to handle calcium loads during synaptic plasticity.