Regulation of Mitochondrial Permeability Transition Pore Opening by Monovalent Cations in Liver Mitochondria

The opening of the permeability transition pore (PTP) in mitochondria is a key event in the initiation of cell death in various pathologic states, including ischemia/reperfusion. The activation of K⁺ transport into mitochondria protects cells from ischemia/reperfusion. However, the role of K⁺ transport in PTP regulation is unclear. Here, we studied the role of K⁺ and other monovalent cations in the regulation of the PTP opening in an in vitro model. The registration of the PTP opening, membrane potential, Ca²⁺-retention capacity, matrix pH, and K⁺ transport was performed using standard spectral and electrode techniques. We found that the presence of all cations tested in the medium (K⁺, Na⁺, choline⁺, and Li⁺) strongly stimulated the PTP opening compared with sucrose. Several possible reasons for this were examined: the effect of ionic strength, the influx of cations through selective and non-selective channels and exchangers, the suppression of Ca²⁺/H⁺ exchange, and the influx of anions. The data obtained indicate that the mechanism of PTP stimulation by cations includes the suppression of K⁺/H⁺ exchange and acidification of the matrix, which facilitates the influx of phosphate. Thus, the K⁺/H⁺ exchanger and the phosphate carrier together with selective K⁺ channels compose a PTP regulatory triad, which might operate in vivo.