The isothiourea derivative, KB-R7943, inhibits the reverse-mode of the plasma 
membrane sodium/calcium exchanger and protects against ischemia/reperfusion 
injury. The mechanism through which KB-R7943 confers protection, however, 
remains controversial. Recently, KB-R7943 has been shown to inhibit 
mitochondrial calcium uptake and matrix overload, which may contribute to its 
protective effects. While using KB-R7943 for this purpose, we find here no 
evidence that KB-R7943 directly blocks mitochondrial calcium uptake. Rather, we 
find that KB-R7943 inhibits opening of the mitochondrial permeability transition 
pore in permeabilized cells and isolated liver mitochondria. Furthermore, we 
find that this observation correlates with protection against calcium 
ionophore-induced mitochondrial membrane potential depolarization and cell 
death, without detrimental effects to basal mitochondrial membrane potential or 
complex I-dependent mitochondrial respiration. Our data reveal another mechanism 
through which KB-R7943 may protect against calcium-induced injury, as well as a 
novel means to inhibit the mitochondrial permeability transition pore.