Closure of mitochondrial potassium channels favors opening of the Tl+-induced permeability transition pore in Ca2+-loaded rat liver mitochondria

It is known that a closure of ATP sensitive (mitoK(ATP)) or BK-type Ca2+ activated (mitoK(Ca)) potassium channels triggers opening of the mitochondrial permeability transition pore (MPTP) in cells and isolated mitochondria. We found earlier that the Tl+-induced MPTP opening in Ca2+-loaded rat liver mitochondria was accompanied by a decrease of 2,4-dinitrophenol-uncoupled respiration and increase of mitochondrial swelling and Delta I-mito dissipation in the medium containing TlNO3 and KNO3. On the other hand, our study showed that the mitoK(ATP) inhibitor, 5-hydroxydecanoate favored the Tl+-induced MPTP opening in the inner membrane of Ca2+-loaded rat heart mitochondria (Korotkov et al. 2013). Here we showed that 5-hydroxydecanoate increased the Tl+-induced MPTP opening in the membrane of rat liver mitochondria regardless of the presence of mitoK(ATP) modulators (diazoxide and pinacidil). This manifested in more pronounced decrease in the uncoupled respiration and acceleration of both the swelling and the Delta I-mito dissipation in isolated rat liver mitochondria, incubated in the medium containing TlNO3, KNO3, and Ca2+. A slight delay in Ca2+-induced swelling of the mitochondria exposed to diazoxide could be result of an inhibition of succinate oxidation by the mitoK(ATP) modulator. Mitochondrial calcium retention capacity (CRC) was markedly decreased in the presence of the mitoK(ATP) inhibitor (5-hydroxydecanoate) or the mitoK(Ca) inhibitor (paxilline). We suggest that the closure of mitoK(ATP) or mitoK(Ca) in calcium loaded mitochondria favors opening of the Tl+-induced MPTP in the inner mitochondrial membrane.