Mitochondrial Ca2+ cycle mediated by the palmitate-activated cyclosporin A-insensitive pore

• Published in: Journal of bioenergetics and biomembranes Vol. 39; no. 2; pp. 167 - 174
• Main Authors: Mironova, Galina D, Belosludtsev, Konstantin N, Belosludtseva, Natalia V, Gritsenko, Elena N, Khodorov, Boris I, Saris, Nils-Erik L
• Format: Journal Article
• Language: English
• Published: United States Springer Nature B.V 01.04.2007
• Subjects: Animals; Calcium (mitochondrial); Calcium - physiology; Calcium Channels - physiology; Calcium efflux; Calcium influx; Calcium ions; Cyclosporin A; Cyclosporine - pharmacology; Depolarization; Efflux; Egtazic Acid - pharmacology; Fatty acids; Fatty Acids - biosynthesis; In Vitro Techniques; Lanthanum - pharmacology; Low concentrations; Membrane potential; Membrane Potential, Mitochondrial; Membranes; Mitochondria; Mitochondria, Liver - drug effects; Mitochondria, Liver - metabolism; Mitochondrial Membranes; Mitochondrial Proteins - physiology; Mitochondrial Swelling; Palmitic acid; Palmitic Acid - pharmacology; Phospholipase A2; Phospholipase A2 Inhibitors; Rats; Rats, Wistar; Ruthenium; Ruthenium red; Ruthenium Red - pharmacology
• ISSN: 0145-479X; 1573-6881
• DOI: 10.1007/s10863-007-9079-9

Earlier we found that in isolated rat liver mitochondria the reversible opening of the mitochondrial cyclosporin A-insensitive pore induced by low concentrations of palmitic acid (Pal) plus Ca(2+) results in the brief loss of Deltapsi [Mironova et al., J Bioenerg Biomembr (2004), 36:171-178]. Now we report that Pal and Ca(2+), increased to 30 and 70 nmol/mg protein respectively, induce a stable and prolonged (10 min) partial depolarization of the mitochondrial membrane, the release of Ca(2+) and the swelling of mitochondria. Inhibitors of the Ca(2+) uniporter, ruthenium red and La(3+), as well as EGTA added in 10 min after the Pal/Ca(2+)-activated pore opening, prevent the release of Ca(2+) and repolarize the membrane to initial level. Similar effects can be observed in the absence of exogeneous Pal, upon mitochondria accumulating high [Sr(2+)], which leads to the activation of phospholipase A(2) and appearance of endogenous fatty acids. The paper proposes a new model of the mitochondrial Ca(2+) cycle, in which Ca(2+) uptake is mediated by the Ca(2+) uniporter and Ca(2+) efflux occurs via a short-living Pal/Ca(2+)-activated pore.