Cyclosporin A suppression of uncoupling in liver mitochondria of ground squirrel during arousal from hibernation

Abstract

Energy coupling parameters were studied in liver mitochondria of ground squirrel during arousal from hibernation. It was found that such mitochondria become uncoupled during incubation with phosphate in a salt medium. The uncoupling was revealed by respiration rate increase and membrane potential decrease in the presence of oligomycin. Both effects were reversed by addition of cyclosporin A. Under the same in vitro conditions, mitochondria from aroused (active) animals showed no uncoupling but could be uncoupled by addition of palmitate in the cyclosporin A-sensitive fashion. It is proposed that formation ofeyclosporin A-sensitive pores can be involved in urgent heat production in arousing hibernators.

Long‐chain fatty acids promote opening of the reconstituted mitochondrial permeability transition pore

“…The present results are in line with previous observations [11–17] that long‐chain fatty acids may promote opening of PTP in intact mitochondria. As discussed by Schönfeld and Bohnensack [13], this may occur in two different ways: (i) indirectly, by collapsing Δ ψ due to the protonophoric effect of fatty acid cycling mediated by ANT [4] and other mitochondrial carrier proteins [10], and (ii) directly, by interaction of fatty acids with ANT and stabilization of its ‘cytosolic’ conformation.…”

“…More recently, participation of other mitochondrial carriers, the glutamate/aspartate [5,6], the dicarboxylate [6], the monocarboxylate [7], the tricarboxylate [7] and the phosphate [8] carriers in fatty acid‐induced proton permeability of the inner mitochondrial membrane has also been shown (reviewed in [9,10]). Apart from this mechanism, in which long‐chain fatty acids supported by mitochondrial carrier proteins function as real protonophores, it has also been proposed [11–14] that fatty acids may promote collapse of the mitochondrial electrochemical proton gradient in an indirect way, namely by opening the permeability transition pore (PTP). Opening of PTP by long‐chain fatty acids has already been observed by other authors using the swelling assay [15–17].…”

Fatty acid‐induced uncoupling of oxidative phosphorylation is partly due to opening of the mitochondrial permeability transition pore

“…In studies on the Ca 2+ ‐dependent uncoupling effect of palmitate (for review see [20]), supposed to be due to the opening of PTP [15], Skulachev and his colleagues [21]proposed that the adenine nucleotide translocase can also be involved in this kind of uncoupling. They found that in incubation media supplemented with Ca 2+ and/or phosphate (but without EGTA) (i) CsA and adenosine diphosphate (ADP) suppressed and carboxyatractyloside potentiated the uncoupling effect of fatty acid [5, 21–23]; (ii) the potentiating effect of carboxyatractyloside did not occur when palmitate was substituted by a chemical protonophore carbonyl cyanide p ‐trifluoromethoxyphenylhydrazone (FCCP) [22]; (iii) in liver mitochondria of ground squirrels arousing from hibernation, when elevated levels of non‐esterified fatty acids could be expected [24], CsA produced a coupling effect whereas carboxyatractyloside potentiated Δψ dissipation [21, 25].…”

Carboxyatractyloside increases the effect of oleate on mitochondrial permeability transition

“…This result is in agreement with the findings of Amerkhanov et al [18]showing that in liver mitochondria from arousing ground squirrels CAT collapses Δ Ψ . According to Brustovetsky et al [19], the drop in Δ Ψ by CAT‐oleate is inhibited by 0.5 μM cyclosporin A (not shown).…”