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LIVER AND BILIARY TRACT

Permeability transition in rat liver mitochondria is modulated by the ATP-Mg/P_i carrier

¹Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom; ²Department of Physiology, Tufts University School of Medicine, Boston 02111; ³Department of Biology, Merrimack College, North Andover, Massachusetts 01845; and ⁴Department of Biology, University of Richmond, Richmond, Virginia 23173

Submitted 30 January 2003 ; accepted in final form 27 March 2003

Mitochondrial permeability transition, due to opening of the permeability transition pore (PTP), is triggered by Ca²⁺ in conjunction with an inducing agent such as phosphate. However, incubation of rat liver mitochondria in the presence of low micromolar concentrations of Ca²⁺ and millimolar concentrations of phosphate is known to also cause net efflux of matrix adenine nucleotides via the ATP-Mg/P_i carrier. This raises the possibility that adenine nucleotide depletion through this mechanism contributes to mitochondrial permeability transition. Results of this study show that phosphate-induced opening of the mitochondrial PTP is, at least in part, secondary to depletion of the intramitochondrial adenine nucleotide content via the ATP-Mg/P_i carrier. Delaying net adenine nucleotide efflux from mitochondria also delays the onset of phosphate-induced PTP opening. Moreover, mitochondria that are depleted of matrix adenine nucleotides via the ATP-Mg/P_i carrier show highly increased susceptibility to swelling induced by high Ca²⁺ concentration, atractyloside, and the prooxidant tert-butylhydroperoxide. Thus the ATPMg/P_i carrier, by regulating the matrix adenine nucleotide content, can modulate the sensitivity of rat liver mitochondria to undergo permeability transition. This has important implications for hepatocytes under cellular conditions in which the intramitochondrial adenine nucleotide pool size is depleted, such as in hypoxia or ischemia, or during reperfusion when the mitochondria are exposed to increased oxidative stress.

adenine nucleotides; calcium; phosphate; hypoxia; transport

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