PARTIAL INHIBITION BY CYCLOSPORINE-A OF THE SWELLING OF LIVER-MITOCHONDRIA INVIVO AND INVITRO INDUCED BY SUBMICROMOLAR [CA-2+], BUT NOT BY BUTYRATE - EVIDENCE FOR 2 DISTINCT SWELLING MECHANISMS

1. The effects of cyclosporin A on the increase in matrix PP1 and consequent swelling of energized liver mitochondria incubated with 1 mM-butyrate, 30 μM-bongkrekic acid or 0.1-35 μM-Ca2+ [Halestrap (1989) Biochim. Biophys. Acta 973, 355-382] were studied. 2. Cyclosporin (1 μM) had no significant effect on the swelling induced by butyrate, bongkrekic acid or Ca2+ at concentrations of less than 0.3 μM. 3. At higher [Ca2+] (> 0.3 μM), swelling became progressively inhibited by cyclosporin, although the increase in matrix PP1 was slightly greater in the presence than in the absence of cyclosporin. 4. Titration with cyclosporin indicated that there are 128 pmol of relevant cyclosporin-binding sites per mg of mitochondrial protein, with a K(i) of about 5 nM. 5. The decrease in light-scattering by hepatocytes induced by butyrate [Davidson and Halestrap (1988) Biochem. J. 254, 379-384] was unaffected by cyclosporin, whereas that induced by vasopressin was inhibited by 20-30% without a significant change in cellular PP1 content. 6. It is suggested that there are two mechanisms for the increase in mitochondrial volume induced by Ca2+: a PP1-mediated mechanism that is insensitive to cyclosporin and an additional Ca2+-mediated effect that is inhibited by cyclosporin. The nature of these pathways and their inter-relationship is discussed in the following paper [Halestrap and Davidson (1990) Biochem. J. 268, 153-160].