The Role of Pyrophosphate and the Adenine Nucleotide Transporter in the Regulation of the Intra-Mitochondrial Volume

Abstract

Hepatic gluconeogenesis, urea syntheses, fatty acid oxidation and respiration are all stimulated by those hormones which cause an increase in the concentration of cyclic AMP (e.g. glucagon) or Ca2+ (e.g. vasopressin and α-adrenergic agonists). Activation of mitochondrial metabolism is an essential feature of the action of these hormones, and we have provided strong evidence that this is achieved through an increase in intramitochondrial matrix volume (see Halestrap et al., 1985; Halestrap, 1988). Thus the hormones cause an increase in intra-mitochondrial volume from a control value of about 1.1 μl/mg mitochondrial protein to 1.25-1.4 μl/mg protein (Quinlan et al., 1983) which, although modest, is sufficient to cause significant activation of respiration, citrulline syntheses, pyruvate carboxylation, fatty acid oxidation and glutaminase (see Halestrap et. al., 1985; Halestrap, 1988). The increase in matrix volume is brought about by influx of K+ into the mitochondria in response to elevated cytoplasmic, and consequently mitochondrial, [Ca2+ ] (Halestrap et al., 1986). More recently we have shown that Ca2+ exerts its effects on K+ permeability indirectly through an increase in mitochondrial inorganic pyrophosphate (PPi) concentration (Davidson & Halestrap, 1987). Thus the ability of Ca2+ (< 1 μM) to increase the intra-mitochondrial matrix volume correlates with the observed rise in matrix PPi. Furthermore exposure of either isolated mitochondria or hepatocytes to butyrate, which is activated to butyryl-CoA in the mitochondrial matrix with consequent production of PPi, also increases the mitochondrial volume.