COUPLING BETWEEN CYTOSOLIC AND MITOCHONDRIAL CALCIUM OSCILLATIONS - ROLE IN THE REGULATION OF HEPATIC-METABOLISM

Mitochondria are strategically localized at sites of Ca2+ release, suc h that increases in cytosolic free Ca2+ ([Ca2+](c)) from either intern al Ca2+ stores or Ca2+ influx across the plasma membrane can be rapidl y transported into the mitochondrial matrix. The consequent elevation in mitochondrial Ca2+ ([Ca2+](m)) stimulates the Ca2+-sensitive intram itochondrial dehydrogenases, resulting in elevation of NAD(P)H. The pr eferential coupling between increases in [Ca2+](c) and [Ca2+](m) is on e proposed mechanism to coordinate mitochondrial ATP production with c ellular energy demand. In liver cells, hormones that act through the s econd messenger inositol 1,4,5-trisphosphate (IP3) generate oscillator y [Ca2+](c) signals, which result from a periodic Ca2+- and IP3-mediat ed activation/deactivation of intracellular Ca2+ release channels. The [Ca2+](c) spiking frequency increases with agonist dose, whereas the amplitude of each [Ca2+](c) spike is constant. This frequency modulati on of [Ca2+](c) spiking encodes the signal from the extracellular agon ist, which is then decoded by the internal Ca2+-sensitive proteins suc h as the Ca2+-sensitive intramitochondrial dehydrogenases. Our studies have investigated the relationship between IP3-dependent [Ca2+](c) si gnals and [Ca2+](m) in primary cultured hepatocytes. In addition, the changes in cellular [Ca2+] levels have been correlated with the regula tion of intramitochondrial NAD(P)H levels, pyruvate dehydrogenase acti vity and the magnitude of the mitochondrial proton motive force. (C) 1 998 Elsevier Science B.V. All rights reserved.