Coupling between cytosolic and mitochondrial calcium oscillations: role in the regulation of hepatic metabolism

• Published in: Biochimica et biophysica acta 1998-08, Vol.1366 (1), p.17-32
• Main Authors: Robb-Gaspers, Lawrence D., Rutter, Guy A., Burnett, Paul, Hajnóczky, György, Denton, Richard M., Thomas, Andrew P.
• Format: Article
• Language: English
• Subjects: Aequorin; Animals; Ca 2+-sensitive mitochondrial dehydrogenase; Calcium - metabolism; Calcium Channels - metabolism; Cytosol - metabolism; Cytosolic calcium; Fura-2; Intracellular Membranes - metabolism; Liver - cytology; Liver - metabolism; Microscopy, Confocal; Mitochondria, Liver - metabolism; Mitochondrial calcium; Mitochondrial metabolism; Mitochondrial proton motive force; Oligomycins; Proton-Motive Force; Pyruvate dehydrogenase; Rhodamines; Vasopressins
• ISSN: 0005-2728; 0006-3002; 1879-2650
• DOI: 10.1016/S0005-2728(98)00118-2

Mitochondria are strategically localized at sites of Ca 2+ release, such that increases in cytosolic free Ca 2+ ([Ca 2+] c) from either internal Ca 2+ stores or Ca 2+ influx across the plasma membrane can be rapidly transported into the mitochondrial matrix. The consequent elevation in mitochondrial Ca 2+ ([Ca 2+] m) stimulates the Ca 2+-sensitive intramitochondrial dehydrogenases, resulting in elevation of NAD(P)H. The preferential coupling between increases in [Ca 2+] c and [Ca 2+] m is one proposed mechanism to coordinate mitochondrial ATP production with cellular energy demand. In liver cells, hormones that act through the second messenger inositol 1,4,5-trisphosphate (IP 3) generate oscillatory [Ca 2+] c signals, which result from a periodic Ca 2+- and IP 3-mediated activation/deactivation of intracellular Ca 2+ release channels. The [Ca 2+] c spiking frequency increases with agonist dose, whereas the amplitude of each [Ca 2+] c spike is constant. This frequency modulation of [Ca 2+] c spiking encodes the signal from the extracellular agonist, which is then decoded by the internal Ca 2+-sensitive proteins such as the Ca 2+-sensitive intramitochondrial dehydrogenases. Our studies have investigated the relationship between IP 3-dependent [Ca 2+] c signals and [Ca 2+] m in primary cultured hepatocytes. In addition, the changes in cellular [Ca 2+] levels have been correlated with the regulation of intramitochondrial NAD(P)H levels, pyruvate dehydrogenase activity and the magnitude of the mitochondrial proton motive force.