Coupling between cytosolic and mitochondrial calcium oscillations: role in the regulation of hepatic metabolism.
Mitochondria are strategically localized at sites of Ca2+ release, such that increases in cytosolic free Ca2+ ([Ca2+]c) from either internal Ca2+ stores or Ca2+ influx across the plasma membrane can be rapidly transported into the mitochondrial matrix. The consequent elevation in mitochondrial Ca2+ ([Ca2+]m) stimulates the Ca2+-sensitive intramitochondrial dehydrogenases, resulting in elevation of NAD(P)H. The preferential coupling between increases in [Ca2+]c and [Ca2+]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 (IP3) generate oscillatory [Ca2+]c signals, which result from a periodic Ca2+- and IP3-mediated 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 modulation of [Ca2+]c spiking encodes the signal from the extracellular agonist, which is then decoded by the internal Ca2+-sensitive proteins such as the Ca2+-sensitive intramitochondrial dehydrogenases. Our studies have investigated the relationship between IP3-dependent [Ca2+]c signals and [Ca2+]m in primary cultured hepatocytes. In addition, the changes in cellular [Ca2+] 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.
Department of Pharmacology and Physiology, New Jersey Medical School of UMDNJ, Newark, NJ 07103, USA.
L D
LD
Robb-Gaspers
G A
GA
Rutter
P
P
Burnett
G
G
Hajnóczky
R M
RM
Denton
A P
AP
Thomas
D000331:Aequorin; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism*; D016257:Fura-2; D007425:Intracellular Membranes / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D018613:Microscopy, Confocal; D008930:Mitochondria, Liver / Q000378:metabolism*; D009840:Oligomycins; D018892:Proton-Motive Force; D012235:Rhodamines; D014667:Vasopressins
D015220:Calcium Channels; D009840:Oligomycins; D012235:Rhodamines; D014667:Vasopressins; D000331:Aequorin; D002118:Calcium; D016257:Fura-2