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.
Robb-Gaspers
L D
LD
Department of Pharmacology and Physiology, New Jersey Medical School of UMDNJ, Newark, NJ 07103, USA.
Rutter
G A
GA
Burnett
P
P
Hajnóczky
G
G
Denton
R M
RM
Thomas
A P
AP
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