Decoding of cytosolic calcium oscillations in the mitochondria.
Frequency-modulated oscillations of cytosolic Ca2+ ([Ca2+]c) are believed to be important in signal transduction, but it has been difficult to correlate [Ca2+]c oscillations directly with the activity of Ca(2+)-regulated targets. We have studied the control of Ca(2+)-sensitive mitochondrial dehydrogenases (CSMDHs) by monitoring mitochondrial Ca2+ ([Ca2+]m) and the redox state of flavoproteins and pyridine nucleotides simultaneously with [Ca2+]c in single hepatocytes. Oscillations of [Ca2+]c induced by IP3-dependent hormones were efficiently transmitted to the mitochondria as [Ca2+]m oscillations. Each [Ca2+]m spike was sufficient to cause a maximal transient activation of the CSMDHs and [Ca2+]m oscillations at frequencies above 0.5 per minute caused a sustained activation of mitochondrial metabolism. By contrast, sustained [Ca2+]c increases yielded only transient CSMDH activation, and slow or partial [Ca2+]c elevations were ineffective in increasing [Ca2+]m or stimulating CSMDHs. We conclude that the mitochondria are tuned to oscillating [Ca2+]c signals, the frequency of which can control the CSMDHs over the full range of potential activities.
Hajnóczky
G
G
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Robb-Gaspers
L D
LD
Seitz
M B
MB
Thomas
A P
AP
D000818:Animals; D002118:Calcium / Q000502:physiology*; D008099:Liver / Q000502:physiology; D008297:Male; D008930:Mitochondria, Liver / Q000502:physiology*; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D010088:Oxidoreductases; D002118:Calcium