Decoding of cytosolic calcium oscillations in the mitochondria

Frequency-modulated oscillations of cytosolic Ca 2+ ([Ca 2+] c) are believed to be important in signal transduction, but it has been difficult to correlate [Ca 2+] 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 mitochondria) Ca 2+ ([Ca 2+] m) and the redox state of flavoproteins and pyridine nucleotides simultaneously with [Ca 2+] c in single hepatocytes. Oscillations of [Ca 2+] c induced by IP 3-dependent hormones were efficiently transmitted to the mitochondria as [Ca 2+] m oscillations. Each [Ca 2+] m spike was sufficient to cause a maximal transient activation of the CSMDHs and [Ca 2+] m oscillations at frequencies above 0.5 per minute caused a sustained activation of mitochondrial metabolism. By contrast, sustained [Ca 2+] c increases yielded only transient CSMDH activation, and slow or partial [Ca 2+] c elevations were ineffective in increasing [Ca 2+] m or stimulating CSMDHs. We conclude that the mitochondria are tuned to oscillating [Ca 2+] c signals, the frequency of which can control the CSMDHs over the full range of potential activities.