Frequency-modulated oscillations of cytosolic Ca 2+([Ca=+] c) are believed to be important in signal transduction, but it has been difficult to correlate [Ca2*] o oscillations directly with the activity of Ca 2+-regulated targets. We have studied the control of Ca=+-eensitive mitochondrial dehydrogenases (CSMDHs) by monitoring mitochond rial Ca=÷([Ca 2+] m) and the redox state of flavoproteins and pyridine nucleotides simultaneously with [Ca2+] o in single hepatocytes. Oscillations of [Ca z*]¢ induced by IP3-dependent hormones were efficiently transmitted to the mitochondria as [Ca=+],. oscillations. Each [Ca=+] m spike was sufficient to cause a maximal transient activation of the CSMDHs and [Ca=*], n oscillations at frequencies above 0.5 per minute caused a sustained activation of mitochondrial metabolism. By contrast, sustained [Ca=*] c increases yielded only transient CSMDH activation, and slow or partial [Ca=+] 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.