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 Ca2+-regulated targets. We have studied the control of Ca2+-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.