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Mitochondria regulate inactivation of L-type Ca²⁺ channels in rat heart

Jorge A. Sánchez, María C. García, Virendra K. Sharma *, Kate C. Young *, Mohammed A. Matlib † and Shey-Shing Sheu *

1. L-type Ca²⁺ channels play an important role in vital cell functions such as muscle contraction and hormone secretion. Both a voltage-dependent and a Ca²⁺-dependent process inactivate these channels. Here we present evidence that inhibition of the mitochondrial Ca²⁺ import mechanism in rat (Sprague-Dawley) ventricular myocytes by ruthenium red (RR), by Ru360 or by carbonyl cyanide m-chlorophenylhydrazone (CCCP) decreases the magnitude of electrically evoked transient elevations of cytosolic Ca²⁺ concentration ([Ca²⁺]_c). These agents were most effective at stimulus rates greater than 1 Hz.
2. RR and CCCP also caused a significant delay in the recovery from inactivation of L-type Ca²⁺ currents (I_Ca). This suggests that sequestration of cytosolic Ca²⁺, probably near the mouth of L-type Ca²⁺ channels, into mitochondria during cardiac contractile cycles, helps to remove the Ca²⁺-dependent inactivation of L-type Ca²⁺ channels.
3. We conclude that impairment of mitochondrial Ca²⁺ transport has no impact on either L-type Ca²⁺ currents or SR Ca²⁺ release at low stimulation frequencies (e.g. 0.1 Hz); however, it causes a depression of cytosolic Ca²⁺ transients attributable to an impaired recovery of L-type Ca²⁺ currents from inactivation at high stimulation frequencies (e.g. 3 Hz). The impairment of mitochondrial Ca²⁺ uptake and subsequent effects on Ca²⁺ transients at high frequencies at room temperature could be physiologically relevant since the normal heart rate of rat is around 5 Hz at body temperature. The role of mitochondria in clearing Ca²⁺ in the micro-domain near L-type Ca²⁺ channels could be impaired during high frequencies of heart beats such as in ventricular tachycardia, explaining, at least in part, the reduction of muscle contractility.

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