Cardiac responses to β‐adrenoceptor stimulation is partly dependent on mitochondrial calcium uniporter activity

Background and Purpose

Despite the importance of mitochondrial Ca²⁺ to metabolic regulation and cell physiology, little is known about the mechanisms that regulate Ca²⁺ entry into the mitochondria. Accordingly, we established a system to determine the role of the mitochondrial Ca²⁺ uniporter in an isolated heart model, at baseline and during increased workload following β‐adrenoceptor stimulation.

Experimental Approach

Cardiac contractility, oxygen consumption and intracellular Ca²⁺ transients were measured in ex vivo perfused murine hearts. Ru₃₆₀ and spermine were used to modify mitochondrial Ca²⁺ uniporter activity. Changes in mitochondrial Ca²⁺ content and energetic phosphate metabolite levels were determined.

Key Results

The addition of Ru₃₆₀, a selective inhibitor of the mitochondrial Ca²⁺ uniporter, induced progressively and sustained negative inotropic effects that were dose‐dependent with an EC₅₀ of 7 μM. Treatment with spermine, a uniporter agonist, showed a positive inotropic effect that was blocked by Ru₃₆₀. Inotropic stimulation with isoprenaline elevated oxygen consumption (2.7‐fold), Ca²⁺‐dependent activation of pyruvate dehydrogenase (5‐fold) and mitochondrial Ca²⁺ content (2.5‐fold). However, in Ru₃₆₀‐treated hearts, this parameter was attenuated. In addition, β‐adrenoceptor stimulation in the presence of Ru₃₆₀ did not affect intracellular Ca²⁺ handling, PKA or Ca²⁺/calmodulin‐dependent PK signalling.

Conclusions and Implications

Inhibition of the mitochondrial Ca²⁺ uniporter decreases β‐adrenoceptor response, uncoupling between workload and production of energetic metabolites. Our results support the hypothesis that the coupling of workload and energy supply is partly dependent on mitochondrial Ca²⁺ uniporter activity.

DOI: 10.1111/bph.12684

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