Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium.

Calcium (Ca ²⁺ ) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca ²⁺ transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca ²⁺ may provide a stimulatory boost. We focused on mitochondrial cardiomyopathies, which feature such dysfunction of oxidative phosphorylation. We study a mouse model where the main transcription factor for mitochondrial DNA (transcription factor A, mitochondrial, Tfam) has been disrupted selectively in cardiomyocytes. By the second postnatal week (10-15day old mice), these mice have developed a dilated cardiomyopathy associated with impaired oxidative phosphorylation. We find evidence of increased mitochondrial Ca ²⁺ during this period using imaging, electrophysiology, and biochemistry. The mitochondrial Ca ²⁺ uniporter, the main portal for Ca ²⁺ entry, displays enhanced activity, whereas the mitochondrial sodium-calcium (Na ⁺ -Ca ²⁺ ) exchanger, the main portal for Ca ²⁺ efflux, is inhibited. These changes in activity reflect changes in protein expression of the corresponding transporter subunits. While decreased transcription of Nclx, the gene encoding the Na ⁺ -Ca ²⁺ exchanger, explains diminished Na ⁺ -Ca ²⁺ exchange, the mechanism for enhanced uniporter expression appears to be post-transcriptional. Notably, such changes allow cardiac mitochondria from Tfam knockout animals to be far more sensitive to Ca ²⁺ -induced increases in respiration. In the absence of Ca ²⁺ , oxygen consumption declines to less than half of control values in these animals, but rebounds to control levels when incubated with Ca ²⁺ . Thus, we demonstrate a phenotype of enhanced mitochondrial Ca ²⁺ in a mitochondrial cardiomyopathy model, and show that such Ca ²⁺ accumulation is capable of rescuing deficits in energy synthesis capacity in vitro.
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