Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

•KO of mitochondrial transcription factor Tfam models mitochondrial cardiomyopathy.•Cardiac mitochondria from Tfam KO mice take up Ca2 + at twice the rate as controls.•Cardiac mitochondria from Tfam KO mice release Ca2 + at half the rate as controls.•These changes reflect increased MCU complexes and decreased NCLX protein.•Mitochondrial Ca2 + maintains respiratory rates despite compromised OXPHOS.

Calcium (Ca2 +) influx into the mitochondrial matrix stimulates ATP synthesis. Here, we investigate whether mitochondrial Ca2 + transport pathways are altered in the setting of deficient mitochondrial energy synthesis, as increased matrix Ca2 + 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 (10-15 day old mice), these mice have developed a dilated cardiomyopathy associated with impaired oxidative phosphorylation. We find evidence of increased mitochondrial Ca2 + during this period using imaging, electrophysiology, and biochemistry. The mitochondrial Ca2 + uniporter, the main portal for Ca2 + entry, displays enhanced activity, whereas the mitochondrial sodium-calcium (Na+-Ca2 +) exchanger, the main portal for Ca2 + 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+-Ca2 + exchanger, explains diminished Na+-Ca2 + 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 Ca2 +-induced increases in respiration. In the absence of Ca2 +, oxygen consumption declines to less than half of control values in these animals, but rebounds to control levels when incubated with Ca2 +. Thus, we demonstrate a phenotype of enhanced mitochondrial Ca2 + in a mitochondrial cardiomyopathy model, and show that such Ca2 + accumulation is capable of rescuing deficits in energy synthesis capacity in vitro.

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