Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

摘要

Abstract 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. Graphical abstract Display Omitted Highlights ? KO of mitochondrial transcription factor Tfam models mitochondrial cardiomyopathy. ? Cardiac mitochondria from Tfam KO mice take up Ca 2+ at twice the rate as controls. ? Cardiac mitochondria from Tfam KO mice release Ca 2+ at half the rate as controls. ? These changes reflect increased MCU complexes and decreased NCLX protein. ? Mitochondrial Ca 2+ maintains respiratory rates despite compromised OXPHOS.