| First Author | Sommakia S | Year | 2017 |
| Journal | J Mol Cell Cardiol | Volume | 113 |
| Pages | 22-32 | PubMed ID | 28962857 |
| Mgi Jnum | J:253735 | Mgi Id | MGI:6102339 |
| Doi | 10.1016/j.yjmcc.2017.09.009 | Citation | Sommakia S, et al. (2017) Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium. J Mol Cell Cardiol 113:22-32 |
| abstractText | 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. |
