Details

Autor(en) / Beteiligte

• Sommakia, Salah
• Houlihan, Patrick R.
• Deane, Sadiki S.
• Simcox, Judith A.
• Torres, Natalia S.
• Jeong, Mi-Young
• Winge, Dennis R.
• Villanueva, Claudio J.
• Chaudhuri, Dipayan

Titel

Mitochondrial cardiomyopathies feature increased uptake and diminished efflux of mitochondrial calcium

Ist Teil von

• Journal of molecular and cellular cardiology, 2017-12, Vol.113, p.22-32

Ort / Verlag

England: Elsevier Ltd

Erscheinungsjahr

2017

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (10–15day 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. [Display omitted] •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.