Cell Metabolism
Volume 17, Issue 6, 4 June 2013, Pages 965-975
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Article
Mitochondrial Ca2+ Uptake Induces Cyclic AMP Generation in the Matrix and Modulates Organelle ATP Levels

https://doi.org/10.1016/j.cmet.2013.05.003Get rights and content
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Highlights

  • cAMP produced in the cytosol does not diffuse into the mitochondrial matrix

  • Mitochondria are endowed with an autonomous cAMP homeostatic mechanism

  • Mitochondrial Ca2+ increases induce mt-cAMP in cell lines and primary cardiomyocytes

  • Intramitochondrial cAMP concentration regulates ATP production

Summary

While the role of mitochondrial Ca2+ homeostasis in cell pathophysiology is widely accepted, the possibility that cAMP regulates mitochondrial functions has only recently received experimental support. The site of cAMP production, its targets, and its functions in the organelles remain uncertain. Using a variety of genetic/pharmacological tools, we here demonstrate that the mitochondrial inner membrane is impermeable to cytosolic cAMP, while an autonomous cAMP signaling toolkit is expressed in the matrix. We demonstrate that rises in matrix Ca2+ powerfully stimulate cAMP increases within mitochondria and that matrix cAMP levels regulate their ATP synthesizing efficiency. In cardiomyocyte cultures, mitochondrial cAMP can be increased by treatments that augment the frequency and amplitude of Ca2+ oscillations within the cytosol and organelles, revealing that mitochondria can integrate an oscillatory Ca2+ signal to increase cAMP in their matrix. The present data reveal the existence, within mitochondria, of a hitherto unknown crosstalk between Ca2+ and cAMP.

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Present address: Department of Nephrology Dialysis & Transplantation, International Renal Research Institute Vicenza (IRRIV), St. Bortolo Hospital, 36100 Vicenza, Italy