title: Mitochondrial Ca²⁺ uptake induces cyclic AMP generation in the matrix and modulates organelle ATP levels.
abstract: 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.
authors.affiliation: Institute of Neuroscience, Italian National Research Council (CNR), Viale G. Colombo 3, 35121 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy. Electronic address: giulietta.dibenedetto@cnr.it.
authors.forename: Giulietta
authors.initials: G
authors.lastname: Di Benedetto
authors.affiliation: Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Scalzotto
authors.affiliation: Institute of Neuroscience, Italian National Research Council (CNR), Viale G. Colombo 3, 35121 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy; Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Mongillo
authors.affiliation: Institute of Neuroscience, Italian National Research Council (CNR), Viale G. Colombo 3, 35121 Padova, Italy; Venetian Institute of Molecular Medicine (VIMM), Via Orus 2, 35129 Padova, Italy; Department of Biomedical Sciences, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Pozzan
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000096:biosynthesis / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D002118:Calcium