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Cells. 2019 Mar 15;8(3). pii: E250. doi: 10.3390/cells8030250.

Increased Levels of cAMP by the Calcium-Dependent Activation of Soluble Adenylyl Cyclase in Parkin-Mutant Fibroblasts.

Author information

1
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", 70124 Bari, Italy. tanzarellapaola87@gmail.com.
2
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", 70124 Bari, Italy. anna.ferretta@uniba.it.
3
Department of Biosciences, Biotechnologies and Biopharmaceutics, University of "Bari Aldo Moro", 70124 Bari, Italy. simona.barile@uniba.it.
4
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", 70124 Bari, Italy. mariellaa83@gmail.com.
5
Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, Italian National Research Council (CNR), 70126 Bari, Italy. d.derasmo@ibiom.cnr.it.
6
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", 70124 Bari, Italy. anna.signorile@uniba.it.
7
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", 70124 Bari, Italy. sergio.papa@uniba.it.
8
Stazione Zoologica Anton Dohrn, 80121 Napoli, Italy. sergio.papa@uniba.it.
9
Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy. nazzareno.capitanio@unifg.it.
10
Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy. consiglia.pacelli@unifg.it.
11
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari "Aldo Moro", 70124 Bari, Italy. tizianamaria.cocco@uniba.it.

Abstract

Almost half of autosomal recessive early-onset parkinsonism has been associated with mutations in PARK2, coding for parkin, which plays an important role in mitochondria function and calcium homeostasis. Cyclic adenosine monophosphate (cAMP) is a major second messenger regulating mitochondrial metabolism, and it is strictly interlocked with calcium homeostasis. Parkin-mutant (Pt) fibroblasts, exhibiting defective mitochondrial respiratory/OxPhos activity, showed a significant higher value of basal intracellular level of cAMP, as compared with normal fibroblasts (CTRL). Specific pharmacological inhibition/activation of members of the adenylyl cyclase- and of the phosphodiesterase-families, respectively, as well as quantitative reverse transcription polymerase chain reaction (RT-qPCR) analysis, indicate that the higher level of cAMP observed in Pt fibroblasts can contribute to a higher level of activity/expression by soluble adenylyl cyclase (sAC) and to low activity/expression of the phosphodiesterase isoform 4 (PDE4). As Ca2+ regulates sAC, we performed quantitative calcium-fluorimetric analysis, showing a higher level of Ca2+ in the both cytosol and mitochondria of Pt fibroblasts as compared with CTRL. Most notably, inhibition of the mitochondrial Ca2+ uniporter decreased, specifically the cAMP level in PD fibroblasts. All together, these findings support the occurrence of an altered mitochondrial Ca2+-mediated cAMP homeostasis in fibroblasts with the parkin mutation.

KEYWORDS:

cAMP; calcium; mitochondria; parkin

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