title: Mitochondrial dysfunction induced by a cytotoxic adenine dinucleotide produced by ADP-ribosyl cyclases from cADPR.
abstract: ADP-ribosyl cyclases were previously shown to produce three new adenine dinucleotides, P1,P2 diadenosine 5'-diphosphate (Ap2A) and two isomers thereof (P18 and P24), from cyclic ADP-ribose (cADPR) and adenine (Basile, G., Taglialatela-Scafati, O., Damonte, G., Armirotti, A., Bruzzone, S., Guida, L., Franco, L., Usai, C., Fattorusso, E., De Flora, A., and Zocchi, E. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 14509-14514). The Ap2A isomer P24, containing an unusual C1'-N3 N-glycosidic bond, is shown here to affect mitochondrial function through (i) opening of the permeability transition pore complex (and consequent proton gradient dissipation) and (ii) inhibition of Complex I of the respiratory chain. Whereas proton gradient dissipation is dependent upon the extracellular Ca(2+) influx triggered by P24, the effect on oxygen consumption is Ca(2+) independent. The proton gradient dissipation induces apoptosis in HeLa cells and thus appears to be responsible for the already described potent cytotoxic effect of P24 on several human cell types. The other products of ADP-ribosyl cyclase activity, Ap2A and cADPR, antagonize P24-induced proton gradient dissipation and cytotoxicity, suggesting that the relative concentration of P24, cADPR, and Ap2A in cyclase-positive cells may affect the balance between cell life and death.
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy and.
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.affiliation: Department of Biochemistry, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Giuliano
authors.initials: G
authors.lastname: Dodoni
authors.affiliation: Department of Biochemistry, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Nina
authors.initials: N
authors.lastname: Kaludercic
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy and.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Basile
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy and.
authors.forename: Enrico
authors.initials: E
authors.lastname: Millo
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy and.
authors.forename: Antonio
authors.initials: A
authors.lastname: De Flora
authors.affiliation: Department of Biochemistry, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Lisa
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, and Center of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV/1, 16132 Genova, Italy and. Electronic address: ezocchi@unige.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Zocchi
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism*; D000225:Adenine / Q000378:metabolism*; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000096:biosynthesis*; D006367:HeLa Cells; D006801:Humans; D007536:Isomerism; D008928:Mitochondria / Q000201:enzymology* / Q000473:pathology; D018892:Proton-Motive Force
chemical_list: D015226:Dinucleoside Phosphates; D036563:Cyclic ADP-Ribose; C012276:diadenosine pyrophosphate; D036541:ADP-ribosyl Cyclase; D000225:Adenine; D002118:Calcium