Mitochondrial dysfunction induced by a cytotoxic adenine dinucleotide produced by ADP-ribosyl cyclases from cADPR.
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.
Bruzzone
Santina
S
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.
Dodoni
Giuliano
G
Department of Biochemistry, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
Kaludercic
Nina
N
Department of Biochemistry, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
Basile
Giovanna
G
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.
Millo
Enrico
E
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.
De Flora
Antonio
A
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.
Di Lisa
Fabio
F
Department of Biochemistry, University of Padova, Viale G. Colombo 3, 35121 Padova, Italy.
Zocchi
Elena
E
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.
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
D015226:Dinucleoside Phosphates; D036563:Cyclic ADP-Ribose; C012276:diadenosine pyrophosphate; D036541:ADP-ribosyl Cyclase; D000225:Adenine; D002118:Calcium