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Protein Kinase C ß and Prolyl Isomerase 1 Regulate Mitochondrial Effects of the Life-Span Determinant p66Shc
Paolo Pinton,1,2*Alessandro Rimessi,1,2*Saverio Marchi,1,2Francesca Orsini,3,4Enrica Migliaccio,3,4Marco Giorgio,3,4Cristina Contursi,5Saverio Minucci,5Fiamma Mantovani,6,7Mariusz R. Wieckowski,1,2,8Giannino Del Sal,6,7Pier Giuseppe Pelicci,3,4,9Rosario Rizzuto1,2
The 66-kilodalton isoform of the growth factor adapter Shc (p66Shc)translates oxidative damage into cell death by acting as reactiveoxygen species (ROS) producer within mitochondria. However,the signaling link between cellular stress and mitochondrialproapoptotic activity of p66Shc was not known. We demonstratethat protein kinase C ß, activated by oxidative conditionsin the cell, induces phosphorylation of p66Shc and triggersmitochondrial accumulation of the protein after it is recognizedby the prolyl isomerase Pin1. Once imported, p66Shc causes alterationsof mitochondrial Ca2+ responses and three-dimensional structure,thus inducing apoptosis. These data identify a signaling routethat activates an apoptotic inducer shortening the life spanand could be a potential target of pharmacological approachesto inhibit aging.
1 Department of Experimental and Diagnostic Medicine, Section of General Pathology and Interdisciplinary Center for the Study of Inflammation (ICSI), University of Ferrara, Ferrera, Italy. 2 Emilia Romagna Laboratory for Genomics and Biotechnology (ER-Gentech), University of Ferrara, Ferrera, Italy. 3 Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. 4 Fondazione Italiana per la Ricerca sul Cancro (FIRC) Institute of Molecular Oncology, Milan, Italy. 5 Congenia s.r.l., Milan, Italy. 6 Laboratorio Nazionale, Consorzio Interuniversitario per le Biotecnologie, Area Science Park, Trieste, Italy. 7 Department of Biochimica Biofisica Chimica delle Macromolecole, University of Trieste, Italy. 8 Department of Cellular Biochemistry, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Poland. 9 Department of Medicine and Surgery, University of Milan, Italy.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: r.rizzuto{at}unife.it
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