Protein kinase C β and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc

Paolo Pinton, Alessandro Rimessi, Saverio Marchi, Francesca Orsini, Enrica Migliaccio, Marco Giorgio, Cristina Contursi, Saverio Minucci, Fiamma Mantovani, Mariusz R. Wieckowski, Giannino Del Sal, Pier Giuseppe Pelicci, Rosario Rizzuto

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Abstract

The 66-kilodalton isoform of the growth factor adapter Shc (p66 Shc) translates oxidative damage into cell death by acting as reactive oxygen species (ROS) producer within mitochondria. However, the signaling link between cellular stress and mitochondrial proapoptotic activity of p66Shc was not known. We demonstrate that protein kinase C β, activated by oxidative conditions in the cell, induces phosphorylation of p66Shc and triggers mitochondrial accumulation of the protein after it is recognized by the prolyl isomerase Pin1. Once imported, p66Shc causes alterations of mitochondrial Ca2+ responses and three-dimensional structure, thus inducing apoptosis. These data identify a signaling route that activates an apoptotic inducer shortening the life span and could be a potential target of pharmacological approaches to inhibit aging.

Original languageEnglish
Pages (from-to)659-663
Number of pages5
JournalScience
Volume315
Issue number5812
DOIs
Publication statusPublished - Feb 2 2007

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    Pinton, P., Rimessi, A., Marchi, S., Orsini, F., Migliaccio, E., Giorgio, M., Contursi, C., Minucci, S., Mantovani, F., Wieckowski, M. R., Del Sal, G., Pelicci, P. G., & Rizzuto, R. (2007). Protein kinase C β and prolyl isomerase 1 regulate mitochondrial effects of the life-span determinant p66Shc . Science, 315(5812), 659-663. https://doi.org/10.1126/science.1135380