Sci. Aging Knowl. Environ., 21 April 2004
Protein that shortens mouse life span opens holes in mitochondria
R. John Davenporthttp://sageke.sciencemag.org/cgi/content/full/2004/16/nf43
Perforating mitochondria might accelerate aging, according to a new study. A protein called p66shc that speeds the demise of mice breaches these organelles, a key event in cell death. The work reveals new information about p66shc's workings, but researchers caution that they don't yet know whether the protein influences life span through this route.
p66shc made a splash in 1999 when molecular biologist Pier Giuseppe Pelicci of the European Institute of Oncology in Milan, Italy, and colleagues discovered that mice without the protein live 30% longer than normal. Their longevity secret might be exceptional resistance to molecular damage. The animals survive longer than usual after an injection of oxidants, and they evade the scarred arteries normally caused by a heart-stopping, high-fat diet (see "Acing the Stress Test"). p66shc's absence might disarm noxious compounds by preventing cell death, or apoptosis: Cultured cells from the mutant animals resist suicide when doused with the oxidant peroxide. The team wondered how the protein prompts cell suicide.
In the new work, Pelicci and his team sought connections between p66shc and steps in the apoptosis pathway. At a crucial point in the process, mitochondria leak a protein called cytochrome c into the cell's cytoplasm. To test whether p66shc influences this step, the team exposed cultured normal cells and those without p66shc to peroxide. p66shc-deficient cells carried lower concentrations of cytochrome c in their cytoplasm than did normal cells. Cytochrome c escapes when mitochondrial membranes crack. These fissures occur when particular molecular channels open and the organelles lose their charge and then swell. To detect these events, the researchers used a fluorescent dye that stops glowing when the mitochondrial battery drains. Normal cells treated with peroxide lost power, but cells without p66shc didn't. The results suggest that p66shc spurs the destruction of mitochondria and the dispersal of cytochrome c.
Other proteins that kindle these steps of apoptosis hang out in mitochondria. To investigate whether p66shc lurks there as well, the researchers tracked the protein using a glowing antibody that binds to it. They determined that in healthy cells, about half of the protein resides in the organelles. After peroxide treatment, slightly more protein congregated there. Further studies revealed that in mitochondria, p66shc normally adheres to Hsp70, a protein that hinders apoptosis. After oxidant treatment, the proteins separated; that release might act as a switch, allowing p66shc to prompt cell death, says Pelicci.
Previous research suggested that p66shc prodded cell death indirectly by quelling antioxidant defenses (see "Stay Mellow, Stay Young"), but the new findings indicate that it "plays a direct role in the collapse of mitochondria," says molecular biologist Qin Chen of the University of Arizona in Tucson. Apoptosis researcher Brian Herman of the University of Texas Health Science Center in San Antonio agrees that the finding is novel, but he cautions that mitochondria house only a fraction of the cell's p66shc; it's still unclear where the protein acts to clip mouse life span, he says. Future work should reveal whether p66shc's ability to open the mitochondrial floodgates influences longevity.
April 21, 2004
Suggested by Patrick Kaminker.
Science of Aging Knowledge Environment. ISSN 1539-6150