p66Shc reduces cytochrome c and generates hydrogen peroxide.


Reactive oxygen species (ROS) are not all accidental and unwanted byproducts. Marco Giorgio, Enrica Migliaccio, Pier Giuseppe Pelicci (University of Milan, Italy), and colleagues report that a protein called p66Shc purposely siphons electrons from the respiratory chain and uses them to trigger apoptosis during times of stress.

Cells that lack p66Shc were known to produce less ROS and be resistant to various pro-apoptosis stimuli. Giorgio et al. now show that p66Shc is sufficient to induce mitochondrial swelling and rupture when added to purified mitochondria. The protein also induces excess ROS production, but only when the organelles are undergoing respiration.p66Shc takes electrons from the respiratory protein cytochrome c and uses them to produce the ROS hydrogen peroxide. p66Shc diverts only a fraction of the electrons though, and respiration continues in its presence.

Because hydrogen peroxide can diffuse through the mitochondria and open holes in the membrane, p66Shc's redirection of electrons must somehow be regulated to prevent unwanted apoptosis. p66Shc increases production of ROS during times of stress, when cellular damage might be too extensive to repair. But just how the cell limits p66Shc activity during healthy times is not yet clear.


Giorgio, M., et al.