ROLE OF CASPASE-3 ON OXIDATIVE STRESS IN THE AGING MOUSE ORGANS

Mitochondrial dysfunction could be a cause or consequence of apoptotic death. This effect may be facilitated by a substantial mitochondrial-dependent increase in the generation of superoxide free radicals and other downstream reactive species (RS). Electron leakage from the respiratory complexes causes reduction of molecular oxygen to form the superoxide free radical. Caspase-3 may induce this leakage of electrons within mitochondria by attacking the respiratory complex proteins. The cellular damage caused by the accumulation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is enhanced with aging. This damage may have a role in the development of age-related neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases, and may also contribute to the pathologies in other organ systems such as heart, kidney and liver. Neurons are extremely susceptible to oxidative stress because they have high oxygen demand, and relatively low antioxidant capacity. An abnormal production of superoxide free radical by mitochondria, and the downstream ROS and RNS renders neurons vulnerable to damage from these RS. Previous studies from our laboratory show that the depletion of Bax or caspase-3 from mouse sympathetic neurons in cell culture significantly decreased the levels of ROS produced during apoptosis. Here we utilized oxidative stress markers to determine whether caspase-3 deletion reduces oxidative damage in the brains of female mice at 12 months of age. Oxidative stress markers such as lipid peroxides and 8-hydroxy-2’-deoxyguanosine (8-OHdG) levels were reduced in the brains from mice with genetically depleted levels of caspase-3. Nitration of protein tyrosine residues caused by RNS was also decreased in the brains of caspase-3 null mice compared to that of wild-type animals of the same age. Caspase-3 deletion had similar effects on lipid peroxidation, oxidative DNA damage (as assessed by 8-OHdG levels), and protein tyrosine nitration in the hearts, livers, and kidneys of these animals. The findings of this study indicate that caspase-3 plays a vital role in the generation of ROS, and hence contributing to the oxidative stress in the mouse brain as well as in other organs.

INDEX WORDS: Aging; oxidative stress; reactive species; apoptosis; caspase-3