p66Shc Inactivation Modifies RNS Production, Regulates Sirt3 Activity, and Improves Mitochondrial Homeostasis, Delaying the Aging Process in Mouse Brain

PAOLA FINOCCHIETO; ELGUERO MARÍA EUGENIA; CARRERAS MARÍA CECILIA; YAEL ALIPPE; VILLALBA NERINA; PEREZ HERNAN; INÉS REBAGLIATI; PODEROSO JUAN JOSE; PAOLA FINOCCHIETO; ELGUERO MARÍA EUGENIA; CARRERAS MARÍA CECILIA; YAEL ALIPPE; VILLALBA NERINA; PEREZ HERNAN; INÉS REBAGLIATI; PODEROSO JUAN JOSE

OXIDATIVE MEDICINE AND CELLULAR LONGEVITY

LANDES BIOSCIENCE

Lugar: Austin, Texas; Año: 2018 p. 1 - 13

1942-0900

Programmed and damage aging theories have traditionally been conceived as stand-alone schools of thought. However, the p66Shc adaptor protein has demonstrated that aging-regulating genes and reactive oxygen species (ROS) are closely interconnected, since itsabsencemodifiesmetabolichomeostasisbyprovidingoxidativestressresistanceandpromotinglongevity.p66Shc(−/−) micearea unique opportunity to further comprehend the bidirectional relationship between redox homeostasis and the imbalance of mitochondrial biogenesis and dynamics during aging. This study shows that brain mitochondria of p66Shc(−/−) aged mice exhibit a reduced alteration of redox balance with a decrease in both ROS generation and its detoxification activity. We also demonstrate a strong link between reactive nitrogen species (RNS) and mitochondrial function, morphology, and biogenesis, where low levels of ONOO− formation present in aged p66Shc(−/−) mouse brain prevent protein nitration, delaying the loss of biological functions characteristic of the aging process. Sirt3 modulates age-associated mitochondrial biology and function via lysine deacetylation of target proteins, and we show that its regulation depends on its nitration status and is benefited by the improved NAD+/NADH ratio in aged p66Shc(−/−) brain mitochondria. Low levels of protein nitration and acetylation could cause the metabolic homeostasis maintenance observed during aging in this group, thus increasing its lifespan.