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

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 its absence modifies metabolic homeostasis by...

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Bibliographic Details
Published in:Oxidative medicine and cellular longevity 2018-01, Vol.2018 (2018), p.1-13
Main Authors: Carreras, María Cecilia, Villalba, Nerina, Elguero, María Eugenia, Rebagliati, Inés, Alippe, Yael, Finocchietto, Paola Vanesa, Pérez, Hernán, Poderoso, Juan José
Format: Article
Language:English
Subjects:
Age
Aging
Biochemistry
Biosynthesis
Brain
Cytochrome
Free radicals
Homeostasis
Kinases
Laboratory animals
Metabolism
Mitochondria
Mitochondrial DNA
Morphology
Nitrates
Oxidative stress
Phosphorylation
Physiology
Proteins
Reactive oxygen species
Rodents
Senescence
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Summary: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 its absence modifies metabolic homeostasis by providing oxidative stress resistance and promoting longevity. p66Shc(−/−) mice are a 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.
ISSN:1942-0900
1942-0994
DOI:10.1155/2018/8561892