El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
Programmed and damage aging theories have traditionally been conceived as stand-alone schools of thought. However, p66shc adaptor protein has demonstrated that aging-regulating genes and reactive oxygen species (ROS) are closely interconnected, since its absence modifies metabolic homeostasis by pro...
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| Formato: | Tesis doctoral acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2018
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=posgraafa&cl=CL1&d=HWA_2770 http://repositoriouba.sisbi.uba.ar/gsdl/collect/posgraafa/index/assoc/HWA_2770.dir/2770.PDF |
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| Sumario: | Programmed and damage aging theories have traditionally been conceived as stand-alone schools of thought. However, 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 both in 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(-/-) mice brain prevent protein nitration delaying 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. |
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