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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Autor principal: Pérez, Hernán
Otros Autores: Poderoso, Juan José
Formato: Tesis doctoral acceptedVersion
Lenguaje:Español
Publicado: Facultad de Farmacia y Bioquímica 2018
Materias:
P66shc
Homeostasis mitocrondrial
Envejecimiento
Enfermedades neurodegenerativas
Ciencia de la vida
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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Repositorio Digital de la Universidad de Buenos Aires (UBA) de Universidad de Buenos Aires
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spelling I28-R145-HWA_27702020-08-07 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. Fil: Pérez, Hernán. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina Poderoso, Juan José Facultad de Farmacia y Bioquímica Carreras, María Cecilia Pérez, Hernán 2018-11-02 La proteína adaptadora p66shc ha demostrado que los genes reguladores delenvejecimiento y las especies reactivas del oxígeno (ROS) están estrechamenteinterconectados. Su ausencia modifica la homeostasis metabólica proporcionando resistenciaal estrés oxidativo y promoviendo la longevidad. En este estudio, las mitocondrias de tejidonervioso de ratones envejecidos p66shc(-/-) presentan una alteración reducida del equilibrioredox con una disminución tanto en la generación de ROS como en su desintoxicación.Demostramos un fuerte vínculo entre las especies reactivas de nitrógeno y la función, la morfología y la biogénesis mitocondrial. Bajos niveles de formación de peroxinitrito resultanen una menor nitración de las proteínas mitocondriales de ratones p66shc(-/-) envejecidos,retrasando la pérdida de funciones biológicas característica del proceso de envejecimiento.Sirt3 modula la biología mitocondrial asociada a la edad y la función a través de ladesacetilación de proteínas. Mostramos que su actividad depende de su estado de nitración yque altos niveles de NAD, como los observados en mitocondrias de ratones p66shc(-/-) durante elenvejecimiento, retrasarían el declive de su función. Los bajos niveles de nitración yacetilación de proteínas en estos ratones, podrían ser responsables de prevenir el desbalancede la homeostasis metabólica durante el envejecimiento, aumentando la esperanza de vida. application/pdf Valdez, Laura Lores Arnaiz, Silvia Morelli, Laura P66shc Homeostasis mitocrondrial Envejecimiento Enfermedades neurodegenerativas spa Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Ciencia de la vida El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento info:eu-repo/semantics/doctoralThesis info:ar-repo/semantics/tesis doctoral info:eu-repo/semantics/acceptedVersion 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
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-145
collection Repositorio Digital de la Universidad de Buenos Aires (UBA)
language Español
orig_language_str_mv spa
topic P66shc
Homeostasis mitocrondrial
Envejecimiento
Enfermedades neurodegenerativas
Ciencia de la vida
spellingShingle P66shc
Homeostasis mitocrondrial
Envejecimiento
Enfermedades neurodegenerativas
Ciencia de la vida
Pérez, Hernán
El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
topic_facet P66shc
Homeostasis mitocrondrial
Envejecimiento
Enfermedades neurodegenerativas
Ciencia de la vida
description 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.
author2 Poderoso, Juan José
author_facet Poderoso, Juan José
Pérez, Hernán
format Tesis doctoral
Tesis doctoral
acceptedVersion
author Pérez, Hernán
author_sort Pérez, Hernán
title El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
title_short El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
title_full El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
title_fullStr El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
title_full_unstemmed El rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
title_sort el rol de p66shc en la homeostasis mitocondrial durante el envejecimiento
publisher Facultad de Farmacia y Bioquímica
publishDate 2018
url 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
work_keys_str_mv AT perezhernan elroldep66shcenlahomeostasismitocondrialduranteelenvejecimiento
_version_ 1766017512250540032

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