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p66Shc Inactivation Modifies RNS Production, Regulates Sirt3 Activity, and Improves Mitochondrial Homeostasis,

Hernán Pérez1, Paola Vanesa Finocchietto1,2, Yael Alippe1

  • 1Laboratory of Oxygen Metabolism, INIGEM-UBA-CONICET, Buenos Aires, Argentina.

Oxidative Medicine and Cellular Longevity
|May 4, 2018
PubMed

Insights

The absence of p66Shc protein in mice enhances resistance to oxidative stress and promotes longevity by improving redox homeostasis and mitochondrial function. This study reveals how reduced reactive nitrogen species and protein nitration contribute to delayed aging.

Area of Science:

  • Gerontology
  • Mitochondrial Biology
  • Oxidative Stress

Background:

  • Aging theories traditionally focus on programmed or damage-related mechanisms.
  • The p66Shc protein links aging genes and reactive oxygen species (ROS), influencing metabolic homeostasis and longevity.
  • p66Shc knockout mice offer insights into redox homeostasis and mitochondrial dynamics in aging.

Purpose of the Study:

  • To investigate the role of p66Shc in the relationship between redox homeostasis and mitochondrial function during aging.
  • To explore the impact of reduced ROS and reactive nitrogen species (RNS) on mitochondrial biogenesis and protein modification in aged p66Shc knockout mice.

Main Methods:

  • Comparative analysis of brain mitochondria from aged p66Shc knockout mice and wild-type controls.
  • Assessment of ROS generation, detoxification activity, and reactive nitrogen species (RNS) levels, including ONOO- formation.
  • Evaluation of mitochondrial function, morphology, biogenesis, protein nitration, and acetylation.

Main Results:

  • Aged p66Shc knockout mice exhibit improved redox balance with decreased ROS generation and detoxification.
  • Reduced ONOO- formation in aged p66Shc knockout mouse brains prevents protein nitration, preserving biological functions.
  • Sirt3 activity is maintained due to lower protein nitration and an improved NAD+/NADH ratio, contributing to metabolic homeostasis.

Conclusions:

  • The absence of p66Shc confers oxidative stress resistance and promotes longevity by maintaining mitochondrial function and redox balance.
  • Reduced protein nitration and acetylation are key factors in the metabolic homeostasis and extended lifespan observed in aged p66Shc knockout mice.
  • Targeting p66Shc pathways may offer strategies for mitigating age-related decline and enhancing healthspan.

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