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Research ArticleJPET Miniseries: Mitochondria

Oxidative Shielding or Oxidative Stress?

Robert K. Naviaux
Journal of Pharmacology and Experimental Therapeutics September 2012, 342 (3) 608-618; DOI: https://doi.org/10.1124/jpet.112.192120
Robert K. Naviaux
The Mitochondrial and Metabolic Disease Center, Departments of Medicine, Pediatrics, and Pathology, University of California San Diego School of Medicine, San Diego, California
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Abstract

In this review I report evidence that the mainstream field of oxidative damage biology has been running fast in the wrong direction for more than 50 years. Reactive oxygen species (ROS) and chronic oxidative changes in membrane lipids and proteins found in many chronic diseases are not the result of accidental damage. Instead, these changes are the result of a highly evolved, stereotyped, and protein-catalyzed “oxidative shielding” response that all eukaryotes adopt when placed in a chemically or microbially hostile environment. The machinery of oxidative shielding evolved from pathways of innate immunity designed to protect the cell from attack and limit the spread of infection. Both oxidative and reductive stress trigger oxidative shielding. In the cases in which it has been studied explicitly, functional and metabolic defects occur in the cell before the increase in ROS and oxidative changes. ROS are the response to disease, not the cause. Therefore, it is not the oxidative changes that should be targeted for therapy, but rather the metabolic conditions that create them. This fresh perspective is relevant to diseases that range from autism, type 1 diabetes, type 2 diabetes, cancer, heart disease, schizophrenia, Parkinson's disease, and Alzheimer disease. Research efforts need to be redirected. Oxidative shielding is protective and is a misguided target for therapy. Identification of the causal chemistry and environmental factors that trigger innate immunity and metabolic memory that initiate and sustain oxidative shielding is paramount for human health.

Footnotes

  • R.K.N. is supported by the University of California San Diego Christini Fund, the Wright Foundation, the Lennox Foundation, the Jane Botsford-Johnson Foundation, and the Hailey's Wish Foundation.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    http://dx.doi.org/10.1124/jpet.112.192120.

  • ABBREVIATIONS:

    ROS
    reactive oxygen species
    GYA
    giga (109) years ago
    Torr
    millimeters of mercury pressure (mm Hg)
    GSH
    glutathione
    GSSG
    GSH disulfide
    CI
    confidence interval
    ER
    endoplasmic reticulum
    pO2
    oxygen partial pressure.

  • Received March 2, 2012.
  • Accepted June 8, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 342 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 342, Issue 3
1 Sep 2012
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Research ArticleJPET Miniseries: Mitochondria

Oxidative Shielding

Robert K. Naviaux
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 608-618; DOI: https://doi.org/10.1124/jpet.112.192120

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Research ArticleJPET Miniseries: Mitochondria

Oxidative Shielding

Robert K. Naviaux
Journal of Pharmacology and Experimental Therapeutics September 1, 2012, 342 (3) 608-618; DOI: https://doi.org/10.1124/jpet.112.192120
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  • Article
    • Abstract
    • Introduction
    • Mitochondria, Innate Immunity, and Cellular Defense
    • Oxidative Shielding
    • Randomized Clinical Trials
    • Evolutionary Conservation of the Oxidative Shielding Response
    • Apoptosis, Cellular Altruism, and the Seductive Clarity of Cell Culture
    • Apoptosis: Bad for Cells in Culture, Good for the Species
    • Hyperoxia: The Uniquely Oxidizing Environment of the Culture Dish
    • NADPH: The Electron Carrier for Biomass Synthesis, Not for Cell Work
    • Multicellularity and Metabolic Complementarity: The Autonomy of Cells in Culture
    • Cell Metabolism Is Like an Ecosystem
    • Metabolic Consequences of Nutrient Excess
    • Tissue Hypoxia and Ocean Hypoxia: Universal Metabolic Response to Nutrient Loading
    • Redox Compartments and Oxygen Gradients in the Cell
    • Cellular Thermodynamics and Work
    • Metabolic Memory and Exercise
    • Antioxidant Therapy Inhibits the Benefits of Exercise
    • Antioxidant Treatment Decreases Tissue Perfusion
    • Phytonutrients and Xenohormesis
    • Conclusions
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

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