Trehalose protects against oxidative stress by regulating the Keap1-Nrf2 and autophagy pathways

Redox Biol. 2018 May;15:115-124. doi: 10.1016/j.redox.2017.09.007. Epub 2017 Sep 20.

Abstract

Dysfunction of autophagy, which regulates cellular homeostasis by degrading organelles and proteins, is associated with pathogenesis of various diseases such as cancer, neurodegeneration and metabolic disease. Trehalose, a naturally occurring nontoxic disaccharide found in plants, insects, microorganisms and invertebrates, but not in mammals, was reported to function as a mechanistic target of the rapamycin (mTOR)-independent inducer of autophagy. In addition, trehalose functions as an antioxidant though its underlying molecular mechanisms remain unclear. In this study, we showed that trehalose not only promoted autophagy, but also increased p62 protein expression, in an autophagy-independent manner. In addition, trehalose increased nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in a p62-dependent manner and enhance expression of its downstream antioxidant factors, heme oxygenase-1 (Ho-1) and nicotinamide adenine dinucleotide phosphate quinone dehydrogenase 1 (Nqo1). Moreover, treatment with trehalose significantly reduced amount of reactive oxygen species. Collectively, these results suggested that trehalose can function as a novel activator of the p62-Keap1/Nrf2 pathway, in addition to inducing autophagy. Therefore, trehalose may be useful to treat many chronic diseases involving oxidative stress and dysfunction of autophagy.

Keywords: Antioxidant; Autophagy; Keap1–Nrf2 system; Oxidative stress; Trehalose; p62.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy / genetics
  • Autophagy-Related Protein 5 / genetics
  • Heme Oxygenase-1 / genetics
  • Humans
  • Kelch-Like ECH-Associated Protein 1 / genetics*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Knockout
  • NAD(P)H Dehydrogenase (Quinone) / genetics
  • NF-E2-Related Factor 2 / genetics*
  • Oxidative Stress / drug effects
  • Proto-Oncogene Proteins c-yes / genetics*
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases / genetics
  • Trehalose / metabolism
  • Trehalose / pharmacology*

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Kelch-Like ECH-Associated Protein 1
  • Membrane Proteins
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Trehalose
  • Heme Oxygenase-1
  • Hmox1 protein, mouse
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse
  • Proto-Oncogene Proteins c-yes
  • Yes1 protein, mouse
  • TOR Serine-Threonine Kinases