Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade

EMBO Rep. 2012 Feb 1;13(2):150-6. doi: 10.1038/embor.2011.246.

Abstract

Sqstm1/p62 functions in the non-canonical activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, its physiological relevance is not certain. Here, we show that p62(-/-) mice exhibited an accelerated presentation of ageing phenotypes, and tissues from these mice created a pro-oxidative environment owing to compromised mitochondrial electron transport. Accordingly, mitochondrial function rapidly declined with age in p62(-/-) mice. In addition, p62 enhanced basal Nrf2 activity, conferring a higher steady-state expression of NAD(P)H dehydrogenase, quinone 1 (Nqo1) to maintain mitochondrial membrane potential and, thereby, restrict excess oxidant generation. Together, the p62-Nrf2-Nqo1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / deficiency
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autophagy
  • Cytoskeletal Proteins / metabolism*
  • Female
  • Heat-Shock Proteins / deficiency
  • Heat-Shock Proteins / metabolism*
  • Kelch-Like ECH-Associated Protein 1
  • Longevity / physiology*
  • Male
  • Mammals / physiology*
  • Mice
  • Mitochondria / metabolism*
  • NAD(P)H Dehydrogenase (Quinone) / metabolism*
  • NF-E2-Related Factor 2 / metabolism*
  • Oxidation-Reduction
  • Sequestosome-1 Protein
  • Signal Transduction

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytoskeletal Proteins
  • Heat-Shock Proteins
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse
  • NAD(P)H Dehydrogenase (Quinone)
  • Nqo1 protein, mouse