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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / deficiency
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Autophagy
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Cytoskeletal Proteins / metabolism*
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Female
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Heat-Shock Proteins / deficiency
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Heat-Shock Proteins / metabolism*
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Kelch-Like ECH-Associated Protein 1
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Longevity / physiology*
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Male
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Mammals / physiology*
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Mice
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Mitochondria / metabolism*
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NAD(P)H Dehydrogenase (Quinone) / metabolism*
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NF-E2-Related Factor 2 / metabolism*
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Oxidation-Reduction
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Sequestosome-1 Protein
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Signal Transduction
Substances
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Adaptor Proteins, Signal Transducing
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Cytoskeletal Proteins
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Heat-Shock Proteins
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Keap1 protein, mouse
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Kelch-Like ECH-Associated Protein 1
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NF-E2-Related Factor 2
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Nfe2l2 protein, mouse
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Sequestosome-1 Protein
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Sqstm1 protein, mouse
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NAD(P)H Dehydrogenase (Quinone)
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Nqo1 protein, mouse