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Assurance of mitochondrial integrity and mammalian longevity by the p62–Keap1–Nrf2–Nqo1 cascade
Author(s) -
Kwon Jeongho,
Han Eunhye,
Bui ChiBao,
Shin Woochul,
Lee Junho,
Lee Sejeong,
Choi YoungBong,
Lee AnnHwee,
Lee KyongHoon,
Park Chankyu,
Obin Martin S,
Park Sung Kyu,
Seo Yun Jeong,
Oh Goo Taeg,
Lee HanWoong,
Shin Jaekyoon
Publication year - 2012
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.1038/embor.2011.246
Subject(s) - mitochondrion , nad+ kinase , oxidative phosphorylation , microbiology and biotechnology , keap1 , mitochondrial dna , longevity , biology , mitochondrial ros , oxidative stress , biochemistry , chemistry , genetics , enzyme , transcription factor , gene
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.