Assurance of mitochondrial integrity and mammalian longevity by the p62-Keap1-Nrf2-Nqo1 cascade.
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.
Sungkyunkwan University School of Medicine and Samsung Biomedical Research Institute, Suwon-Si, Kyonggi-Do 440-746, Korea.
Jeongho
J
Kwon
Eunhye
E
Han
Chi-Bao
CB
Bui
Woochul
W
Shin
Junho
J
Lee
Sejeong
S
Lee
Young-Bong
YB
Choi
Ann-Hwee
AH
Lee
Kyong-Hoon
KH
Lee
Chankyu
C
Park
Martin S
MS
Obin
Sung Kyu
SK
Park
Yun Jeong
YJ
Seo
Goo Taeg
GT
Oh
Han-Woong
HW
Lee
Jaekyoon
J
Shin
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001343:Autophagy; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D006360:Heat-Shock Proteins / Q000172:deficiency / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1; D008136:Longevity / Q000502:physiology*; D008297:Male; D008322:Mammals / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071456:Sequestosome-1 Protein; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; D006360:Heat-Shock Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse