Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis

Autophagy, an intracellular degradation mechanism eliminating unused or damaged cytoplasmic components for recycling, is often activated in response to diverse types of stress, profoundly influencing cellular physiology or pathophysiology. Upon encountering oxidative stress, autophagy acts rapidly a...

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Main Authors: Lin Zhao, Hao Li, Yan Wang, Adi Zheng, Liu Cao, Jiankang Liu
Format: Article
Language:English
Published: Hindawi Limited 2019-01-01
Series:Oxidative Medicine and Cellular Longevity
Online Access:http://dx.doi.org/10.1155/2019/2526314
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spelling doaj-400b43a948cf4360bf0b9afdfc27c68e2020-11-25T02:53:49ZengHindawi LimitedOxidative Medicine and Cellular Longevity1942-09001942-09942019-01-01201910.1155/2019/25263142526314Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 AxisLin Zhao0Hao Li1Yan Wang2Adi Zheng3Liu Cao4Jiankang Liu5Institute of Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, ChinaInstitute of Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, ChinaInstitute of Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, ChinaInstitute of Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, ChinaKey Laboratory of Medical Cell Biology, China Medical University, Shenyang 110001, ChinaInstitute of Mitochondrial Biology and Medicine, The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology and Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an 710049, ChinaAutophagy, an intracellular degradation mechanism eliminating unused or damaged cytoplasmic components for recycling, is often activated in response to diverse types of stress, profoundly influencing cellular physiology or pathophysiology. Upon encountering oxidative stress, autophagy acts rapidly and effectively to remove oxidized proteins or organelles, including damaged mitochondria that generate more ROS, thereby indirectly contributing to the maintenance of redox homeostasis. Emerging studies are shedding light on the crosstalks among autophagy, mitochondria, and oxidative stress; however, whether and how autophagy could directly modulate antioxidant defense and redox homeostasis remains unaddressed. Here, we showed mitochondrial dysfunction, elevated ROS level, impaired antioxidant enzymes, and loss of FOXO1/3 in autophagy deficiency cellular models established by either chemical inhibitors or knocking down/out key molecules implementing autophagy, and overexpression of FOXO1/3 restored antioxidant enzymes hence suppressed elevated ROS; knockdown of p62 increased protein level of FOXO1/3 and recovered FOXO1 in Atg5-knockdown cells. Our data demonstrates that the loss of FOXO1/3 is responsible for the impairment of antioxidant enzymes and the consequent elevation of ROS, and accumulation of p62 under condition of autophagy deficiency might be mediating the loss of FOXO1/3. Furthermore, we found in an animal model that the p62-FOXO1/3 axis could be dominant in aging liver but not in type 2 diabetic liver. Together, these evidences uncover the p62-FOXO1/3 axis as the molecular cue that underlies the impairment of antioxidant defense in autophagy deficiency and suggest its potential involvement in aging, substantiating the impact of inadequate autophagy on mitochondria and redox homeostasis.http://dx.doi.org/10.1155/2019/2526314
collection DOAJ
language English
format Article
sources DOAJ
author Lin Zhao
Hao Li
Yan Wang
Adi Zheng
Liu Cao
Jiankang Liu
spellingShingle Lin Zhao
Hao Li
Yan Wang
Adi Zheng
Liu Cao
Jiankang Liu
Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis
Oxidative Medicine and Cellular Longevity
author_facet Lin Zhao
Hao Li
Yan Wang
Adi Zheng
Liu Cao
Jiankang Liu
author_sort Lin Zhao
title Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis
title_short Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis
title_full Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis
title_fullStr Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis
title_full_unstemmed Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis
title_sort autophagy deficiency leads to impaired antioxidant defense via p62-foxo1/3 axis
publisher Hindawi Limited
series Oxidative Medicine and Cellular Longevity
issn 1942-0900
1942-0994
publishDate 2019-01-01
description Autophagy, an intracellular degradation mechanism eliminating unused or damaged cytoplasmic components for recycling, is often activated in response to diverse types of stress, profoundly influencing cellular physiology or pathophysiology. Upon encountering oxidative stress, autophagy acts rapidly and effectively to remove oxidized proteins or organelles, including damaged mitochondria that generate more ROS, thereby indirectly contributing to the maintenance of redox homeostasis. Emerging studies are shedding light on the crosstalks among autophagy, mitochondria, and oxidative stress; however, whether and how autophagy could directly modulate antioxidant defense and redox homeostasis remains unaddressed. Here, we showed mitochondrial dysfunction, elevated ROS level, impaired antioxidant enzymes, and loss of FOXO1/3 in autophagy deficiency cellular models established by either chemical inhibitors or knocking down/out key molecules implementing autophagy, and overexpression of FOXO1/3 restored antioxidant enzymes hence suppressed elevated ROS; knockdown of p62 increased protein level of FOXO1/3 and recovered FOXO1 in Atg5-knockdown cells. Our data demonstrates that the loss of FOXO1/3 is responsible for the impairment of antioxidant enzymes and the consequent elevation of ROS, and accumulation of p62 under condition of autophagy deficiency might be mediating the loss of FOXO1/3. Furthermore, we found in an animal model that the p62-FOXO1/3 axis could be dominant in aging liver but not in type 2 diabetic liver. Together, these evidences uncover the p62-FOXO1/3 axis as the molecular cue that underlies the impairment of antioxidant defense in autophagy deficiency and suggest its potential involvement in aging, substantiating the impact of inadequate autophagy on mitochondria and redox homeostasis.
url http://dx.doi.org/10.1155/2019/2526314
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