Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Zhao L

PROVIDER: S-EPMC6935825 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Zhao Lin L Li Hao H Wang Yan Y Zheng Adi A Cao Liu L Liu Jiankang J

Oxidative medicine and cellular longevity 20191217

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 studi ...[more]

PMID: 31949875

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Dataset Information

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

Publications

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

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