Autophagy Deficiency Leads to Impaired Antioxidant Defense via p62-FOXO1/3 Axis
| Autor: | Yan Wang, Liu Cao, Lin Zhao, Hao Li, Jiankang Liu, Adi Zheng |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
Cell physiology Aging Antioxidant Article Subject medicine.medical_treatment FOXO1 Mitochondrion medicine.disease_cause Autophagy-Related Protein 7 Biochemistry Antioxidants Rats Sprague-Dawley Mice Autophagy medicine Animals Humans lcsh:QH573-671 Mice Knockout Gene knockdown lcsh:Cytology Forkhead Box Protein O1 Chemistry RNA-Binding Proteins Cell Biology General Medicine Mitochondria Rats Cell biology Oxidative Stress HEK293 Cells Reactive Oxygen Species Oxidation-Reduction Intracellular Oxidative stress Research Article |
| Zdroj: | Oxidative Medicine and Cellular Longevity Oxidative Medicine and Cellular Longevity, Vol 2019 (2019) |
| ISSN: | 1942-0994 1942-0900 |
| DOI: | 10.1155/2019/2526314 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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