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      Autophagy protects auditory hair cells against neomycin-induced damage

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          ABSTRACT

          Aminoglycosides are toxic to sensory hair cells (HCs). Macroautophagy/autophagy is an essential and highly conserved self-digestion pathway that plays important roles in the maintenance of cellular function and viability under stress. However, the role of autophagy in aminoglycoside-induced HC injury is unknown. Here, we first found that autophagy activity was significantly increased, including enhanced autophagosome-lysosome fusion, in both cochlear HCs and HEI-OC-1 cells after neomycin or gentamicin injury, suggesting that autophagy might be correlated with aminoglycoside-induced cell death. We then used rapamycin, an autophagy activator, to increase the autophagy activity and found that the ROS levels, apoptosis, and cell death were significantly decreased after neomycin or gentamicin injury. In contrast, treatment with the autophagy inhibitor 3-methyladenine (3-MA) or knockdown of autophagy-related (ATG) proteins resulted in reduced autophagy activity and significantly increased ROS levels, apoptosis, and cell death after neomycin or gentamicin injury. Finally, after neomycin injury, the antioxidant N-acetylcysteine could successfully prevent the increased apoptosis and HC loss induced by 3-MA treatment or ATG knockdown, suggesting that autophagy protects against neomycin-induced HC damage by inhibiting oxidative stress. We also found that the dysfunctional mitochondria were not eliminated by selective autophagy (mitophagy) in HEI-OC-1 cells after neomycin treatment, suggesting that autophagy might not directly target the damaged mitochondria for degradation. This study demonstrates that moderate ROS levels can promote autophagy to recycle damaged cellular constituents and maintain cellular homeostasis, while the induction of autophagy can inhibit apoptosis and protect the HCs by suppressing ROS accumulation after aminoglycoside injury.

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          Most cited references 65

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          The role of Atg proteins in autophagosome formation.

          Macroautophagy is mediated by a unique organelle, the autophagosome, which encloses a portion of cytoplasm for delivery to the lysosome. Autophagosome formation is dynamically regulated by starvation and other stresses and involves complicated membrane reorganization. Since the discovery of yeast Atg-related proteins, autophagosome formation has been dissected at the molecular level. In this review we describe the molecular mechanism of autophagosome formation with particular focus on the function of Atg proteins and the long-standing discussion regarding the origin of the autophagosome membrane.
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            Dynamics and diversity in autophagy mechanisms: lessons from yeast.

            Autophagy is a fundamental function of eukaryotic cells and is well conserved from yeast to humans. The most remarkable feature of autophagy is the synthesis of double membrane-bound compartments that sequester materials to be degraded in lytic compartments, a process that seems to be mechanistically distinct from conventional membrane traffic. The discovery of autophagy in yeast and the genetic tractability of this organism have allowed us to identify genes that are responsible for this process, which has led to the explosive growth of this research field seen today. Analyses of autophagy-related (Atg) proteins have unveiled dynamic and diverse aspects of mechanisms that underlie membrane formation during autophagy.
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              Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.

              Autophagy is a process by which cytoplasmic organelles can be catabolized either to remove defective structures or as a means of providing macromolecules for energy generation under conditions of nutrient starvation. In this study we demonstrate that mitochondrial autophagy is induced by hypoxia, that this process requires the hypoxia-dependent factor-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1 and Atg5, and that in cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
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                Author and article information

                Journal
                Autophagy
                Autophagy
                KAUP
                kaup20
                Autophagy
                Taylor & Francis
                1554-8627
                1554-8635
                2017
                2 October 2017
                2 October 2017
                : 13
                : 11
                : 1884-1904
                Affiliations
                [a ]Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University , Nanjing, China
                [b ]Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China
                [c ]Co-Innovation Center of Neuroregeneration, Nantong University , Nantong, China
                [d ]Department of Otolaryngology, Hearing Research Institute, Affiliated Eye and ENT Hospital of Fudan University , Shanghai, China
                [e ]Key Laboratory of Hearing Medicine, National Health and Family Planning Commission , Shanghai, China
                [f ]Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, Jiangsu Provincial Key Medical Discipline (Laboratory) , Nanjing, China
                [g ]Department of Otolaryngology Head and Neck Surgery, Zhongda Hospital, Southeast University , Nanjing, China
                [h ]Department of Pathology and Laboratory Medicine, Medical University of South Carolina , Charleston, SC, USA
                [i ]Research Institute of Otolaryngology , Nanjing, China
                Author notes
                Renjie Chai renjiec@ 123456seu.edu.cn , Co-Innovation Center of Neuroregeneration, Key Laboratory for Developmental Genes and Human Disease, Ministry of Education, Institute of Life Sciences, Southeast University, Nanjing 210096, China
                Xia Gao xiagao@ 123456aliyun.com , Department of Otorhinolaryngology Head and Neck Surgery, Nanjing Drum Tower Hospital, 321 Zhongshan Road, Nanjing 210096, China
                Huawei Li lihuawei63@ 123456gmail.com , Department of Otorhinolaryngology, Affiliated Eye and ENT Hospital of Fudan University, Room 611, Building 9, No. 83 Fenyang Road, Xuhui District, Shanghai 200031, China
                [†]

                These authors contributed equally to this work.

                Article
                1359449
                10.1080/15548627.2017.1359449
                5788479
                28968134
                © 2017 The Author(s). Published with license by Taylor & Francis

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.

                Page count
                Figures: 12, Tables: 0, References: 98, Pages: 21
                Product
                Funding
                Funded by: National Key Research Development Program of China
                Award ID: 2017YFA0103900, 2015CB965000, 2017YFA0103903
                Funded by: National Natural Science Foundation of China
                Award ID: 81622013, 81771019, 81771013, 81570913, 81470692, 81371094, 81500790, 81570921, 31500852, 31501194, 81670938
                Funded by: Jiangsu Province Natural Science Foundation
                Award ID: BK20150022, BK20140620, BK20150598, BK20160125
                Funded by: Science and Technology Commission of Shanghai Municipality
                Award ID: 15pj1401000
                Funded by: Yingdong Huo Education Foundation
                Funded by: Boehringer Ingelheim Pharma GmbH
                Funded by: Fundamental Research Funds for the Central Universities
                Funded by: Project of Invigorating Health Care through Science Technology and Education
                This work was supported by grants from the National Key Research Development Program of China (2017YFA0103900, 2015CB965000, 2017YFA0103903), the National Natural Science Foundation of China (Nos. 81622013, 81771019, 81771013, 81570913, 81470692, 81371094, 81500790, 81570921, 31500852, 31501194, 81670938), the Jiangsu Province Natural Science Foundation (BK20150022, BK20140620, BK20150598, BK20160125), the Science and Technology Commission of Shanghai Municipality (15pj1401000), the Yingdong Huo Education Foundation, the Boehringer Ingelheim Pharma GmbH, the Fundamental Research Funds for the Central Universities, and the Project of Invigorating Health Care through Science Technology and Education.
                Categories
                Basic Research Paper

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