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      Disruption of Atg7-dependent autophagy causes electromotility disturbances, outer hair cell loss, and deafness in mice

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          Abstract

          Atg7 is an indispensable factor that plays a role in canonical nonselective autophagy. Here we show that genetic ablation of Atg7 in outer hair cells (OHCs) in mice caused stereocilium damage, somatic electromotility disturbances, and presynaptic ribbon degeneration over time, which led to the gradual wholesale loss of OHCs and subsequent early-onset profound hearing loss. Impaired autophagy disrupted OHC mitochondrial function and triggered the accumulation of dysfunctional mitochondria that would otherwise be eliminated in a timely manner. Atg7-independent autophagy/mitophagy processes could not compensate for Atg7 deficiency and failed to rescue the terminally differentiated, non-proliferating OHCs. Our results show that OHCs orchestrate intricate nonselective and selective autophagic/mitophagy pathways working in concert to maintain cellular homeostasis. Overall, our results demonstrate that Atg7-dependent autophagy plays a pivotal cytoprotective role in preserving OHCs and maintaining hearing function.

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          Most cited references 65

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          A new pathway for mitochondrial quality control: mitochondrial-derived vesicles.

          The last decade has been marked by tremendous progress in our understanding of the cell biology of mitochondria, with the identification of molecules and mechanisms that regulate their fusion, fission, motility, and the architectural transitions within the inner membrane. More importantly, the manipulation of these machineries in tissues has provided links between mitochondrial dynamics and physiology. Indeed, just as the proteins required for fusion and fission were identified, they were quickly linked to both rare and common human diseases. This highlighted the critical importance of this emerging field to medicine, with new hopes of finding drugable targets for numerous pathologies, from neurodegenerative diseases to inflammation and cancer. In the midst of these exciting new discoveries, an unexpected new aspect of mitochondrial cell biology has been uncovered; the generation of small vesicular carriers that transport mitochondrial proteins and lipids to other intracellular organelles. These mitochondrial-derived vesicles (MDVs) were first found to transport a mitochondrial outer membrane protein MAPL to a subpopulation of peroxisomes. However, other MDVs did not target peroxisomes and instead fused with the late endosome, or multivesicular body. The Parkinson's disease-associated proteins Vps35, Parkin, and PINK1 are involved in the biogenesis of a subset of these MDVs, linking this novel trafficking pathway to human disease. In this review, we outline what has been learned about the mechanisms and functional importance of MDV transport and speculate on the greater impact of these pathways in cellular physiology. © 2014 The Authors.
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            Prestin is the motor protein of cochlear outer hair cells.

            The outer and inner hair cells of the mammalian cochlea perform different functions. In response to changes in membrane potential, the cylindrical outer hair cell rapidly alters its length and stiffness. These mechanical changes, driven by putative molecular motors, are assumed to produce amplification of vibrations in the cochlea that are transduced by inner hair cells. Here we have identified an abundant complementary DNA from a gene, designated Prestin, which is specifically expressed in outer hair cells. Regions of the encoded protein show moderate sequence similarity to pendrin and related sulphate/anion transport proteins. Voltage-induced shape changes can be elicited in cultured human kidney cells that express prestin. The mechanical response of outer hair cells to voltage change is accompanied by a 'gating current', which is manifested as nonlinear capacitance. We also demonstrate this nonlinear capacitance in transfected kidney cells. We conclude that prestin is the motor protein of the cochlear outer hair cell.
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              Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice.

              Autophagy is an intracellular bulk degradation process through which a portion of the cytoplasm is delivered to lysosomes to be degraded. Although the primary role of autophagy in many organisms is in adaptation to starvation, autophagy is also thought to be important for normal turnover of cytoplasmic contents, particularly in quiescent cells such as neurons. Autophagy may have a protective role against the development of a number of neurodegenerative diseases. Here we report that loss of autophagy causes neurodegeneration even in the absence of any disease-associated mutant proteins. Mice deficient for Atg5 (autophagy-related 5) specifically in neural cells develop progressive deficits in motor function that are accompanied by the accumulation of cytoplasmic inclusion bodies in neurons. In Atg5-/- cells, diffuse, abnormal intracellular proteins accumulate, and then form aggregates and inclusions. These results suggest that the continuous clearance of diffuse cytosolic proteins through basal autophagy is important for preventing the accumulation of abnormal proteins, which can disrupt neural function and ultimately lead to neurodegeneration.
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                Author and article information

                Contributors
                jietang@smu.edu.cn
                renjiec@seu.edu.cn
                xiagaogao@hotmail.com
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                24 October 2020
                24 October 2020
                October 2020
                : 11
                : 10
                Affiliations
                [1 ]GRID grid.428392.6, ISNI 0000 0004 1800 1685, Department of Otolaryngology Head and Neck Surgery, Affiliated Drum Tower Hospital of Nanjing University Medical School, , Jiangsu Provincial Key Medical Discipline (Laboratory), ; No. 321 Zhongshan Road, 210008 Nanjing, China
                [2 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Department of Physiology, School of Basic Medical Sciences, , Southern Medical University, ; 510515 Guangzhou, China
                [3 ]GRID grid.263826.b, ISNI 0000 0004 1761 0489, MOE Key Laboratory for Developmental Genes and Human Disease, School of Life Sciences and Technology, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, , Southeast University, ; 210096 Nanjing, China
                [4 ]GRID grid.452511.6, Children’s Hospital of Nanjing Medical University, ; 210008 Nanjing, China
                [5 ]GRID grid.284723.8, ISNI 0000 0000 8877 7471, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, , Southern Medical University, ; Guangzhou, China
                [6 ]GRID grid.260483.b, ISNI 0000 0000 9530 8833, Co-Innovation Center of Neuroregeneration, , Nantong University, ; 226001 Nantong, China
                [7 ]GRID grid.9227.e, ISNI 0000000119573309, Institute for Stem Cell and Regeneration, , Chinese Academy of Science, ; Beijing, China
                [8 ]Research Institute of Otolaryngology, No. 321 Zhongshan Road, 210008 Nanjing, China
                [9 ]GRID grid.24696.3f, ISNI 0000 0004 0369 153X, Beijing Key Laboratory of Neural Regeneration and Repair, , Capital Medical University, ; 100069 Beijing, China
                Article
                3110
                10.1038/s41419-020-03110-8
                7585579
                33099575
                © The Author(s) 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: the National Key R&D Program of China (2017YFA0103903), the Strategic Priority Research Program of the Chinese Academy of Science (XDA16010303), the National Natural Science Foundation of China (81970882, 81771019, 82030029), the Jiangsu Province Natural Science Foundation (BE2019711, BK20190121)
                Funded by: the National Natural Science Foundation of China (81970885)
                Funded by: the National Natural Science Foundation of China (81700913), the Jiangsu Provincial Medical Youth Talent of the Project of Invigorating Health Care through Science, Technology, and Education (QNRC2016002)
                Funded by: the Key-Area Research and Development Program of Guangdong Province (2018B030331001)
                Funded by: the National Natural Science Foundation of China (81970884)
                Categories
                Article
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                © The Author(s) 2020

                Cell biology

                macroautophagy, cochlea

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