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.
Highlights
IntroductionMacroautophagy ( referred as autophagy) is conserved in all eukaryotes that degrades damaged proteins, nucleic acids, and cellular organelles
Macroautophagy is conserved in all eukaryotes that degrades damaged proteins, nucleic acids, and cellular organelles
outer hair cells (OHCs)-specific Atg7-deficient mice were born at Mendelian frequency, healthy and fertile, and did not show any overt phenotype compared to their Atg7flox/flox siblings
Summary
Macroautophagy ( referred as autophagy) is conserved in all eukaryotes that degrades damaged proteins, nucleic acids, and cellular organelles. Autophagy can be induced in response to physiological/pathological stimuli and helps to maintain cytosolic homeostasis[1]. To date, >30 autophagy-related genes (Atgs) have been identified[2]. In contrast to the embryonic lethality observed in Ambra1−/−, FIP200−/−, and beclin 1−/− mouse phenotypes, Atg7−/− mice, similar to Atg5−/−, Atg3−/−, Atg9−/−, and Atg16L1−/− knockouts, die within the neonatal period[5]. To investigate the roles of autophagy in mammals, Atg[7] and Atg[5] conditional knockout mice were created by the Cre-Loxp method[6,7]. A line of transgenic mice expressing the Cre recombinase were bred with Atg7flox/flox or Atg5flox/flox mice, and most of the homozygous mice exhibited pathological phenotypes[5,8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
