Autophagy in the Vertebrate Inner Ear

Abstract

Autophagy is a conserved catabolic process that results in the lysosomal degradation of cell components. During development, autophagy is associated with tissue and organ remodeling, and under physiological conditions it is tightly regulated as it plays a housekeeping role in removing misfolded proteins and damaged organelles. The vertebrate inner ear is a complex sensory organ responsible for the perception of sound and for balance. Cell survival, death and proliferation, as well as cell fate specification and differentiation, are processes that are strictly coordinated during the development of the inner ear in order to generate the more than a dozen specialized cell types that constitute this structure. Here, we review the existing evidence that implicates autophagy in the generation of the vertebrate inner ear. At early stages of chicken otic development, inhibiting autophagy impairs neurogenesis and causes aberrant otocyst morphogenesis. Autophagy provides energy for the clearing of dying cells and it favors neuronal differentiation. Moreover, autophagy is required for proper vestibular development in the mouse inner ear. The autophagy-related genes Becn1, Atg4g, Atg5, and Atg9, are expressed in the inner ear from late developmental stages to adulthood, and Atg4b mutants show impaired vestibular behavior associated to defects in otoconial biogenesis that are also common to Atg5 mutants. Autophagic flux appears to be age-regulated, augmenting from perinatal stages to young adulthood in mice. This up-regulation is concomitant with the functional maturation of the hearing receptor. Hence, autophagy can be considered an intracellular pathway fundamental for in vertebrate inner ear development and maturation.

Complementary and distinct roles of autophagy, apoptosis and senescence during early inner ear development

“…Autophagy emerged as an evolutionary conserved mechanism of cell death, which was later shown to play other central roles in mammalian development, metabolic homeostasis, human disease and ageing (Booth et al, 2014;Magariños et al, 2017;Doherty and Baehrecke, 2018). Autophagy is activated by stress conditions, which include growth factor deprivation, and depending on the cellular context it is classified as macroautophagy, microautophagy and chaperone-mediated autophagy, only reported in mammals (Hansen et al, 2018;Kaushik and Cuervo, 2018).…”

“…This complex process involves more than thirty autophagy related genes (ATG), whose precise roles and regulation are still under study. Thus, autophagy is used by cells to degrade cytoplasmic macromolecules and dysfunctional organelles to recycle intracellular components and to generate energy, being an essential process during the development of the nervous system (Aburto et al, 2012a;Magariños et al, 2017).…”

“…Autophagy has also been reported to be essential for the development of the mouse vestibular system (Mariño et al, 2010) although much research effort should be placed into studying this process during mammalian inner ear development. Later in development and lifelong autophagy plays a role in inner ear homeostasis (de Iriarte Rodríguez et al, 2015;Magariños et al, 2017) and response to injury (Taylor et al, 2008;Yuan et al, 2015) in the mouse.…”

“…where it has been implicated in diverse processes, including clearance of apoptotic cells, migration of epithelial neuroblasts and formation of otoconia in the vestibular system, possibly linked to the elimination of ROS (Magariños et al, 2017). The existence of crosstalk between autophagy and senescence during inner ear development has not been described experimentally yet, however, it could be speculated that some of the forms of autophagy could participate in the acquisition and maintenance of the developmental senescent phenotype.…”

Role of Autophagy in Auditory System Development and Survival

“…Autophagy plays an important role in the survival of living cells, particularly in the stress conditions, such as starvation and oxidative stress [5][6][7]. Autophagy also participates in regulating many physiological processes such as cell survival, death, proliferation, and differentiation [7][8][9]. Autophagy dysfunction has been suggested to induce several pathological changes, such as cancer, inflammation, neurodegenerative diseases, and metabolic disorders [10][11][12].…”