Role of ER stress in the pathology of hearing loss
The increase in mitochondrial metabolism seen in this study and the decrease of protein folding processes, can also be explained by the presence of cellular ER stress leading to an unfolded protein response. Mitochondria and ER form an interconnected network which is important for several biological processes mediating an adaptive response under various cellular stress conditions (De Brito and Scorrano, 2010; Marchi et al., 2014). The association between mutDFNA5 and the GO terms related to lipid metabolism, protein targeting to ER and the ER membrane, suggest the presence of ER stress (Schroder, 2008). Mitochondria depend on the ER for the import of several proteins and lipids and for Ca2+ exchange involved in cell death and mitochondrial metabolism (Sauner and Levy, 1971; Zecchini et al., 2007; Stiban et al., 2008; Wiel et al., 2014). Enhanced Ca2+ supply will increase ATP production and mitochondrial respiration, processes which were indeed both up-regulated at the post-diauxic shift upon mutDFNA5 expression. Prolonged enhancement however will eventually have a detrimental effect on the mitochondria.
Despite limited knowledge correlating mutDFNA5 with ER stress, a correlation has been established between ER stress and certain causes of HL. Ototoxicity (HL due to the use of pharmaceuticals such as aminoglycoside antibiotics and platinum-based chemotherapeutics) was shown to be correlated with ER stress-dependent pathways. Certain pain relievers, contributing to tinnitus and progressive bilateral sensorineural HL, were shown to induce ROS overproduction, altered ER morphology and changes in ER stress markers, such as CHOP (Kalinec et al., 2014).
Taken together, the previous observation of the importance of the mitochondria in mutDFNA5-related cell death and the known correlation between the ER and the mitochondria points to a potential role for the ER in DFNA5-induced cell death. The failing of the protein quality control system in mutDFNA5 suggests the involvement of the ER, but this remains unclear at this moment and needs to be further investigated in the future.