Oxidative stress and hearing loss
The up-regulation of different cytochrome c oxidase (COX) genes revealed a potential association of the mutDFNA5-related cell death mechanisms with oxidative stress in yeast. Increased oxidative stress was already demonstrated in yeast (Van Rossom et al., 2012) and was later confirmed in human cell lines (unpublished results). Enhanced COX activity has indeed been associated with increased oxidative stress (Singh et al., 2009; Srinivasan and Avadhani, 2012). COX is the rate limiting enzyme of respiration which regulates the bio-energetic status of the cell. Dependent on the cellular energetic requirements, the COX activity can be rapidly adapted. The ratio of ATP/ADP is one of the regulators of the COX activity. High ADP levels or ATP utilization will increase the enzyme activity and stimulate the respiration (Napiwotzki and Kadenbach, 1998; Arnold and Kadenbach, 1999). Activation of the COX activity could result in higher oxidative stress generated at the mitochondria.
Additionally, the correlation of mutDFNA5 with several genes of the PPP can also be linked to oxidative stress in yeast as the PPP plays a major role in the anti-oxidant response. Reduced expression of CDC19, the yeast homolog of PK, and of TPI has been correlated with the activation of the PPP and the redirection of the metabolic flux from glycolysis to PPP both in human cell lines and in yeast (Christofk et al., 2008; Gruning et al., 2011, 2014). This study revealed reduced gene expression of both TPI and CDC19, indicating a shift in redox sensing in eukaryotes mediating a fast response to oxidative stress. Activation of the PPP is correlated with the inhibition of ROS accumulation and enhancement of the anti-oxidant response upon shift from fermentation to respiration. PPP activation will enhance the anti-oxidant response and hence increase the tolerance for oxidative stress (Ralser et al., 2007; Gruning et al., 2011; Kruger et al., 2011). These data clearly demonstrate a change in redox homeostasis due to mutDFNA5 expression which was shown previously in yeast (Van Rossom et al., 2012).
Furthermore, enhanced oxidative stress is often related to a failing protein quality control system (Davies, 2001; Shang et al., 2001; Bender et al., 2010, 2011; Shang and Taylor, 2011). This possibility was already suggested by the proteolytic degradation previously seen upon wtDFNA5 transformation, but which was absent in mutDFNA5-transformed yeast cells (Van Rossom et al., 2012). MutDFNA5 seemed to escape this quality control system, in contrast to wtDFNA5 which was subject to the normal clearance system. Moreover, the authors suggested a possible link between protein degradation and the mitochondria in mutDFNA5-induced cell death as yeast seemed to have problems with proper mutDFNA5 protein turnover. The same link was confirmed in both model organisms used in the current study.