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Resumen del trabajo presentado en el 43rd Annual MidWinter Meeting-ARO, celebrado en San José, California (Estados Unidos) del 25 al 29 de enero de 2020., Ageing of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative-derived damage in macromolecules, which contribute to cellular malfunction, compromise cell viability and, finally, causes functional decline. The cellular detoxification power partially relies in NADPH production, which is a cofactor for major cellular antioxidant enzymes. NADPH is mainly produced by glucose-6-phosphate dehydrogenase (G6PD), an enzyme that catalyzes the rate-limiting step in the pentose phosphate pathway. We show here that the transgenic mouse G6PD-Tg, which shows enhanced NADPH production along life, maintains lower auditory thresholds than wild type mice during ageing. G6PD overexpression preserved inner (IHC) and outer hair cells (OHC), OHC innervation and number of synapses per IHC. Transcripts for antioxidant enzymes were increased whereas levels of pro-apoptotic proteins were reduced in 3-month-old G6PD-Tg. Consequently, nitration of proteins, mitochondrial damage and TUNEL+ apoptotic cells were reduced in 9-month-old G6PDTg compared to wild type mice. Unexpectedly, G6PD overexpression triggered low grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophages infiltration. In conclusion, we propose here that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the generation of ROS and the cell detoxification power along ageing and, therefore to prevent hearing loss progression., This work has been founded by Spanish MINECO/ FEDER SAF2017-86107-R to IVN. JMBM was supported by contracts from MINECO/FEDER SAF2014-AGEAR and MINECO/FEDER SAF2017-86107-R.

Resumen del trabajo presentado al 43rd Annual MidWinter Meeting-ARO, celebrado en San Jose, California (US) del 25 al 29 de enero de 2020., This work has been founded by Spanish MINECO/ FEDER SAF2017-86107-R to IVN. JMBM was supported by contracts from MINECO/FEDER SAF2014-AGEAR and MINECO/FEDER SAF2017-86107-R .

Resumen del póster presentado al 42nd Congress of the Spanish Society of Biochemistry and Molecular Biology (SEBBM), celebrado en Madrid del 16 al 19 de julio de 2019., Ageing of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative-derived damage in macromolecules, which contribute to cellular malfunction, compromise cell viability and, finally, causes functional decline. The cellular detoxification power partially relies in the production of the cofactor for the activity of key antioxidant enzymes NADPH. This is mainly produced by the glucose-6-phosphate dehydrogenase (G6PD), an enzyme that catalyzes the rate-limiting step in the pentose phosphate pathway. We show here that the transgenic mouse hG6PD-Tg, which shows enhanced NADPH production along life, maintains lower auditory thresholds than wild type mice during ageing. G6PD overexpression preserves irreplaceable cochlear cell populations, thus hG6PD-Tg mice exhibit significantly higher number of inner and outer hair cells (OHC) and more widespread OHC innervation than wild type mice. Transcripts for antioxidant enzymes were significantly increased in 3-month old hG6PD-Tg, particularly remarkable those of glutathione reductase and thioredoxin reductase 1, whose activity depends on NADPH availability. Accordingly, tyrosine modification by nitration in proteins was reduced in 9-month old G6PD-Tg compared with wild type mice. As well as lesser TUNEL positive apoptotic cells were detected in whole mount preparations of the organ of Corti of hG6PD-Tg mice. Western blotting analysis of cochlear extracts further showed increased survival and reduced pro-apoptotic signaling in the transgenic versus the wild type mice. In conclusion, we propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the generation of ROS and the cell detoxification power along ageing and, therefore to prevent hearing loss progression., This work was supported by FP7-2013-TARGEAR and FEDER/SAF 2014-AGEAR and 2017-HEARCODE.