SOD2 Alleviates Hearing Loss Induced by Noise and Kanamycin in Mitochondrial DNA4834-deficient Rats by Regulating PI3K/MAPK Signaling

Superoxide dismutase 2(SOD2)-mediated gene therapy has significant protective effects against kanamycin-induced hearing loss and hair cell loss in the inner ear,but the underlying mechanisms are still unclear.Herein,an in vivo aging model of mitochondrial DNA(mtDNA)4834 deletion mutation was established using D-galactose,and the effects of noise or kanamycin on inner ear injury was investigated.Rats subjected to mtDNA4834 mutation via D-galactose administration showed hearing loss characterized by the disruption of inner ear structure(abnormal cell morphology,hair cell lysis,and the absence of the organ of Corti),increased SOD2 promoter methylation,and an increase in the degree of apoptosis.Exposure to noise or kanamycin further contributed to the effects of D-galactose.SOD2 overexpression induced by viral injection accordingly counteracted the effects of noise and kanamycin and ameliorated the symptoms of hearing loss,suggesting the critical involvement of SOD2 in preventing deafness and hearing-related conditions.The PI3K and MAPK signaling pathways were also regulated by noise/kanamycin exposure and/or SOD2 overexpression,indicating that they may be involved in the therapeutic effect of SOD2 against age-related hearing loss.

Deletions are easy detectable in cochlear mitochondrial DNA of Cu/Zn superoxide dismutase gene knockout mice

Abstract Objectives To investigate the tissue specificity of reactive oxygen species (ROS) damage to mitochondrial DNA (mtDNA) and to determine whether cochlear mtDNA is a sensitive target for ROS damage. Methods 10 Cu/ZnSOD gene (Cu/Zn superoxide dismutase gene, Sod1) knockout mice and 16 wild-type mice were analyzed by nested polymerase chain reaction (PCR).Results Three deletions were detected in various tissues of Sod1 knockout mice. MtDNA3867bp and mtDNA3726bp deletions were the most visible, and mtDNA4236bp deletion was barely detected in these tissues. There were obvious differences in the ratio of deleted mtDNA/total mtDNA in different tissue. Deleted mtDNA was most abundant in the liver and kidney and less in cochlea, heart and brain. The lowest was in spleen and skin. The ratio in various tissues was 3-20 times in Sod1 knockout mice over wild-type mice. In cochlea, the ratio was about 15. Conclusions Without the protection of Sod1, ROS can lead to mtDNA deletions in various tissues with significant tissue specificity. Cochlear mtDNA is a sensitive target for ROS damage.