cyclic-guanosine-monophosphate-adenosine-monophosphate and Presbycusis

Melatonin supplementation has been shown to delay age-related hearing loss (ARHL) progression. Previously, melatonin was found to inhibit neuronal mitochondrial DNA (mtDNA) release, as well as inhibit cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling, thereby delaying the onset of central nervous system diseases. Therefore, we hypothesized that melatonin may delay the progression of hearing loss in the C57BL/6J presbycusis mouse model by inhibiting cGAS-STING signaling in the auditory pathway. Oral melatonin at 10 mg/kg/d was administered to 3-month-old C57BL/6J mice until 12 months of age. The auditory brainstem response (ABR) threshold was used to assess their hearing ability. By real-time polymerase chain reaction and Western blot analysis, the levels of cytosolic mtDNA, cGAS/STING, and cytokines were examined in the mouse cochlea, inferior colliculus, and auditory cortex. We found that the 12-month-old control mice exhibited significant hearing loss, increased cytosolic mtDNA, increased expression of inflammatory factors TNF-α, IL-6, IFN-β, Cxcl10, and Ifit3, up-regulated cGAS and STING expression, and enhanced interferon regulatory factor 3 (IRF3) phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. Melatonin treatment significantly improved hearing, decreased cytosolic mtDNA, suppressed the expression of inflammatory cytokines TNF-α, IL-6, IFN-β, Ifit3, and Cxcl10, down-regulated cGAS and STING expression, and attenuated IRF3 phosphorylation in the C57BL/6J mouse cochlea, inferior colliculus, and auditory cortex. This study suggested that melatonin had a protective effect on auditory function in the C57BL/6J presbycusis mouse model, which may be mediated through reducing mtDNA release, inhibiting the cGAS-STING signaling pathway in the auditory pathway.

Topics: Animals; Cytokines; Deafness; DNA, Mitochondrial; Interferons; Interleukin-6; Melatonin; Mice; Mice, Inbred C57BL; Nucleotidyltransferases; Presbycusis; Signal Transduction; Tumor Necrosis Factor-alpha

Presbycusis, or age-related hearing loss (ARHL), is primarily associated with sensory or transduction nerve cell degeneration in the peripheral and/or central auditory systems. During aging, the auditory system shows mitochondrial dysfunction and increased inflammatory responses. Mitochondrial dysfunction promotes leakage of mitochondrial DNA (mtDNA) into the cytosol, which activates the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway to induce type I interferon and inflammatory responses. However, whether this pathway is involved in the occurrence and development of ARHL is unknown. This study aimed to determine whether there are age-related changes in the levels of cytosolic mtDNA and cGAS-STING pathway activation in the auditory pathway and to explore their relationship with ARHL. The results showed that cGAS-positive immunoreactive cells were observed in the cochlea, inferior colliculus, and auditory cortex. Levels of cytosolic mtDNA, cGAS, STING, phosphorylated interferon regulatory factor 3, and cytokines were significantly increased in the cochlea, inferior colliculus, and auditory cortex of 6-, 9-, and 12-month-old mice compared with 3-month-old mice. These findings suggested that cytosolic mtDNA may play an important role in the pathogenesis of ARHL by activating cGAS-STING-mediated type I interferon and inflammatory responses.

Topics: Animals; Interferons; Male; Membrane Proteins; Mice; Mice, Inbred C57BL; Nucleotides, Cyclic; Nucleotidyltransferases; Presbycusis