Methionine Sulfoxide Reductase A, B1 and B2 Are Likely to Be Involved in the Protection against Oxidative Stress in the Inner Ear

Abstract

The methionine sulfoxide reductase (Msr) family of proteins is a class of repair enzymes that reduce methionine-S (MsrA) or methionine-R (MsrB) sulfoxide to methionine. Recent studies have reported that mutations in the MSRB3 gene cause autosomal recessive hearing loss in humans, and in mice MsrB3 deficiency leads to profound hearing loss due to hair cell apoptosis and stereocilia degeneration. However, apart from MsrB3, studies on Msr proteins in the inner ear have not yet been reported. In this study, we identified and characterized Msr expression in the cochlea and vestibule. First, we confirmed RNA expression levels of Msr family members in the cochlea and vestibule using reverse transcription PCR and detected Msr family members in both tissues. We also conducted immunohistochemical staining to localize Msr family members within the cochlea and vestibule. In the cochlea, MsrA was detected in supporting cells, spiral ligament, spiral limbus, Reissner's membrane and the spiral ganglion. MsrB1 was specifically expressed in hair cells and the spiral ganglion. MsrB2 was noted in the spiral ganglion, tectorial membrane and stria vascularis. In the vestibule, MsrA and MsrB1 were detected in hair cells and the vestibular ganglion, while MsrB2 was restricted to the vestibular ganglion. In this study, we identified distinct distributions of Msr family members in the organ of Corti and hypothesized that MsrA, MsrB1 and MsrB2 protect proteins in the organ of Corti from oxidative stress.

Methionine Sulfoxide Reductase A Knockout Mice Show Progressive Hearing Loss and Sensitivity to Acoustic Trauma

“…The expression of MsrB1 in the outer and inner hair cells of the Corti organ and in the spiral ganglion suggests a possible role of MsrB1 in the protection from cochlear oxidative stress [Kwon et al, 2014b]. In this study, we observed that MsrB1 expression in young MsrA knockout mice was similar to that of young wild-type mice (Fig.…”

“…The MsrA gene has a role in supporting the cells linked to the spiral ligaments and spiral ganglion neurons [Kwon, et al 2014b]. Our current study indicates that young MsrA knockout mice consist of high-frequency threshold elevation for distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR), which usually gets worse by 6 months of age.…”

“…The cochlear expressions of MsrA in the cells of the spiral ganglion, Corti cells, and the lateral wall have suggested that the presence of MsrB and MsrA in these structures can prevent cochlear damage as a result of oxidative stress [Ahmed et al, 2011;Kwon et al, 2014b]. The loss of cells in the organs of Corti, spiral ganglion, and lateral wall has been reported in hearing loss studies [Fernandez et al, 2015;Hequembourg and Liberman, 2001;Ng et al, 2015].…”

“…MsrA aids in the protection of the age-related complications in the central nervous system [Oien et al, 2008]. The MsrA gene is also involved in the maintenance of proper functions of the neurons in the brain's dopaminergic system, located within the olivary sections of the brain that projects their fibers in the cochlea and safeguards them from acoustic trauma [Darrow et al, 2006;Kwon et al, 2014b;Maison et al, 2012;Oestreicher et al, 1997]. Thus, MsrA knockout mice are better tools for examining the roles of MsrA in the ears of adult mice.…”

Mitochondrial MsrB2 serves as a switch and transducer for mitophagy

“…Oxidative stress‐induced methionine sulfoxidation is recognized to modify diverse proteins, altering function, and potentially leading to disease (Gu et al , ) [calmodulin (Gao et al , ), thrombomodulin (Glaser et al , ), CaMKII (Erickson et al , )]. The methionine sulfoxide reductase family can reverse such protein damage (MsrA, B1, B2, and B3) (Marchetti et al , ; Cabreiro et al , ; Kwon et al , ), serving a protective role in all cells including blood cells (Rosen et al , ; Ouseph et al , ). Distinct from MsrA (mitochondria, cytosol, and nucleus), MsrB1 (cytosol and nucleus), and MsrB3 (ER and mitochondria), all localized to multiple cellular compartments, MsrB2 is located only in the mitochondrial matrix (Yermolaieva et al , ; Fischer et al , ).…”