Abstract
CMP-Neu5Ac hydroxylase (Cmah) disruption caused several abnormalities and diseases including hearing loss in old age. However, underling molecular mechanisms that give rise to age-related hearing loss (AHL) in Cmah-null mouse are still obscure. In this study, Cmah-null mice showed age-related decline of hearing associated with loss of sensory hair cells, spiral ganglion neurons, and/or stria vascularis degeneration in the cochlea. To identify differential gene expression profiles and pathway associated with AHL, we performed microarray analysis using Illumina MouseRef-8 v2 Expression BeadChip and pathway-focused PCR array in the cochlear tissues of Cmah-null mouse. Pathway and molecular mechanism analysis using differentially expressed genes provided evidences that altered biological pathway due to oxidative damage by low expressed antioxidants and dysregulated reactive oxygen species (ROS) metabolism. Especially, low sirtuin 3 (Sirt3) gene expressions in Cmah-null mice decreased both of downstream regulator (Foxo1 and MnSod) and regulatory transcription factor (Hif1αand Foxo3α) gene expression. Taken together, we suggest that down-regulation of Sirt3 expression leads to oxidative stress and mitochondrial dysfunction by regulation of ROS and that it could alter various signaling pathways in Cmah-null mice with AHL.
Highlights
N-glycolylneuraminic acid (Neu5Gc) is generated by hydroxylation of CMP-Neu5Ac to CMP-Neu5Gc, catalyzed by CMP-Neu5Ac hydroxylase (Cmah) [1, 2]
We propose a possible hypothetical model that down-regulated sirtuin 3 (Sirt3) lead to oxidative damage and mitochondrial dysfunction by reactive oxygen species (ROS) and it could alter various signaling pathways involved in Cmah-null mice with age-related hearing loss (AHL)
To clarify differential mRNAs expression of oxidative stress and antioxidant defense-related genes, we examined the expression of genes related to oxidative damage and ROS metabolism pathway in the cochlear tissues from WT- and Cmah-null mice, using a pathway-focused PCR array
Summary
N-glycolylneuraminic acid (Neu5Gc) is generated by hydroxylation of CMP-Neu5Ac to CMP-Neu5Gc, catalyzed by CMP-Neu5Ac hydroxylase (Cmah) [1, 2]. Humans lack this common mammalian cell surface molecule, Neu5Gc, due to inactivation of the Cmah gene during evolution [3, 4]. Cmah-null mouse showed histological abnormalities of the inner ear occurred in older mice, which had impaired hearing [5]. It was reported in a study that, in a senescence-accelerated mouse, prone 8 (SAMP8) strain mouse shows premature hearing loss and cochlear degeneration repeating the processes noticed in human presbycusis (i.e., strial, sensory, and neural degeneration) [8]. The molecular mechanisms correlated with premature age-related hearing loss (AHL) in SAMP8 mice comprises oxidative stress, distorted levels of antioxidant enzymes, and decreased www.impactaging.com
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