Kwon Deug-Nam, Park Woo-Jin, Choi Yun-Jung, Gurunathan Sangiliyandi, Kim Jin-Hoi
Department of Animal Biotechnology, Konkuk University, Seoul 143-701, Republic of Korea.
Aging (Albany NY). 2015 Aug;7(8):579-94. doi: 10.18632/aging.100800.
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.
CMP-N-乙酰神经氨酸羟化酶（Cmah）缺失会引发多种异常和疾病，包括老年听力丧失。然而，导致Cmah基因敲除小鼠出现年龄相关性听力损失（AHL）的潜在分子机制仍不清楚。在本研究中，Cmah基因敲除小鼠表现出与耳蜗中感觉毛细胞、螺旋神经节神经元丧失和/或血管纹变性相关的年龄相关性听力下降。为了确定与AHL相关的差异基因表达谱和通路，我们使用Illumina MouseRef-8 v2表达微珠芯片和通路聚焦PCR阵列对Cmah基因敲除小鼠的耳蜗组织进行了微阵列分析。使用差异表达基因进行的通路和分子机制分析提供了证据，表明低表达抗氧化剂导致的氧化损伤和活性氧（ROS）代谢失调改变了生物通路。特别是，Cmah基因敲除小鼠中低水平的沉默调节蛋白3（Sirt3）基因表达降低了下游调节因子（Foxo1和MnSod）和调节转录因子（Hif1α和Foxo3α）的基因表达。综上所述，我们认为Sirt3表达下调通过调节ROS导致氧化应激和线粒体功能障碍，并且它可能改变AHL的Cmah基因敲除小鼠中的各种信号通路。
