Hypervulnerability to sound-exposure through impaired adaptive proliferation of peroxisomes

A deficiency of pejvakin, a protein of unknown function, causes a strikingly heterogeneous form of deafness. Pejvakin-deficient (Pjvk-/-) mice also exhibited variable auditory phenotypes. Correlation between their hearing thresholds and the number of pups per cage suggested a possible harmful effect of pup vocalizations. Direct sound or electrical stimulation showed that the cochlear sensory hair cells and auditory pathway neurons of Pjvk-/- mice and patients were exceptionally vulnerable to sound. Pjvk-/- cochleas displayed features of marked oxidative stress and impaired anti-oxidant defenses. We showed that pejvakin is associated with peroxisomes, and is required for the oxidative stress-induced proliferation of these organelles. In Pjvk-/- hair cells, peroxisomes displayed structural abnormalities after the onset of hearing. Noise-exposure of wild-type mice rapidly upregulated Pjvk cochlear transcription, and triggered peroxisome proliferation in hair cells and primary auditory neurons. Our results reveal that the anti-oxidant activity of peroxisomes protects the auditory system against noise-induced damage. Three RNA samples was extracted from dissected organ of Corti (OC) for each genotype (Pjvk-/- and Pjvk+/+ mice) and analyzed (triplicate OCmm-1, OCmm-2, and OCmm-3 for Pjvk-/-, and triplicate OCpp-1, OCpp-2, and OCpp-3 for Pjvk+/+).功能未知的蛋白佩贾文激酶（pejvakin）的缺失，可引发表型高度异质性的耳聋。佩贾文激酶敲除（Pjvk-/-）小鼠同样表现出可变的听觉表型。其听力阈值与每笼幼崽数量之间的相关性，提示幼崽发声可能存在有害影响。直接声刺激与电刺激实验证实，Pjvk-/-小鼠及患者的耳蜗感觉毛细胞与听觉通路神经元，对声音刺激表现出异常的易感性。Pjvk-/-小鼠的耳蜗组织呈现出显著的氧化应激特征，且抗氧化防御功能受损。本研究证实，佩贾文激酶定位于过氧化物酶体（peroxisomes），且是该细胞器在氧化应激诱导下发生增殖所必需的因子。在听力功能启动后，Pjvk-/-毛细胞内的过氧化物酶体出现结构异常。野生型小鼠经噪声暴露后，其耳蜗内的Pjvk转录水平会快速上调，并触发毛细胞与初级听觉神经元内的过氧化物酶体增殖。本研究结果揭示，过氧化物酶体的抗氧化活性可保护听觉系统免受噪声诱导的损伤。我们从每种基因型（Pjvk-/-与Pjvk+/+小鼠）的解剖分离的耳蜗螺旋器（organ of Corti，OC）中提取了三份RNA样本，并进行了重复检测分析（Pjvk-/-组的重复样本编号为OCmm-1、OCmm-2与OCmm-3，Pjvk+/+组的重复样本编号为OCpp-1、OCpp-2与OCpp-3）。