Department of Aging and Geriatric Research, University of Florida, Gainesville, FL 32611, USA.
Center for Hearing and Deafness, State University of New York at Buffalo, NY, USA.
Exp Gerontol. 2020 May;133:110872. doi: 10.1016/j.exger.2020.110872. Epub 2020 Feb 7.
The glutathione transferase (GST) detoxification system converts exogenous and endogenous toxins into a less toxic form by conjugating the toxic compound to reduced glutathione (GSH) by a variety of GST enzymes. Of the ~20 GST isoforms, GSTA4 exhibits high catalytic efficiency toward 4-hydroxynonenal (4-HNE), one of the most abundant end products of lipid peroxidation that contributes to neurodegenerative diseases and age-related disorders. Conjugation to GSH by GSTA4 is thought to be a major route of 4-HNE elimination. In the current study, we investigated the effects of Gsta4 deficiency on age-related cochlear pathology and hearing loss using young (3-5 months old) and old (24-25 months old) Gsta4 and Gsta4 mice that were backcrossed onto the CBA/CaJ mouse strain, a well-established model of age-related hearing loss (AHL). At 3-5 months of age, loss of Gsta4 resulted in decreased total GSTA activity toward 4-HNE in the inner ears of young mice. However, there were no differences in the levels of 4-HNE in the inner ears between Gsta4 and Gsta4 mice at 3-5 or 24-25 months of age. No histological abnormalities were observed in the cochlea and no hearing impairments were observed in young Gsta4 mice. At 24-25 months of age, both Gsta4 and Gsta4 mice showed elevated ABR thresholds compared to 3-month-old mice, but there were no differences in ABR thresholds, cochlear spiral ganglion neuron densities, or stria vascularis thickness between Gsta4 and Gsta4 mice. Together, these results suggest that under normal physiological conditions or during normal aging, GSTA4 is not essential for removal of 4-HNE in mouse inner ears.
谷胱甘肽转移酶 (GST) 解毒系统通过各种 GST 酶将有毒化合物与还原型谷胱甘肽 (GSH) 缀合，将外源性和内源性毒素转化为毒性较小的形式。在大约 20 种 GST 同工酶中，GSTA4 对 4-羟基壬烯醛 (4-HNE) 表现出高催化效率，4-HNE 是脂质过氧化的最丰富的终产物之一，导致神经退行性疾病和与年龄相关的疾病。GSTA4 将 4-HNE 缀合到 GSH 上被认为是消除 4-HNE 的主要途径。在本研究中，我们使用经过回交的年轻（3-5 个月大）和年老（24-25 个月大）Gsta4 和 Gsta4 小鼠研究了 Gsta4 缺乏对年龄相关的耳蜗病理学和听力损失的影响，这些小鼠被回交至 CBA/CaJ 小鼠品系，这是一种成熟的年龄相关听力损失（AHL）模型。在 3-5 个月大时，Gsta4 的缺失导致年轻小鼠内耳中对 4-HNE 的总 GSTA 活性降低。然而，在 3-5 或 24-25 个月大时，Gsta4 和 Gsta4 小鼠内耳中的 4-HNE 水平没有差异。在内耳中没有观察到耳蜗的组织学异常，也没有观察到年轻的 Gsta4 小鼠的听力损伤。在 24-25 个月大时，与 3 个月大的小鼠相比，Gsta4 和 Gsta4 小鼠的 ABR 阈值均升高，但 Gsta4 和 Gsta4 小鼠之间的 ABR 阈值、耳蜗螺旋神经节神经元密度或血管纹厚度没有差异。综上所述，这些结果表明，在正常生理条件下或在正常衰老过程中，GSTA4 对于去除小鼠内耳中的 4-HNE 不是必需的。
