G6PD overexpression protects from oxidative stress and age-related hearing loss.
G6PD overexpression protects from oxidative stress and age-related hearing loss.
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G6PD过表达可保护氧化应激和与年龄相关的听力损失。
DOI：
10.1111/acel.13275
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发表时间：
2020-12
期刊：
影响因子：
7.8
通讯作者：
Varela-Nieto I
中科院分区：
文献类型：
--
作者：
Bermúdez-Muñoz JM;Celaya AM;Hijazo-Pechero S;Wang J;Serrano M;Varela-Nieto I
听觉系统的衰老与活性氧（ROS）的增加和大分子氧化损伤的积累有关，这会导致细胞功能障碍，损害细胞活力，并最终导致功能衰退。细胞解毒部分依赖于 NADPH 的产生，NADPH 是主要细胞抗氧化系统的重要辅助因子。 NADPH 主要由管家酶葡萄糖-6-磷酸脱氢酶 (G6PD) 产生，它催化磷酸戊糖途径中的限速步骤。我们在此表明，G6PD 转基因小鼠 (G6PD-Tg) 在整个生命过程中表现出增强的组成性 G6PD 活性和 NADPH 产生，在衰老过程中比野生型小鼠具有更低的听觉阈值，同时保留了内毛细胞 (IHC) 和外毛细胞 (OHC)、OHC 神经支配以及每个 IHC 的保守数量的突触。 3 个月大的 G6PD-Tg 小鼠的抗氧化酶基因表达高于野生型小鼠，而促凋亡蛋白的水平较低。因此，9 个月大的 G6PD-Tg 中的蛋白质硝化、线粒体损伤和 TUNEL+ 凋亡细胞均低于野生型对应物。出乎意料的是，G6PD 过度表达引发了低度炎症，这种炎症在年轻小鼠中得到了有效解决，耳蜗细胞损伤和巨噬细胞浸润的缺失就表明了这一点。我们的研究结果使我们提出，早期阶段 NADPH 的过量产生是一种有效的机制，可以在衰老过程中维持 ROS 产生和细胞解毒能力之间的平衡，从而防止听力损失进展。 G6PD 过度表达有助于克服耳蜗氧化损伤，防止毛细胞和神经元损失，从而延缓与年龄相关的听力损失。先天性 NADPH 水平升高，从而通过 Nrf2 诱导抗氧化基因表达，增强抗氧化防御系统，减少氧化损伤积累，并防止成年小鼠不可替代的耳蜗细胞群的线粒体功能障碍和凋亡。
Aging of the auditory system is associated with the incremental production of reactive oxygen species (ROS) and the accumulation of oxidative damage in macromolecules, which contributes to cellular malfunction, compromises cell viability, and, ultimately, leads to functional decline. Cellular detoxification relies in part on the production of NADPH, which is an important cofactor for major cellular antioxidant systems. NADPH is produced principally by the housekeeping enzyme glucose‐6‐phosphate dehydrogenase (G6PD), which catalyzes the rate‐limiting step in the pentose phosphate pathway. We show here that G6PD transgenic mice (G6PD‐Tg), which show enhanced constitutive G6PD activity and NADPH production along life, have lower auditory thresholds than wild‐type mice during aging, together with preserved inner hair cell (IHC) and outer hair cell (OHC), OHC innervation, and a conserved number of synapses per IHC. Gene expression of antioxidant enzymes was higher in 3‐month‐old G6PD‐Tg mice than in wild‐type counterparts, whereas the levels of pro‐apoptotic proteins were lower. Consequently, nitration of proteins, mitochondrial damage, and TUNEL+ apoptotic cells were all lower in 9‐month‐old G6PD‐Tg than in wild‐type counterparts. Unexpectedly, G6PD overexpression triggered low‐grade inflammation that was effectively resolved in young mice, as shown by the absence of cochlear cellular damage and macrophage infiltration. Our results lead us to propose that NADPH overproduction from an early stage is an efficient mechanism to maintain the balance between the production of ROS and cellular detoxification power along aging and thus prevents hearing loss progression. G6PD overexpression contributes to overcome cochlear oxidative damage, prevents hair cell and neuronal loss, and, thereby, delays age‐related hearing loss. Congenital levels of NADPH are increased, thus inducing the expression of antioxidant genes via Nrf2, enhancing antioxidant defense systems, reducing oxidative‐derived damage accumulation, and preventing mitochondrial dysfunction and apoptosis of irreplaceable cochlear cell populations in adult mice.
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影响因子：
4.8
作者：
Partearroyo T;Vallecillo N;Pajares MA;Varela-Moreiras G;Varela-Nieto I
通讯作者：
Varela-Nieto I
影响因子：
3.4
作者：
Cediel, R;Riquelme, R;Varela-Nieto, I
通讯作者：
Varela-Nieto, I
影响因子：
168.9
作者：
Gates, GA;Mills, JH
通讯作者：
Mills, JH
影响因子：
12.4
作者：
Fico, A;Paglialunga, F;Filosa, S
通讯作者：
Filosa, S
影响因子：
7.8
作者：
Kim, Hyung-Jin;Cao, Wa;So, Hong-Seob
通讯作者：
So, Hong-Seob