Chan Chi-Ming, Sekar Ponarulselvam, Huang Duen-Yi, Hsu Shu-Hao, Lin Wan-Wan
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan;.
Department of Ophthalmology, Cardinal Tien Hospital, New Taipei City 23148, Taiwan.
Antioxidants (Basel). 2020 Oct 28;9(11):1057. doi: 10.3390/antiox9111057.
Oxidative stress-associated retinal pigment epithelium (RPE) cell death is critically implicated in the pathogenesis of visual dysfunction and blindness of retinal degenerative diseases. Sodium iodate (NaIO) is an oxidative retinotoxin and causes RPE damage. Previously, we found that NaIO can induce human ARPE-19 cell death via inducing mitochondrial fission and mitochondrial dysfunction. Although metformin has been demonstrated to benefit several diseases possibly via AMP-activated protein kinase (AMPK) activation, it remains unknown how AMPK affects retinopathy in NaIO model. Therefore, in this study, we compared the effects of metformin and AMPK activator A769662 on NaIO-induced cellular stress and toxicity. We found that A769662 can protect cells against NaIO-induced cytotoxicity, while metformin exerts an enhancement in cell death. The mitochondrial reactive oxygen species (ROS) production as well as mitochondrial membrane potential loss induced by NaIO were not altered by both agents. In addition, NaIO-induced cytosolic ROS production, possibly from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and counteracting cell death, was not altered by A769662 and metformin. Notably, NaIO-induced mitochondrial fission and inhibition of mitochondrial respiration for ATP turnover were reversed by A769662 but not by metformin. In agreement with the changes on mitochondrial morphology, the ERK-Akt signal axis dependent Drp-1 phosphorylation at S616 (an index of mitochondrial fission) under NaIO treatment was blocked by A769662, but not by metformin. In summary, NaIO-induced cell death in ARPE cells primarily comes from mitochondrial dysfunction due to dramatic fission and inhibition of mitochondrial respiration. AMPK activation can exert a protection by restoring mitochondrial respiration and inhibition of ERK/Akt/Drp-1 phosphorylation, leading to a reduction in mitochondrial fission. However, inhibition of respiratory complex I by metformin might deteriorate mitochondrial dysfunction and cell death under NaIO stress.
氧化应激相关的视网膜色素上皮（RPE）细胞死亡在视网膜退行性疾病的视觉功能障碍和失明的发病机制中起关键作用。碘酸钠（NaIO）是一种氧化性视网膜毒素，可导致RPE损伤。此前，我们发现NaIO可通过诱导线粒体分裂和线粒体功能障碍诱导人ARPE-19细胞死亡。尽管已证明二甲双胍可能通过激活AMP活化蛋白激酶（AMPK）对多种疾病有益，但AMPK如何影响NaIO模型中的视网膜病变仍不清楚。因此，在本研究中，我们比较了二甲双胍和AMPK激活剂A769662对NaIO诱导的细胞应激和毒性的影响。我们发现A769662可以保护细胞免受NaIO诱导的细胞毒性，而二甲双胍则增强细胞死亡。两种药物均未改变NaIO诱导的线粒体活性氧（ROS）产生以及线粒体膜电位丧失。此外，A769662和二甲双胍均未改变NaIO诱导的胞质ROS产生，其可能源于烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶激活并抵消细胞死亡。值得注意的是，A769662可逆转NaIO诱导的线粒体分裂和对ATP周转的线粒体呼吸抑制，但二甲双胍则不能。与线粒体形态的变化一致，NaIO处理下依赖ERK-Akt信号轴的Drp-1在S616处的磷酸化（线粒体分裂指标）被A769662阻断，但未被二甲双胍阻断。总之，NaIO诱导的ARPE细胞死亡主要源于线粒体功能障碍，这是由于线粒体剧烈分裂和呼吸抑制所致。AMPK激活可通过恢复线粒体呼吸和抑制ERK/Akt/Drp-1磷酸化发挥保护作用，从而减少线粒体分裂。然而，二甲双胍对呼吸复合体I的抑制可能会加剧NaIO应激下的线粒体功能障碍和细胞死亡。
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