Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
Department of Pharmaceutical Sciences, North Texas Eye Research Institute, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Antioxid Redox Signal. 2021 Dec;35(16):1341-1357. doi: 10.1089/ars.2020.8180. Epub 2021 Apr 29.
Cellular response to hypoxia can include transition from respiration to glycolysis upregulation of glycolytic enzymes and transporters, as well as mitophagy induction to eliminate surplus mitochondria. Our purpose was to evaluate the impact of hypoxia-inducible factor-1α (HIF-1α) stabilization on mitochondrial homeostasis and oxidative stress in a chronic model of glaucoma. Retina and optic nerve (ON) were evaluated from young and aged DBA/2J (D2) glaucoma model mice and the control strain, the DBA/2-. Hypoxic retinal ganglion cells (RGCs) were observed in young and aged D2 retina, with a significant increase in HIF-1α protein in the aged D2 retina. Reactive oxygen species observed in young D2 retina and ON were followed by significant decreases in antioxidant capacity in aged D2 retina and ON. HIF-1α targets such as neuron-specific glucose transporter-3 and lactate dehydrogenase were decreased or unchanged, respectively, in aged D2 retina despite an increased hypoxia response in RGCs. Mitochondrial mass was decreased in aged D2 retina concomitant with decreased mitochondrially encoded electron transport chain transcripts despite a stable nuclear-encoded TFAM (mitochondrial transcription factor), suggesting a breakdown in the nuclear-mitochondrial communication. Decreased mitophagy-associated proteins p62 and Rheb were observed in aged D2 retina, although p62 was significantly increased in the aged D2 ON. The increased reactive oxygen species concomitant with HIF-1α upregulation despite reduced glucose transporters, mis-match of nuclear- and mitochondrial-encoded transcripts, and signs of reduced mitophagy suggest that retinas from D2 mice with chronic intraocular pressure elevation transition to pseudohypoxia without consistent metabolic reprogramming before significant RGC loss. 35, 1341-1357.
细胞对缺氧的反应可以包括从呼吸到糖酵解的转变，上调糖酵解酶和转运蛋白，以及诱导线粒体自噬以消除多余的线粒体。我们的目的是评估缺氧诱导因子-1α（HIF-1α）稳定对慢性青光眼模型中线粒体动态平衡和氧化应激的影响。从小鼠的视网膜和视神经（ON）评估年轻和年老的 DBA/2J（D2）青光眼模型以及对照品系 DBA/2-。在年轻和年老的 D2 视网膜中观察到缺氧的视网膜神经节细胞（RGC），并且在年老的 D2 视网膜中 HIF-1α 蛋白显著增加。在年轻的 D2 视网膜和 ON 中观察到活性氧（ROS），随后在年老的 D2 视网膜和 ON 中抗氧化能力显著下降。尽管 RGC 中的缺氧反应增加，但在年老的 D2 视网膜中，神经元特异性葡萄糖转运蛋白-3 和乳酸脱氢酶等 HIF-1α 靶标分别减少或不变。尽管核编码 TFAM（线粒体转录因子）稳定，但年老的 D2 视网膜中线粒体质量减少，同时线粒体编码的电子传递链转录物减少，提示核-线粒体通讯中断。在年老的 D2 视网膜中观察到与线粒体自噬相关的蛋白质 p62 和 Rheb 减少，尽管 p62 在年老的 D2 ON 中显著增加。尽管葡萄糖转运蛋白减少、核和线粒体编码的转录物不匹配以及线粒体自噬减少的迹象，但活性氧的增加伴随着 HIF-1α 的上调，这表明来自慢性眼内压升高的 D2 小鼠的视网膜在显著的 RGC 损失之前，在没有一致的代谢重编程的情况下，向假性缺氧转变。35，1341-1357。
