Sreekumar Parameswaran G, Ferrington Deborah A, Kannan Ram
The Stephen J. Ryan Initiative for Macular Research (RIMR), Doheny Eye Institute, Los Angeles, CA 90033, USA.
Department of Ophthalmology and Visual Neurosciences and Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Antioxidants (Basel). 2021 Apr 24;10(5):661. doi: 10.3390/antiox10050661.
Glutathione (GSH) is present ubiquitously, and its role as a crucial cellular antioxidant in tissues, including the retina, is well established. GSH's antioxidant function arises from its ability to scavenge reactive oxygen species or to serve as an essential cofactor for GSH S-transferases and peroxidases. This review summarizes the general functions, retinal distribution, disorders linked to GSH deficiency, and the emerging role for mitochondrial GSH (mGSH) in retinal function. Though synthesized only in the cytosol, the presence of GSH in multiple cell organelles suggests the requirement for its active transport across organellar membranes. The localization and distribution of 2-oxoglutarate carrier (OGC) and dicarboxylate carrier (DIC), two recently characterized mitochondrial carrier proteins in RPE and retina, show that these transporters are highly expressed in human retinal pigment epithelium (RPE) cells and retinal layers, and their expression increases with RPE polarity in cultured cells. Depletion of mGSH levels via inhibition of the two transporters resulted in reduced mitochondrial bioenergetic parameters (basal respiration, ATP production, maximal respiration, and spare respiratory capacity) and increased RPE cell death. These results begin to reveal a critical role for mGSH in maintaining RPE bioenergetics and cell health. Thus, augmentation of mGSH pool under GSH-deficient conditions may be a valuable tool in treating retinal disorders, such as age-related macular degeneration and optic neuropathies, whose pathologies have been associated with mitochondrial dysfunction.
谷胱甘肽（GSH）普遍存在，其作为包括视网膜在内的组织中关键的细胞抗氧化剂的作用已得到充分证实。GSH的抗氧化功能源于其清除活性氧的能力，或作为谷胱甘肽S-转移酶和过氧化物酶的必需辅助因子。本综述总结了GSH的一般功能、视网膜分布、与GSH缺乏相关的疾病，以及线粒体谷胱甘肽（mGSH）在视网膜功能中的新作用。尽管GSH仅在细胞质中合成，但它在多个细胞器中的存在表明其需要通过细胞器膜进行主动转运。最近在视网膜色素上皮（RPE）和视网膜中鉴定出的两种线粒体载体蛋白——2-氧代戊二酸载体（OGC）和二羧酸载体（DIC）的定位和分布表明，这些转运蛋白在人视网膜色素上皮（RPE）细胞和视网膜层中高度表达，并且它们的表达随着培养细胞中RPE极性的增加而增加。通过抑制这两种转运蛋白来降低mGSH水平，导致线粒体生物能量参数（基础呼吸、ATP产生、最大呼吸和备用呼吸能力）降低，并增加RPE细胞死亡。这些结果开始揭示mGSH在维持RPE生物能量和细胞健康方面的关键作用。因此在GSH缺乏的情况下增加mGSH库可能是治疗视网膜疾病（如年龄相关性黄斑变性和视神经病变）的一种有价值的工具，这些疾病的病理与线粒体功能障碍有关。
