Choi Seunghwan, Choi Soo-Ho, Bastola Tonking, Kim Keun-Young, Park Sungsik, Weinreb Robert N, Miller Yury I, Ju Won-Kyu
Hamilton Glaucoma Center, Shiley Eye Institute, Viterbi Family Department of Ophthalmology, University of California San Diego, La Jolla, CA 92039, USA.
Department of Medicine, University of California San Diego, La Jolla, CA 92039, USA.
Antioxidants (Basel). 2024 Oct 17;13(10):1252. doi: 10.3390/antiox13101252.
Glaucoma, an optic neuropathy with the loss of retinal ganglion cells (RGCs), is a leading cause of irreversible vision loss. Oxidative stress and mitochondrial dysfunction have a significant role in triggering glia-driven neuroinflammation and subsequent glaucomatous RGC degeneration in the context of glaucoma. It has previously been shown that apolipoprotein A-I binding protein (APOA1BP or AIBP) has an anti-inflammatory function. Moreover, mice are characterized by retinal neuroinflammation and RGC loss. In this study, we found that AIBP deficiency exacerbated the oxidative stress-induced disruption of mitochondrial dynamics and function in the retina, leading to a further decline in visual function. Mechanistically, AIBP deficiency-induced oxidative stress triggered a reduction in glycogen synthase kinase 3β and dynamin-related protein 1 phosphorylation, optic atrophy type 1 and mitofusin 1 and 2 expression, and oxidative phosphorylation, as well as the activation of mitogen-activated protein kinase (MAPK) in Müller glia dysfunction, leading to cell death and inflammatory responses. In vivo, the administration of recombinant AIBP (rAIBP) effectively protected the structural and functional integrity of retinal mitochondria under oxidative stress conditions and prevented vision loss. In vitro, incubation with rAIBP safeguarded the structural integrity and bioenergetic performance of mitochondria and concurrently suppressed MAPK activation, apoptotic cell death, and inflammatory response in Müller glia. These findings support the possibility that AIBP promotes RGC survival and restores visual function in glaucomatous mice by ameliorating glia-driven mitochondrial dysfunction and neuroinflammation.
青光眼是一种伴有视网膜神经节细胞（RGCs）丧失的视神经病变，是不可逆视力丧失的主要原因。在青光眼的背景下，氧化应激和线粒体功能障碍在引发神经胶质细胞驱动的神经炎症以及随后的青光眼性RGCs变性中起重要作用。先前已经表明，载脂蛋白A-I结合蛋白（APOA1BP或AIBP）具有抗炎功能。此外，小鼠具有视网膜神经炎症和RGCs丧失的特征。在本研究中，我们发现AIBP缺乏加剧了氧化应激诱导的视网膜线粒体动力学和功能破坏，导致视觉功能进一步下降。从机制上讲，AIBP缺乏诱导的氧化应激引发糖原合酶激酶3β和发动蛋白相关蛋白1磷酸化、视神经萎缩蛋白1以及线粒体融合蛋白1和2表达减少，以及氧化磷酸化减少，同时激活了Müller胶质细胞功能障碍中的丝裂原活化蛋白激酶（MAPK），导致细胞死亡和炎症反应。在体内，重组AIBP（rAIBP）的给药在氧化应激条件下有效保护了视网膜线粒体的结构和功能完整性，并防止了视力丧失。在体外，与rAIBP孵育可保护线粒体的结构完整性和生物能量性能，同时抑制Müller胶质细胞中的MAPK激活、凋亡细胞死亡和炎症反应。这些发现支持了AIBP通过改善神经胶质细胞驱动的线粒体功能障碍和神经炎症来促进青光眼小鼠RGCs存活并恢复视觉功能的可能性。
