Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells
Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells
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DOI：
10.1038/s41419-020-2456-6
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发表时间：
2020-04-20
影响因子：
9
通讯作者：
Ju, Won-Kyu
中科院分区：
文献类型：
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作者：
Edwards, Genea;Perkins, Guy A.;Ju, Won-Kyu
线粒体结构和功能的损伤与青光眼的发病密切相关。尽管人们普遍认识到线粒体功能障碍和丢失与疾病的相关性，但青光眼中线粒体断裂和代谢应激的分子机制却知之甚少。我们发现青光眼视网膜神经节细胞(RGC)在丝氨酸637(Ser637)处表现出A-激酶锚定蛋白1(AKAP1)的丢失，钙调神经磷酸酶(CaN)的激活和动力蛋白相关蛋白1(Drp1)的磷酸化减少。这些发现表明，AKAP1介导的DRp1在Ser637处的磷酸化在青光眼神经变性的RGC生存中起着关键作用。缺乏AKAP1的雄性小鼠显示出视网膜中CaN和总Drp1水平的增加，以及视网膜Ser637处Drp1磷酸化的减少。线粒体的超微结构分析表明，AKAP1的缺失触发了RGCs线粒体的碎裂和丢失，以及线粒体吞噬小体的形成。AKAP1的缺失通过增加CXII和降低CXIII-V来解除对氧化磷酸化(OXPHOS)复合体(CXS)的调控，导致代谢和氧化应激。此外，AKAP1的缺失减少了丝氨酸473(Ser473)和苏氨酸308(Thr308)的Akt磷酸化，并激活了视网膜中的Bim/Bax信号通路。这些结果表明，AKAP1的缺失在青光眼神经退行性变中可能通过降低Drp1在Ser637的磷酸化，解除OXPHOS的调控，减少Ser473和Thr308的Akt磷酸化，以及激活Bim/Bax通路而在RGC功能障碍中起关键作用。因此，我们认为在青光眼和其他线粒体相关视神经疾病中，过表达AKAP1或调节Ser637处的Drp1磷酸化是潜在的神经保护干预策略。
Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637). These findings suggest that AKAP1-mediated phosphorylation of Drp1 at Ser637 has a critical role in RGC survival in glaucomatous neurodegeneration. Male mice lacking AKAP1 show increases in CaN and total Drp1 levels, as well as a decrease in Drp1 phosphorylation at Ser637 in the retina. Ultrastructural analysis of mitochondria shows that loss of AKAP1 triggers mitochondrial fragmentation and loss, as well as mitophagosome formation in RGCs. Loss of AKAP1 deregulates oxidative phosphorylation (OXPHOS) complexes (Cxs) by increasing CxII and decreasing CxIII-V, leading to metabolic and oxidative stress. Also, loss of AKAP1 decreases Akt phosphorylation at Serine 473 (Ser473) and threonine 308 (Thr308) and activates the Bim/Bax signaling pathway in the retina. These results suggest that loss of AKAP1 has a critical role in RGC dysfunction by decreasing Drp1 phosphorylation at Ser637, deregulating OXPHOS, decreasing Akt phosphorylation at Ser473 and Thr308, and activating the Bim/Bax pathway in glaucomatous neurodegeneration. Thus, we propose that overexpression of AKAP1 or modulation of Drp1 phosphorylation at Ser637 are potential therapeutic strategies for neuroprotective intervention in glaucoma and other mitochondria-related optic neuropathies.