Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve
Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve
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DOI：
10.1167/iovs.07-1661
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发表时间：
2008-11-01
影响因子：
4.4
通讯作者：
Weinreb, Robert N.
中科院分区：
文献类型：
--
作者：
Ju, Won-Kyu;Kim, Keun-Young;Weinreb, Robert N.
目的.目的探讨眼内压（IOP）升高是否引起DBA/2 J小鼠视神经（ON）线粒体分裂和超微结构改变，以及OPA 1的表达和分布。测量DBA/2 J小鼠眼中的IOP，并通过常规电子显微镜（EM）和EM断层扫描评估线粒体结构变化。通过定量（q）PCR测定细胞色素c氧化酶IV亚基1（考克斯）、OPA 1和Dnm 1（动力蛋白相关蛋白-1的大鼠同源物）mRNA。免疫细胞化学和Western blot检测考克斯和OPA 1蛋白分布。在眼压升高> 20 mm Hg的10个月大的青光眼性视神经乳头（ONH）中，轴突缺失和考克斯减少是明显的。EM分析显示，线粒体分裂，基质肿胀，嵴体积大幅减少，和异常嵴消耗在10个月大的脑胶质瘤ONH轴突。这些轴突中的线粒体横截面的平均长度从3月龄小鼠的858.2 +/- 515.3 nm降低到10月龄脑肿瘤小鼠的583.3 +/- 298.6 nm（P < 0.001）。在10月龄DBA/2 J小鼠的ONH中观察到考克斯mRNA的中度减少。在10个月大的胶质瘤性ONH中，OPA 1免疫反应性和基因表达的较大减少与Dnm 1基因表达的较大增加相结合。亚细胞分级分析表明10个月大的脑肉瘤中线粒体释放OPA 1和细胞色素c增加。眼压升高可能通过促进考克斯减少、线粒体分裂和嵴缺失、OPA 1和Dnm 1表达改变以及诱导OPA 1释放而直接损伤ONH轴突中的线粒体。因此，保护线粒体的干预措施可能有助于防止青光眼中的ON变性。（Invest Ophthalmol维斯科学。2008;49：4903-4911）DOI：10.1167/iovs.07-1661
PURPOSE. To determine whether elevation of intraocular pressure (IOP) triggers mitochondrial fission and ultrastructural changes and alters optic atrophy type 1 (OPA1) expression and distribution in the optic nerve (ON) of glaucomatous DBA/2J mice.METHODS. IOP in the eyes of DBA/2J mice was measured, and mitochondrial structural changes were assessed by conventional electron microscopy (EM) and EM tomography. Cytochrome c oxidase IV subunit 1 (COX), OPA1, and Dnm1, a rat homologue of dynamin-related protein-1, mRNA were measured by quantitative (q) PCR. COX and OPA1 protein distribution was assessed by immunocytochemistry and Western blot.RESULTS. Excavation of the optic nerve head (ONH), axon loss, and COX reduction were evident in 10-month-old glaucomatous ONHs of eyes with > 20 mm Hg IOP elevation. EM analysis showed mitochondrial fission, matrix swelling, substantially reduced cristae volume, and abnormal cristae depletion in 10-month-old glaucomatous ONH axons. The mean length of mitochondrial cross section in these axons decreased from 858.2 +/- 515.3 nm in 3-month-old mice to 583.3 +/- 298.6 nm in 10-month-old glaucomatous mice (P < 0.001). Moderate reductions of COX mRNA were observed in the 10-month-old DBA/2J mice's ONHs. Larger reductions of OPA1 immunoreactivity and gene expression were coupled with larger increases of Dnm1 gene expression in 10-month-old glaucomatous ONH. Subcellular fractionation analysis indicates increased release of both OPA1 and cytochrome c from mitochondria in 10-month-old glaucomatous ONs.CONCLUSIONS. IOP elevation may directly damage mitochondria in the ONH axons by promoting reduction of COX, mitochondrial fission and cristae depletion, alterations of OPA1 and Dnm1 expression, and induction of OPA1 release. Thus, interventions to preserve mitochondria may be useful for protecting against ON degeneration in glaucoma. (Invest Ophthalmol Vis Sci. 2008;49:4903-4911) DOI: 10.1167/iovs.07-1661