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W.-K. Ju, K.-Y. Kim, J. D. Lindsey, M. Angert, K. X. Duong-Polk, R. T. Scott, I. Kukhmazov, M. H. Ellisman, G. A. Perkins, R. N. Weinreb; Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3674.
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To determine whether intraocular pressure (IOP) elevation 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 that spontaneously develop elevated IOP.
IOP in the eye of DBA/2J mice was measured and mitochondrial structural changes were assessed by conventional electron microscopy (EM) and the 3D technique of electron tomography. cytochrome c oxidase IV subunit 1 (COX), OPA1 and Dnm1, a rat homologue of dynamin related protein-1, mRNA were measured by Taqman qPCR. The cellular distribution of COX or OPA1 protein was assessed by immunocytochemistry or Western blot.
Excavation of the optic nerve head (ONH), axon loss, and COX reduction were evident in 10 month-old glaucomatous ONH of eyes with IOP elevation. Two-dimensional and three-dimensional structural analyses using conventional EM and electron tomography, respectively, showed mitochondrial fission, matrix swelling, and substantially reduced cristae volume and abnormal cristae depletion in 10 month-old glaucomatous ONH. The mean length of mitochondrial cross section in the unmyelinated ONH decreased from 916.6 ± 768.4 nm in control mice to 582.87 ± 303.3 nm in 10 month-old glaucomatous mice (P<0.001). OPA1 immunoreactivity and gene expression were decreased but Dnm1 gene expression was increased in 10 month-old glaucomatous ONH. In addition, subcellular fractionation analysis showed OPA1 release from mitochondria in 10 month-old glaucomatous ONs.
These findings indicate that IOP elevation may directly damage mitochondria in the ONH axons by injuring mitochondria and subsequently induce ONH axon loss 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 ON degeneration in glaucoma.
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