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Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve.

ABSTRACT: 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.

SUBMITTER: Ju WK

PROVIDER: S-EPMC2688012 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve.

Ju Won-Kyu WK Kim Keun-Young KY Lindsey James D JD Angert Mila M Duong-Polk Karen X KX Scott Ray T RT Kim James Jaeyoung JJ Kukhmazov Ismail I Ellisman Mark H MH Perkins Guy A GA Weinreb Robert N RN

Investigative ophthalmology & visual science 20080509 11

<h4>Purpose</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 18469184

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Project description:Axonal transport blockade is an initial step in retinal ganglion cell (RGC) degeneration in glaucoma and targeting maintenance of normal axonal transport could confer neuroprotection. We present an objective, quantitative method for assessing axonal transport blockade in mouse glaucoma models. Intraocular pressure (IOP) was elevated unilaterally in CD1 mice for 3 days using intracameral microbead injection. Longitudinal sections of optic nerve head (ONH) were immunofluorescently labeled for myelin basic protein (MBP) and amyloid precursor protein (APP), which is transported predominantly orthograde by neurons. The beginning of the myelin transition zone, visualized with the MBP label, was more posterior with elevated IOP, 288.8 ± 40.9 μm, compared to normotensive control eyes, 228.7 ± 32.7 μm (p = 0.030, N = 6 pairs). Glaucomatous regional APP accumulations in retina, prelaminar ONH, unmyelinated ONH, and myelinated optic nerve were identified by objective qualification of pixels with fluorescent intensity greater than the 97.5th percentile value of control eyes (suprathreshold pixels). This method segregated images with APP blockade from those with normal transport of APP. The fraction of suprathreshold pixels was significantly higher following IOP elevation than in normotensive controls in the unmyelinated ONH and myelinated nerve regions (paired analyses, p = 0.02 and 0.003, respectively, N = 12), but not in retina or prelaminar ONH (p = 0.91 and 0.08, respectively). The mean intensity of suprathreshold pixels was also significantly greater in glaucoma than in normotensive controls in prelaminar ONH, unmyelinated ONH and myelinated optic nerve (p = 0.01, 0.01, 0.002, respectively). Using this method, subconjunctival glyceraldehyde, which is known to worsen long-term RGC loss with IOP elevation, also produced greater APP blockade, but not statistically significant compared to glaucoma alone. Systemic losartan, which aids RGC axonal survival in glaucoma, reduced APP blockade, but not statistically significant compared to glaucoma alone. The method provides a short-term assessment of axonal injury for use in initial tests of neuroprotective therapies that may beneficially affect RGC transport in animal models of glaucoma.

Project description:Intraocular pressure (IOP) is an important risk factor for glaucoma, and the response of the ONH and surrounding tissues to elevated IOP are often investigated to better understand pathophysiology. In vivo structure including that of the optic nerve head (ONH) and surrounding tissue of the eye are often assessed using optical coherence tomography (OCT). With advances in OCT technology, both large vessels and capillaries can be imaged non-invasively (OCT Angiography). Because a significant portion of retinal thickness is comprised of vasculature, the purpose of the current study was to investigate OCT structural and vascular changes in healthy non-human primate eyes with systematic graded increases and decreases in IOP. Six healthy animals with no previous experimental intervention were used. The pressure in the anterior chamber was adjusted from 10?mmHg to 60?mmHg and back to 10?mmHg in 10?mmHg steps every 10?min. Using optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thickness, minimum rim width (MRW), Bruch's membrane opening (BMO) size and relative height, anterior lamina cribrosa surface (ALCS) depth, choroidal thickness, and angiography (OCTA) were quantified. With IOP challenge there were significant changes in all morphological measures quantified (p?<?0.01) other than BMO size (p?=?0.30) and RNFL thickness (p?=?0.29). Specifically, the position of the BMO was sensitive to both an increase and decease in IOP. The inner retinal capillary density gradually decreased with increasing IOP, reaching statistical significance when pressure exceeded 50?mmHg, but returned when IOP was reduced. The average choroidal thickness around the ONH decreased for elliptical annuli 500-1000??m and 1000-1500??m, from the BMO, with increasing IOP (p?<?0.01). For the 1000-1500??m annulus, choroid thickness did not return to baseline with IOP reduction. Similarly, the MRW decreased with increase in IOP, but with pressure reduction did not return, and at the final 10?mmHg time point was thinner than at baseline (p?<?0.01). The results from this experiment illustrate differences in ONH neural rim tissue, RNFL and vessel density changes with acute IOP challenge. Overall, vessel collapse could not completely account for changes in RNFL or ONH MRW thickness. The study supports the hypothesis neural rim compression may be an important part of IOP-induced damage.

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Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve.

Publications

Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve.

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