Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve

¹ Hamilton Glaucoma Center and Ophthalmology, University of California San Diego, La Jolla, California, United States
² National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, California, United States

^* To whom correspondence should be addressed. E-mail: danielju{at}glaucoma.ucsd.edu.

	Abstract

PURPOSE. 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. METHODS. IOP in the eyes of DBA/2J mice was measured and mitochondrial structural changes were assessed by conventional 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 Taqman qPCR. 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 ONH of eyes with >20 mmHg 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 916.6 ± 768.4 nm in 3 month-old mice to 582.87 ± 303.3 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 optic nerve heads. 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 ON degeneration in glaucoma.

Key Words: mitochondria, glaucoma, optic nerve head, ganglion cell, axonal degeneration