May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Intraocular Pressure Elevation Induces Mitochondrial Fission and Triggers OPA1 Release in Glaucomatous Optic Nerve
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
Author Affiliations & Notes
  • W.-K. Ju
    University of California San Diego, La Jolla, California
    Hamilton Glaucoma Center,
  • K.-Y. Kim
    University of California San Diego, La Jolla, California
    National Center for Microscopy and Imaging Research,
  • J. D. Lindsey
    University of California San Diego, La Jolla, California
    Hamilton Glaucoma Center,
  • M. Angert
    University of California San Diego, La Jolla, California
    Hamilton Glaucoma Center,
  • K. X. Duong-Polk
    University of California San Diego, La Jolla, California
    Hamilton Glaucoma Center,
  • R. T. Scott
    University of California San Diego, La Jolla, California
    National Center for Microscopy and Imaging Research,
  • I. Kukhmazov
    University of California San Diego, La Jolla, California
    Hamilton Glaucoma Center,
  • M. H. Ellisman
    University of California San Diego, La Jolla, California
    National Center for Microscopy and Imaging Research,
  • G. A. Perkins
    University of California San Diego, La Jolla, California
    National Center for Microscopy and Imaging Research,
  • R. N. Weinreb
    University of California San Diego, La Jolla, California
    Hamilton Glaucoma Center,
  • Footnotes
    Commercial Relationships  W. Ju, None; K. Kim, None; J.D. Lindsey, None; M. Angert, None; K.X. Duong-Polk, None; R.T. Scott, None; I. Kukhmazov, None; M.H. Ellisman, None; G.A. Perkins, None; R.N. Weinreb, None.
  • Footnotes
    Support  NIH grants EY01466 (JDL), NCRR P41 RR004050 (MHE), and EY105990 (RNW)
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 3674. doi:
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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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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 that spontaneously develop elevated IOP.

Methods: : 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.

Results: : 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.

Conclusions: : 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.

Keywords: intraocular pressure • mitochondria • optic nerve 
© 2008, The Association for Research in Vision and Ophthalmology, Inc., all rights reserved. Permission to republish any abstract or part of an abstract in any form must be obtained in writing from the ARVO Office prior to publication.
Copyright © 2025 Association for Research in Vision and Ophthalmology.
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