title: Intraocular pressure elevation induces mitochondrial fission and triggers OPA1 release in glaucomatous optic nerve.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Ophthalmology, Hamilton Glaucoma Center, School of Medicine, University of California San Diego, La Jolla, California 92037-0946, USA.
authors.forename: Won-Kyu
authors.initials: WK
authors.lastname: Ju
authors.forename: Keun-Young
authors.initials: KY
authors.lastname: Kim
authors.forename: James D
authors.initials: JD
authors.lastname: Lindsey
authors.forename: Mila
authors.initials: M
authors.lastname: Angert
authors.forename: Karen X
authors.initials: KX
authors.lastname: Duong-Polk
authors.forename: Ray T
authors.initials: RT
authors.lastname: Scott
authors.forename: James Jaeyoung
authors.initials: JJ
authors.lastname: Kim
authors.forename: Ismail
authors.initials: I
authors.lastname: Kukhmazov
authors.forename: Mark H
authors.initials: MH
authors.lastname: Ellisman
authors.forename: Guy A
authors.initials: GA
authors.lastname: Perkins
authors.forename: Robert N
authors.initials: RN
authors.lastname: Weinreb
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D034284:Dynamin I / Q000096:biosynthesis / Q000235:genetics; D003576:Electron Transport Complex IV / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression; D005901:Glaucoma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D007150:Immunohistochemistry; D007429:Intraocular Pressure / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008928:Mitochondria / Q000648:ultrastructure*; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D003576:Electron Transport Complex IV; C526871:cytochrome c oxidase subunit I, mouse; D034284:Dynamin I; D020558:GTP Phosphohydrolases; C498809:Opa1 protein, mouse