title: Mitochondrial morphology differences and mitophagy deficit in murine glaucomatous optic nerve.
abstract: OBJECTIVE
  Decreased ATP correlates with intraocular pressure exposure in the optic nerves of mice with glaucoma. To understand what underlies this energy deficit, we examined mitochondria in the myelinated optic nerve axons of the DBA/2J mouse, a model of glaucoma secondary to iris pigment disease, and the DBA/2(wt-gpnmb) control strain.
  
  
  METHODS
  Mitochondrial length, width, surface area, and health status were measured in 30 electron microscopic fields within the myelinated portion of optic nerves from DBA/2J and DBA/2(wt-gpnmb) mice at 3, 6, and 10 months of age. Protein was isolated from optic nerve for analysis of PINK1, Parkin, LC3-I and -II, and lysosome-associated membrane protein 1 (LAMP1) by Western blot.
  
  
  RESULTS
  The number of mitochondria in DBA/2J optic nerve was increased, and they had significantly smaller surface area. Mitochondria in DBA/2J were closer to the axolemma, more spatially isolated, and their cristae were more disrupted at every age group as compared to DBA/2(wt-gpnmb). Autophagosomes were significantly increased in DBA/2J optic nerve at all ages. Protein analysis showed higher LC3-II to LC3-I ratio in aged DBA/2J optic nerve than in DBA/2(wt-gpnmb). PINK1 and Parkin levels were not statistically different across age groups. LAMP1 was significantly decreased in the aged DBA/2J optic nerve.
  
  
  CONCLUSIONS
  Decreased surface area, combined with reduced oxidative capacity in mitochondria from the aged DBA/2J axon, indicate that mitochondrial pathology may contribute to the energy deficit in glaucomatous optic nerve. Though autophagosomes were increased in DBA/2J optic nerve, the increased mitochondria and decreased LAMP1 suggest deteriorating mitochondria are not being efficiently recycled by mitophagy.
authors: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, United States School of Biomedical Sciences, Kent State University, Kent, Ohio, United States.
authors: Lucy
authors: L
authors: Coughlin
authors: Department of Neurological Surgery, University of Washington, Seattle, Washington, United States.
authors: Richard S
authors: RS
authors: Morrison
authors: Department of Neurological Surgery, University of Washington, Seattle, Washington, United States.
authors: Philip J
authors: PJ
authors: Horner
authors: Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, United States.
authors: Denise M
authors: DM
authors: Inman
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D001369:Axons / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D008811:Mice, Inbred DBA; D008854:Microscopy, Electron; D008928:Mitochondria / Q000473:pathology*; D063306:Mitophagy / Q000502:physiology*; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D009900:Optic Nerve / Q000473:pathology*
chemical_list: D000255:Adenosine Triphosphate
keywords: autophagosome; mitochondria; mitophagy
references: Front Neurosci. 2014 Sep 17;8:290
references: 25278826
references: Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4564-72
references: 17898279
references: Invest Ophthalmol Vis Sci. 2013 Mar;54(3):2346-52
references: 23412088
references: Cell Host Microbe. 2014 Apr 9;15(4):403-11
references: 24721569
references: J Neurosci. 2010 Apr 21;30(16):5644-52
references: 20410117
references: J Neurosci. 2010 Mar 10;30(10):3555-66
references: 20219989
references: Invest Ophthalmol Vis Sci. 2007 May;48(5):2145-51
references: 17460273
references: Annu Rev Genet. 2005;39:359-407
references: 16285865
references: J Neurosci. 2010 Jan 20;30(3):1015-26
references: 20089910
references: Proc Natl Acad Sci U S A. 2010 Mar 16;107(11):5196-201
references: 20194762
references: Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4439-48
references: 25294927
references: Cell. 2011 Nov 11;147(4):728-41
references: 22078875
references: Science. 2002 Feb 8;295(5557):1077-9
references: 11834836
references: J Neurosci. 2008 Mar 12;28(11):2735-44
references: 18337403
references: Cell Death Dis. 2013;4:e917
references: 24232093
references: Vis Neurosci. 2005 Sep-Oct;22(5):637-48
references: 16332275
references: Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9633-8
references: 24979790
references: J Cell Biol. 2014 Sep 1;206(5):655-70
references: 25154397
references: J Neurosci. 2011 May 18;31(20):7249-58
references: 21593309
references: Cell Death Dis. 2013;4:e860
references: 24136224
references: J Cell Biol. 2012 Feb 20;196(4):407-17
references: 22331844
references: J Cell Biol. 2008 Dec 1;183(5):795-803
references: 19029340
references: J Neurosci. 2010 May 12;30(19):6658-66
references: 20463228
references: PLoS Biol. 2010 Jan;8(1):e1000298
references: 20126261
references: Brain. 2011 Jul;134(Pt 7):1901-13
references: 21705418
references: J Cell Biol. 2010 Apr 19;189(2):211-21
references: 20404107
references: Science. 2012 Aug 31;337(6098):1062-5
references: 22936770
references: Invest Ophthalmol Vis Sci. 2008 Nov;49(11):4903-11
references: 18469184
references: Invest Ophthalmol Vis Sci. 2006 Jun;47(6):2533-41
references: 16723467
references: J Neurosci. 2009 Jun 17;29(24):7917-28
references: 19535603
references: Am J Pathol. 2014 Apr;184(4):1017-29
references: 24508229
references: Trends Neurosci. 2012 Jun;35(6):364-72
references: 22578891