title: DRP1 inhibition rescues retinal ganglion cells and their axons by preserving mitochondrial integrity in a mouse model of glaucoma.
abstract: Glaucoma is the leading cause of irreversible blindness and is characterized by slow and progressive degeneration of the optic nerve head axons and retinal ganglion cell (RGC), leading to loss of visual function. Although oxidative stress and/or alteration of mitochondrial (mt) dynamics induced by elevated intraocular pressure (IOP) are associated with this neurodegenerative disease, the mechanisms that regulate mt dysfunction-mediated glaucomatous neurodegeneration are poorly understood. Using a mouse model of glaucoma, DBA/2J (D2), which spontaneously develops elevated IOP, as well as an in vitro RGC culture system, we show here that oxidative stress, as evidenced by increasing superoxide dismutase 2 (SOD2) and mt transcription factor A (Tfam) protein expression, triggers mt fission and loss by increasing dynamin-related protein 1 (DRP1) in the retina of glaucomatous D2 mice as well as in cultured RGCs exposed to elevated hydrostatic pressure in vitro. DRP1 inhibition by overexpressing DRP1 K38A mutant blocks mt fission and triggers a subsequent reduction of oxidative stress, as evidenced by decreasing SOD2 and Tfam protein expression. DRP1 inhibition promotes RGC survival by increasing phosphorylation of Bad at serine 112 in the retina and preserves RGC axons by maintaining mt integrity in the glial lamina of glaucomatous D2 mice. These findings demonstrate an important vicious cycle involved in glaucomatous neurodegeneration that starts with elevated IOP producing oxidative stress; the oxidative stress then leads to mt fission and a specific form of mt dysfunction that generates further oxidative stress, thus perpetuating the cycle. Our findings suggest that DRP1 is a potential therapeutic target for ameliorating oxidative stress-mediated mt fission and dysfunction in RGC and its axons during glaucomatous neurodegeneration. Thus, DRP1 inhibition may provide a new therapeutic strategy for protecting both RGCs and their axons in glaucoma and other optic neuropathies.
authors.affiliation: Department of Neuroscience, Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: K-Y
authors.initials: KY
authors.lastname: Kim
authors.affiliation: Department of Neuroscience, Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Perkins
authors.affiliation: Laboratory for Optic Nerve Biology, Department of Ophthalmology, Hamilton Glaucoma Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Shim
authors.affiliation: Department of Neuroscience, Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Bushong
authors.affiliation: Department of Neuroscience, Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Alcasid
authors.affiliation: Department of Neuroscience, Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Ju
authors.affiliation: Department of Neuroscience, Center for Research in Biological Systems, National Center for Microscopy and Imaging Research, University of California, San Diego, La Jolla, CA, USA.
authors.forename: M H
authors.initials: MH
authors.lastname: Ellisman
authors.affiliation: Laboratory for Optic Nerve Biology, Department of Ophthalmology, Hamilton Glaucoma Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: R N
authors.initials: RN
authors.lastname: Weinreb
authors.affiliation: Laboratory for Optic Nerve Biology, Department of Ophthalmology, Hamilton Glaucoma Center, University of California, San Diego, La Jolla, CA, USA.
authors.forename: W-K
authors.initials: WK
authors.lastname: Ju
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D034281:Dynamins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000494:pharmacology; D005786:Gene Expression Regulation; D005901:Glaucoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007429:Intraocular Pressure / Q000235:genetics*; D051379:Mice; D008811:Mice, Inbred DBA; D063154:Mitochondrial Dynamics / Q000187:drug effects* / Q000235:genetics; D009154:Mutation; D009898:Optic Disk / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D020011:Protective Agents / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D004268:DNA-Binding Proteins; D034281:Dynamins; D020558:GTP Phosphohydrolases; D006609:High Mobility Group Proteins; D010446:Peptide Fragments; D020011:Protective Agents; D052999:Quinazolinones; D013482:Superoxide Dismutase; D051025:bcl-Associated Death Protein; D000099156:Superoxide Dismutase 2; C549041:3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; C494820:Bad protein, mouse; C583855:P110 peptide; C081930:Tfam protein, mouse; C486391:Dnm1l protein, mouse