Maintaining mitochondrial membrane impermeability. an opportunity for new therapy in glaucoma?
Apoptosis may contribute to retinal ganglion cell loss in glaucoma and glaucoma models. Recent research has suggested that mitochondrially dependent apoptosis signaling may contribute to apoptosis in a rat model of glaucoma involving chronic increases in intraocular pressure. In some forms of apoptosis, mitochondrially dependent signaling involves increases in mitochondrial membrane permeability and the mitochondrial release of factors that signal for cell degradation. Opening of a multi-protein, mitochondrial megapore is one factor that contributes to the increased permeability and some anti-apoptotic proteins, particularly BCL-2 and BCL-X(L), bind at the megapore and facilitate megapore closure and reduce increases in mitochondrial membrane permeability. Phosphorylated protein kinase B (Akt) serves as an integrator for cellular survival signals and facilitates the megapore actions of BCL-2 and BCL-X(L), which could protect retinal ganglion cells against insults that induce apoptosis. Several anti-apoptotic agents are being evaluated for use in glaucoma, including brimonidine and propargylamines, which oppose mitochondrially dependent apoptosis through pathways involving phosphorylated Akt.
Tatton
W G
WG
Departments of Ophthalmology, Mount Sinai School of Medicine, New York, NY 10029, USA. william.tatton@mssm.edu
Chalmers-Redman
R M
RM
Sud
A
A
Podos
S M
SM
Mittag
T W
TW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000068438:Brimonidine Tartrate; D002463:Cell Membrane Permeability / Q000187:drug effects*; D005901:Glaucoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007429:Intraocular Pressure; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010293:Pargyline / Q000031:analogs & derivatives / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D011437:Propylamines; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; D051020:bcl-X Protein; C009054:propargylamine; D000068438:Brimonidine Tartrate; D010293:Pargyline