April 2009
Volume 50, Issue 13
ARVO Annual Meeting Abstract  |   April 2009
Mitochondrial Defects and Dysfunction in Calcium Regulation in Glaucomatous Trabecular Meshwork Cells
Author Affiliations & Notes
  • Y. He
    Neural & Behavior Sci, Penn State Univ Coll of Med, Hershey, Pennsylvania
  • J. Ge
    Zhongshan Ophthalmic Center, Guangzhou, China
  • T.-T. Joyce
    Neural & Behavior Sci, Penn State Univ Coll of Med, Hershey, Pennsylvania
  • Footnotes
    Commercial Relationships  Y. He, None; J. Ge, None; T.-T. Joyce, None.
  • Footnotes
    Support  Ben Franklin Foundation, PA, USA;National Natural Science Foundation of China (No.30672275, No30400486), the Clinical Key Program of the Ministry of Health (No. [2004] 468)
Investigative Ophthalmology & Visual Science April 2009, Vol.50, 4887. doi:
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      Y. He, J. Ge, T.-T. Joyce; Mitochondrial Defects and Dysfunction in Calcium Regulation in Glaucomatous Trabecular Meshwork Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4887.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: : Disruption in intracellular calcium ion (Ca2+) homeostasis has important consequences for health. Persistent Ca2+ overload induces mitochondrial permeability transition pore (MPTP) opening prompting mitochondrial release of calcium (mCICR) and ROS into the cytosol which, in turn, compromises mitochondrial function. Here, we examined intracellular Ca2+ levels and mitochondrial vulnerability to Ca2+ stress in trabecular meshwork (TM) of individuals with primary open angle glaucoma (POAG).

Methods: : Primary cultures of TM cells from POAG (GTM) and age-matched, non-diseased (NTM) individuals obtained by standard surgical trabeculectomy, from postmortem donors eyes, were treated with the following calcium regulators: mitochondrial respiratory chain I inhibitor, rotenone (ROT); mitochondrial permeability transition pore (MPTP) inhibitor, cyclosporine A (CsA) and aristolochic acid (ArA); Ca2+ chelators, BAPTA/AM, or EDTA; mitochondrial Ca2+ uniporter inhibitor, ruthenium red (RR); Ca2+/Na+ exchanger inhibitor, trifluoperazine; and the inositol 1,4,5-triphosphate receptor type 3 (IP3R) inhibitors, 2-aminoethoxydiphenyl borane (2-APB) or Xestospongin C (Xe-C). Ca2+ concentrations in the cytoplasm ([Ca2+]c) and mitochondria ([Ca2+]m) were determined by confocal microscopy and flow cytometry using the fluorescent Ca2+ indicators, fluo-3/AM and rhod-2/AM, respectively. Mitochondrial membrane potential (ΔΨm) was examined using the fluorescent probe tetramethylrhodamine ethyl ester (TMRE). We also studied the expression of cyclophilin D, a protein that induces MPTP opening.

Results: : There was increased [Ca2+]c, [Ca2+]m, mCICR, MPTP opening and expression of cyclophilin D, and decreased ΔΨm in POAG TM cells compared to controls. ROT artificially exacerbated these conditions in GTM cells. Chelation of [Ca2+]c and inhibition of IP3R and MPTP opening suppressed mitochondrial dysfunction and reduced the additional effects of ROT in GTM cells.

Conclusions: : We propose that POAG TM cells have defective mitochondrial function, which causes them to be abnormally vulnerable to Ca2+ stress. The dysfunction in calcium regulation by these cells may contribute to the failure of this tissue to control IOP. Pharmacological inhibitors of IP3R, MPTP opening, and cyclophilin D could have clinical implications for primary open angle glaucoma.

Keywords: calcium • mitochondria • degenerations/dystrophies 

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