Lysosomal basification and decreased autophagic flux in oxidatively stressed trabecular meshwork cells: implications for glaucoma pathogenesis.
Increasing evidence suggests oxidative damage as a key factor contributing to the failure of the conventional outflow pathway tissue to maintain appropriate levels of intraocular pressure, and thus increase the risk for developing glaucoma, a late-onset disease which is the second leading cause of permanent blindness worldwide. Autophagy is emerging as an essential cellular survival mechanism against a variety of stressors, including oxidative stress. Here, we have monitored, by using different methodologies (LC3-I to LC3-II turnover, tfLC3, and Cyto ID), the induction of autophagy and autophagy flux in TM cells subjected to a normobaric hyperoxic model of mild chronic oxidative stress. Our data indicate the MTOR-mediated activation of autophagy and nuclear translocation of TFEB in oxidatively stressed TM cells, as well as the role of autophagy in the occurrence of SA-GLB1/SA-β-gal. Concomitant with the activation of the autophagic pathway, TM cells grown under oxidative stress conditions displayed, however, reduced cathepsin (CTS) activities, reduced lysosomal acidification and impaired CTSB proteolytic maturation, resulting in decreased autophagic flux. We propose that diminished autophagic flux induced by oxidative stress might represent one of the factors leading to progressive failure of cellular TM function with age and contribute to the pathogenesis of primary open angle glaucoma.
Department of Ophthalmology, Duke University, Durham, NC, USA.
Kristine
K
Porter
Jeyabalan
J
Nallathambi
Yizhi
Y
Lin
Paloma B
PB
Liton
D000818:Animals; D001343:Autophagy / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D016922:Cellular Senescence; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D005901:Glaucoma / Q000473:pathology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008247:Lysosomes / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D013312:Stress, Physiological; D034421:Sus scrofa; D014129:Trabecular Meshwork / Q000378:metabolism* / Q000473:pathology*; D001616:beta-Galactosidase / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D015415:Biomarkers; D008869:Microtubule-Associated Proteins; D001616:beta-Galactosidase
TFEB; autophagy; cathepsin; glaucoma; lysosomes; oxidative stress; senescence-associated-β-galactosidase; trabecular meshwork