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Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy.

Publication ,  Journal Article
Shyam, R; Ogando, DG; Choi, M; Liton, PB; Bonanno, JA
Published in: Invest Ophthalmol Vis Sci
September 2, 2021

PURPOSE: The Slc4a11 knock out (KO) mouse model recapitulates the human disease phenotype associated with congenital hereditary endothelial dystrophy (CHED). Increased mitochondrial reactive oxygen species (ROS) in the Slc4a11 KO mouse model is a major cause of edema and endothelial cell loss. Here, we asked if autophagy was activated by ROS in the KO mice. METHODS: Immortalized cell lines and mouse corneal endothelia were used to measure autophagy and lysosome associated protein expressions using Protein Simple Wes immunoassay. Autophagy and lysosome functions were examined in wild type (WT) and KO cells as well as animals treated with the mitochondrial ROS quencher MitoQ. RESULTS: Even though autophagy activation was evident, autophagy flux was aberrant in Slc4a11 KO cells and corneal endothelium. Expression of lysosomal proteins and lysosomal mass were decreased along with reduced nuclear translocation of lysosomal master regulator, transcription factor EB (TFEB). MitoQ reversed aberrant lysosomal functions and TFEB nuclear localization in KO cells. MitoQ injections in KO animals reduced corneal edema and decreased the rate of endothelial cell loss. CONCLUSIONS: Mitochondrial ROS disrupts TFEB signaling causing lysosomal dysfunction with impairment of autophagy in Slc4a11 KO corneal endothelium. Our study is the first to identify the presence as well as cause of lysosomal dysfunction in an animal model of CHED, and to identify a potential therapeutic approach.

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Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

September 2, 2021

Volume

62

Issue

12

Start / End Page

15

Location

United States

Related Subject Headings

  • Ubiquinone
  • Transfection
  • Symporters
  • Real-Time Polymerase Chain Reaction
  • Reactive Oxygen Species
  • Organophosphorus Compounds
  • Ophthalmology & Optometry
  • Mitochondria
  • Microscopy, Fluorescence
  • Mice, Knockout
 

Citation

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Shyam, R., Ogando, D. G., Choi, M., Liton, P. B., & Bonanno, J. A. (2021). Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy. Invest Ophthalmol Vis Sci, 62(12), 15. https://doi.org/10.1167/iovs.62.12.15
Shyam, Rajalekshmy, Diego G. Ogando, Moonjung Choi, Paloma B. Liton, and Joseph A. Bonanno. “Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy.Invest Ophthalmol Vis Sci 62, no. 12 (September 2, 2021): 15. https://doi.org/10.1167/iovs.62.12.15.
Shyam R, Ogando DG, Choi M, Liton PB, Bonanno JA. Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy. Invest Ophthalmol Vis Sci. 2021 Sep 2;62(12):15.
Shyam, Rajalekshmy, et al. “Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy.Invest Ophthalmol Vis Sci, vol. 62, no. 12, Sept. 2021, p. 15. Pubmed, doi:10.1167/iovs.62.12.15.
Shyam R, Ogando DG, Choi M, Liton PB, Bonanno JA. Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy. Invest Ophthalmol Vis Sci. 2021 Sep 2;62(12):15.

Published In

Invest Ophthalmol Vis Sci

DOI

EISSN

1552-5783

Publication Date

September 2, 2021

Volume

62

Issue

12

Start / End Page

15

Location

United States

Related Subject Headings

  • Ubiquinone
  • Transfection
  • Symporters
  • Real-Time Polymerase Chain Reaction
  • Reactive Oxygen Species
  • Organophosphorus Compounds
  • Ophthalmology & Optometry
  • Mitochondria
  • Microscopy, Fluorescence
  • Mice, Knockout