Journal article
Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy
Investigative ophthalmology & visual science, Vol.62(12), p.15
09/17/2021
DOI: 10.1167/iovs.62.12.15
PMCID: PMC8458782
PMID: 34533563
Abstract
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.
Details
- Title: Subtitle
- Mitochondrial ROS Induced Lysosomal Dysfunction and Autophagy Impairment in an Animal Model of Congenital Hereditary Endothelial Dystrophy
- Creators
- Rajalekshmy Shyam - Indiana University BloomingtonDiego G. Ogando - Indiana University BloomingtonMoonjung Choi - Indiana University BloomingtonPaloma B. Liton - Duke UniversityJoseph A. Bonanno - Indiana University Bloomington
- Resource Type
- Journal article
- Publication Details
- Investigative ophthalmology & visual science, Vol.62(12), p.15
- DOI
- 10.1167/iovs.62.12.15
- PMID
- 34533563
- PMCID
- PMC8458782
- NLM abbreviation
- Invest Ophthalmol Vis Sci
- ISSN
- 0146-0404
- eISSN
- 1552-5783
- Publisher
- Assoc Research Vision Ophthalmology Inc
- Number of pages
- 14
- Grant note
- Knights Templar Eye Foundation TL1 TR002531; UL1 TR002529 / NIH/NCATS CTSI
- Language
- English
- Date published
- 09/17/2021
- Academic Unit
- Anatomy and Cell Biology
- Record Identifier
- 9984949263702771
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