Enhanced mitochondria-associated membrane formation in Fuchs endothelial corneal dystrophy: a novel link between endoplasmic reticulum stress and mitochondrial dysfunction.
Saki Matusmoto, Saori Kadoya, Yuna Horiuchi, Hirokazu Okuda, Keita Miyadai, Yu Shima, Robert D Young, Andrew J Quantock, Ursula Schlötzer-Schrehardt, Friedrich Kruse, Noriko Koizumi, Naoki Okumura
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Abstract
Purpose: To investigate the presence and characteristics of mitochondria-associated membranes (MAMs) in Fuchs endothelial corneal dystrophy (FECD) and to assess the relationship between endoplasmic reticulum (ER) stress and MAM formation in corneal endothelial cells, given the established roles of mitochondrial dysfunction and ER stress in FECD pathogenesis.
Study design: Experimental laboratory investigation.
Methods: Corneal endothelial tissues from FECD patients and controls were examined by use of transmission electron microscopy to evaluate the ultrastructural features of mitochondria-ER contacts. An established FECD cell model was used for immunofluorescence colocalization analysis and protein expression profiling. Experimental models of protein misfolding (MG132) and direct ER stress induction (tunicamycin) were implemented to explore the relationship between ER stress and MAM formation.
Results: The FECD specimens exhibited extensive mitochondria-ER contacts with evident tethering complexes and distances reduced to <20 nm when compared with normal corneal endothelium. Quantitative analysis showed significantly increased mitochondria-ER colocalization in iFECD cells (P <0.01). The FECD cell model showed significant upregulation of MAM-associated proteins, including GRP75, Mfn1, Mfn2, Sigma1 receptor, VDAC, and IP3R. MG132 and tunicamycin treatments both increased MAM formation while activating all UPR pathways.
Conclusions: This study provides the first evidence of enhanced MAM formation in FECD and identifies ER stress as a key driver of this structural change. While these findings suggest a potential role for MAMs in linking ER stress and mitochondrial dysfunction in FECD pathogenesis, further investigation is needed to clarify whether such changes are protective adaptations or whether they contribute to disease progression.
期刊介绍：
The Japanese Journal of Ophthalmology (JJO) was inaugurated in 1957 as a quarterly journal published in English by the Ophthalmology Department of the University of Tokyo, with the aim of disseminating the achievements of Japanese ophthalmologists worldwide. JJO remains the only Japanese ophthalmology journal published in English. In 1997, the Japanese Ophthalmological Society assumed the responsibility for publishing the Japanese Journal of Ophthalmology as its official English-language publication.
Currently the journal is published bimonthly and accepts papers from authors worldwide. JJO has become an international interdisciplinary forum for the publication of basic science and clinical research papers.
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