Mitochondria and Endoplasmic Reticulum Stress in Retinal Organoids from Patients with Vision Loss.

Autor:	Lee EJ; Department of Ophthalmology, Stanford University, Stanford, California; Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California., Diaz-Aguilar MS; Department of Ophthalmology, Stanford University, Stanford, California; Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California; Department of Medicine, Rush University Medical College, Chicago, Illinois., Min H; Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California., Choi J; Department of Pathology, Stanford University, Stanford, California., Valdez Duran DA; Department of Pathology, Stanford University, Stanford, California., Grandjean JM; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California., Wiseman RL; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California., Kroeger H; Department of Cellular Biology, University of Georgia, Athens, Georgia., Lin JH; Department of Ophthalmology, Stanford University, Stanford, California; Department of Pathology, VA Palo Alto Healthcare System, Palo Alto, California; Department of Pathology, Stanford University, Stanford, California. Electronic address: jonathan.h.lin@stanford.edu.
Jazyk:	angličtina
Zdroj:	The American journal of pathology [Am J Pathol] 2023 Nov; Vol. 193 (11), pp. 1721-1739. Date of Electronic Publication: 2022 Dec 17.
DOI:	10.1016/j.ajpath.2022.12.002
Abstrakt:	Activating transcription factor 6 (ATF6), a key regulator of the unfolded protein response, plays a key role in endoplasmic reticulum function and protein homeostasis. Variants of ATF6 that abrogate transcriptional activity cause morphologic and molecular defects in cones, clinically manifesting as the human vision loss disease achromatopsia (ACHM). ATF6 is expressed in all retinal cells. However, the effect of disease-associated ATF6 variants on other retinal cell types remains unclear. Herein, this was investigated by analyzing bulk RNA-sequencing transcriptomes from retinal organoids generated from patients with ACHM, carrying homozygous loss-of-function ATF6 variants. Marked dysregulation in mitochondrial respiratory complex gene expression and disrupted mitochondrial morphology in ACHM retinal organoids were identified. This indicated that loss of ATF6 leads to previously unappreciated mitochondrial defects in the retina. Next, gene expression from control and ACHM retinal organoids were compared with transcriptome profiles of seven major retinal cell types generated from recent single-cell transcriptomic maps of nondiseased human retina. This indicated pronounced down-regulation of cone genes and up-regulation in Müller glia genes, with no significant effects on other retinal cells. Overall, the current analysis of ACHM patient retinal organoids identified new cellular and molecular phenotypes in addition to cone dysfunction: activation of Müller cells, increased endoplasmic reticulum stress, disrupted mitochondrial structure, and elevated respiratory chain activity gene expression. (Copyright © 2023 American Society for Investigative Pathology. All rights reserved.)
Databáze:	MEDLINE
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