bims-mideyd 2022-01-09 papers

J Biol Chem. 2021 Dec 29. pii: S0021-9258(21)01363-6. [Epub ahead of print] 101553

Gasdermin E mediates photoreceptor damage by all-trans-retinal in the mouse retina.

Binxiang Cai, Chunyan Liao, Danxue He, Jingmeng Chen, Jiahuai Han, Jiaying Lu, Kaiqi Qin, Wenxu Liang, Xiaoling Wu, Zuguo Liu, Yalin Wu.

The breakdown of all-trans-retinal (atRAL) clearance is closely associated with photoreceptor cell death in dry age-related macular degeneration (AMD) and autosomal recessive Stargardt disease (STGD1), but its potential mechanisms remain elusive. In this study, we demonstrate that activation of gasdermin E (GSDME) but not gasdermin D (GSDMD) promotes atRAL-induced photoreceptor damage by activating pyroptosis and aggravating apoptosis through a mitochondria-mediated caspase-3-dependent signaling pathway. Activation of c-Jun N-terminal kinase (JNK) was identified as one of major causes of mitochondrial membrane rupture in atRAL-loaded photoreceptor cells, resulting in release of cytochrome c (Cyt c) from mitochondria to the cytosol, where it stimulated caspase-3 activation required for cleavage of GSDME. Aggregation of the N-terminal fragment of GSDME (GSDME-N) in the mitochondria revealed that GSDME was likely to directly penetrate mitochondrial membranes in photoreceptor cells following atRAL exposure. ABCA4 and RDH8 are two key proteins responsible for clearing atRAL in the retina. Abca4-/-Rdh8-/- mice exhibit serious defects in atRAL clearance upon light exposure, and serve as an acute model for dry AMD and STGD1. We found that GSDME-N was distinctly localized in the photoreceptor outer nuclear layer of light-exposed Abca4-/-Rdh8-/- mice. Of note, degeneration and caspase-3 activation in photoreceptors were significantly alleviated in Abca4-/-Rdh8-/-Gsdme-/- mice after exposure to light. The results of this study indicate that GSDME is a common causative factor of both photoreceptor pyroptosis and apoptosis arising from atRAL overload, suggesting that repression of GSDME activation may represent a potential treatment of photoreceptor atrophy in dry AMD and STGD1.

Keywords: Stargardt’s disease; age-related macular degeneration; apoptosis; c-Jun N-terminal kinase; gasdermin E; photoreceptor; pyroptosis; reactive oxygen species

DOI: https://doi.org/10.1016/j.jbc.2021.101553

Cell Biosci. 2022 Jan 03. 12(1): 1

The interplay of autophagy and oxidative stress in the pathogenesis and therapy of retinal degenerative diseases.

Kun-Che Chang, Pei-Feng Liu, Chia-Hsuan Chang, Ying-Cheng Lin, Yen-Ju Chen, Chih-Wen Shu.

Oxidative stress is mainly caused by intracellular reactive oxygen species (ROS) production, which is highly associated with normal physiological homeostasis and the pathogenesis of diseases, particularly ocular diseases. Autophagy is a self-clearance pathway that removes oxidized cellular components and regulates cellular ROS levels. ROS can modulate autophagy activity through transcriptional and posttranslational mechanisms. Autophagy further triggers transcription factor activation and degrades impaired organelles and proteins to eliminate excessive ROS in cells. Thus, autophagy may play an antioxidant role in protecting ocular cells from oxidative stress. Nevertheless, excessive autophagy may cause autophagic cell death. In this review, we summarize the mechanisms of interaction between ROS and autophagy and their roles in the pathogenesis of several ocular diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and optic nerve atrophy, which are major causes of blindness. The autophagy modulators used to treat ocular diseases are further discussed. The findings of the studies reviewed here might shed light on the development and use of autophagy modulators for the future treatment of ocular diseases.

Keywords: Age-related macular degeneration; Autophagy; Diabetic retinopathy; Glaucoma; Optic nerve atrophy; Reactive oxygen species

DOI: https://doi.org/10.1186/s13578-021-00736-9

Front Genet. 2021 ;12 781189

Mitochondrial Genome Study Identifies Association Between Primary Open-Angle Glaucoma and Variants in MT-CYB, MT-ND4 Genes and Haplogroups.

Valeria Lo Faro, Ilja M Nolte, Jacoline B Ten Brink, Harold Snieder, Nomdo M Jansonius, Arthur A Bergen.

Background and purpose: Primary open-angle glaucoma (POAG) is an optic neuropathy characterized by death of retinal ganglion cells and atrophy of the optic nerve head. The susceptibility of the optic nerve to damage has been shown to be mediated by mitochondrial dysfunction. In this study, we aimed to determine a possible association between mitochondrial SNPs or haplogroups and POAG. Methods: Mitochondrial DNA single nucleotide polymorphisms (mtSNPs) were genotyped using the Illumina Infinium Global Screening Array-24 (GSA) 700K array set. Genetic analyses were performed in a POAG case-control study involving the cohorts, Groningen Longitudinal Glaucoma Study-Lifelines Cohort Study and Amsterdam Glaucoma Study, including 721 patients and 1951 controls in total. We excluded samples not passing quality control for nuclear genotypes and samples with low call rate for mitochondrial variation. The mitochondrial variants were analyzed both as SNPs and haplogroups. These were determined with the bioinformatics software HaploGrep, and logistic regression analysis was used for the association, as well as for SNPs. Results: Meta-analysis of the results from both cohorts revealed a significant association between POAG and the allele A of rs2853496 [odds ratio (OR) = 0.64; p = 0.006] within the MT-ND4 gene, and for the T allele of rs35788393 (OR = 0.75; p = 0.041) located in the MT-CYB gene. In the mitochondrial haplogroup analysis, the most significant p-value was reached by haplogroup K (p = 1.2 × 10-05), which increases the risk of POAG with an OR of 5.8 (95% CI 2.7-13.1). Conclusion: We identified an association between POAG and polymorphisms in the mitochondrial genes MT-ND4 (rs2853496) and MT-CYB (rs35788393), and with haplogroup K. The present study provides further evidence that mitochondrial genome variations are implicated in POAG. Further genetic and functional studies are required to substantiate the association between mitochondrial gene polymorphisms and POAG and to define the pathophysiological mechanisms of mitochondrial dysfunction in glaucoma.

Keywords: MT-CYB; MT-ND4; genetic association study; haplogroup K; mitochondrial haplogroup; mitochondrial polymorphism; primary open-angle glaucoma (POAG)

DOI: https://doi.org/10.3389/fgene.2021.781189