bims-mideyd 2024-04-07 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2024–04–07
six papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Metabolic Reprogramming of the Retinal Pigment Epithelium by Cytokines Associated with Age-related Macular Degeneration.
PGC-1α regulates the interplay between oxidative stress, senescence and autophagy in the ageing retina important in age-related macular degeneration.
Mitochondrial quality control in non-exudative age-related macular degeneration: From molecular mechanisms to structural and functional recovery.
Influence of Substrate Stiffness on iPSC-Derived Retinal Pigmented Epithelial Cells.
Transcriptional patterns of human retinal pigment epithelial cells under protracted high glucose.
Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease.

Biosci Rep. 2024 Apr 03. pii: BSR20231904. [Epub ahead of print]

Metabolic Reprogramming of the Retinal Pigment Epithelium by Cytokines Associated with Age-related Macular Degeneration.

David S Hansman, Yuefang Ma, Daniel Thomas, Justine R Smith, Robert J Casson, Daniel Peet.

  The complex metabolic relationship between the retinal pigment epithelium (RPE) and photoreceptors is essential for maintaining retinal health. Recent evidence indicates the RPE acts as an adjacent lactate sink, suppressing glycolysis in the epithelium in order to maximize glycolysis in the photoreceptors. Dysregulated metabolism within the RPE has been implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of vision loss. In this study, we investigate the effects of four cytokines associated with AMD, TNFα, TGF-β2, IL-6, and IL-1β, as well as a cocktail containing all four cytokines, on RPE metabolism using ARPE-19 cells, primary human RPE cells, and ex vivo rat eyecups. Strikingly, we found cytokine-specific changes in numerous metabolic markers including lactate production, glucose consumption, extracellular acidification rate, and oxygen consumption rate accompanied by increases in total mitochondrial volume and ATP production. Together, all four cytokines, could potently override the constitutive suppression of glycolysis in the RPE, through a mechanism independent by PI3K/AKT, MEK/ERK, or NF-κB. Finally, we observed changes in glycolytic gene expression with cytokine treatment, including in lactate dehydrogenase subunit and glucose transporter expression. Our findings provide new insights into the metabolic changes in the RPE under inflammatory conditions and highlight potential therapeutic targets for AMD.

Keywords:  carbohydrate metabolism; cytokines; glycolysis; inflammation; retinal degeneration; retinal pigment epithelium

DOI:  https://doi.org/10.1042/BSR20231904
J Cell Mol Med. 2024 Apr;28(8): e18051

PGC-1α regulates the interplay between oxidative stress, senescence and autophagy in the ageing retina important in age-related macular degeneration.

Iswariyaraja Sridevi Gurubaran, Cezary Watala, Joanna Kostanek, Joanna Szczepanska, Elzbieta Pawlowska, Kai Kaarniranta, Janusz Blasiak.

  We previously showed that mice with knockout in the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PPARGC1A) gene encoding the PGC-1α protein, and nuclear factor erythroid 2 like 2 (NFE2L2) gene, exhibited some features of the age-related macular degeneration (AMD) phenotype. To further explore the mechanism behind the involvement of PGC-1α in AMD pathogenesis we used young (3-month) and old (12-month) mice with knockout in the PPARGC1A gene and age-matched wild-type (WT) animals. An immunohistochemical analysis showed age-dependent different expression of markers of oxidative stress defence, senescence and autophagy in the retinal pigment epithelium of KO animals as compared with their WT counterparts. Multivariate inference testing showed that senescence and autophagy proteins had the greatest impact on the discrimination between KO and WT 3-month animals, but proteins of antioxidant defence also contributed to that discrimination. A bioinformatic analysis showed that PGC-1α might coordinate the interplay between genes encoding proteins involved in antioxidant defence, senescence and autophagy in the ageing retina. These data support importance of PGC-1α in AMD pathogenesis and confirm the utility of mice with PGC-1α knockout as an animal model to study AMD pathogenesis.

Keywords:  AMD; PGC‐1α; ageing retina; age‐related macular degeneration; autophagy; cellular senescence; oxidative stress; peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha

DOI:  https://doi.org/10.1111/jcmm.18051
Free Radic Biol Med. 2024 Apr 03. pii: S0891-5849(24)00161-8. [Epub ahead of print]

Mitochondrial quality control in non-exudative age-related macular degeneration: From molecular mechanisms to structural and functional recovery.

Hernán H Dieguez, Horacio E Romeo, Agustina Alaimo, Nathaly A Bernal Aguirre, Juan S Calanni, Juan S Adán Aréan, Silvia Alvarez, Roberta Sciurano, Ruth E Rosenstein, Damián Dorfman.

  Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical and experimental evidence supports that early alterations in macular retinal pigment epithelium (RPE) mitochondria play a key role in NE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, and mitophagy), which is under the central control of AMP-activated kinase (AMPK), in turn, determines mitochondrial quality. We have developed a NE-AMD model in C57BL/6J mice induced by unilateral superior cervical ganglionectomy (SCGx), which progressively reproduces the disease hallmarks circumscribed to the temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters' regulation at the nasal and temporal RPE from control eyes and at an early stage of experimental NE-AMD (i.e., 4 weeks post-SCGx). Although RPE mitochondrial mass was preserved, their function, which was higher at the temporal than at the nasal RPE in control eyes, was significantly decreased at 4 weeks post-SCGx at the same region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD.

Keywords:  AMPK; Metformin; Mitochondria dynamics; Non-exudative age-related macular degeneration; Retinal pigment epithelium

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.024
Stem Cells Transl Med. 2024 Apr 01. pii: szae022. [Epub ahead of print]

Influence of Substrate Stiffness on iPSC-Derived Retinal Pigmented Epithelial Cells.

Rion J Wendland, Budd A Tucker, Kristan S Worthington.

  Retinal degenerative diseases are a major cause of blindness involving the dysfunction of photoreceptors, retinal pigmented epithelium (RPE), or both. A promising treatment approach involves replacing these cells via surgical transplantation, and previous work has shown that cell delivery scaffolds are vital to ensure sufficient cell survival. Thus, identifying scaffold properties that are conducive to cell viability and maturation (such as suitable material and mechanical properties) is critical to ensuring a successful treatment approach. In this study, we investigated the effect of scaffold stiffness on human RPE attachment, survival, and differentiation, comparing immortalized (ARPE-19) and stem cell-derived RPE (iRPE) cells. Polydimethylsiloxane was used as a model polymer substrate, and varying stiffness (~12 to 800 kPa) was achieved by modulating the cross-link-to-base ratio. Post-attachment changes in gene and protein expression were assessed using qPCR and immunocytochemistry. We found that while ARPE-19 and iRPE exhibited significant differences in morphology and expression of RPE markers, substrate stiffness did not have a substantial impact on cell growth or maturation for either cell type. These results highlight the differences in expression between immortalized and iPSC-derived RPE cells, and also suggest that stiffnesses in this range (~12-800 kPa) may not result in significant differences in RPE growth and maturation, an important consideration in scaffold design.

Keywords:  cell transplantation; microenvironment; retina; retinal pigmented epithelium; tissue engineering

DOI:  https://doi.org/10.1093/stcltm/szae022
Mol Biol Rep. 2024 Apr 04. 51(1): 477

Transcriptional patterns of human retinal pigment epithelial cells under protracted high glucose.

Hao Huang, Jingshu Zeng, Xielan Kuang, Fan He, Jianjun Yan, Bowen Li, Wei Liu, Huangxuan Shen.

   BACKGROUND: The retinal pigment epithelium (RPE) is essential for retinal homeostasis. Comprehensively exploring the transcriptional patterns of diabetic human RPE promotes the understanding of diabetic retinopathy (DR).
METHODS AND RESULTS: A total of 4125 differentially expressed genes (DEGs) were screened out from the human primary RPE cells subjected to prolonged high glucose (HG). The subsequent bioinformatics analysis is divided into 3 steps. In Step 1, 21 genes were revealed by intersecting the enriched genes from the KEGG, WIKI, and Reactome databases. In Step 2, WGCNA was applied and intersected with the DEGs. Further intersection based on the enrichments with the GO biological processes, GO cellular components, and GO molecular functions databases screened out 12 candidate genes. In Step 3, 13 genes were found to be simultaneously up-regulated in the DEGs and a GEO dataset involving human diabetic retinal tissues. VEGFA and ERN1 were the 2 starred genes finally screened out by overlapping the 3 Steps.
CONCLUSION: In this study, multiple genes were identified as crucial in the pathological process of RPE under protracted HG, providing potential candidates for future researches on DR. The current study highlights the importance of RPE in DR pathogenesis.

Keywords:  Diabetic retinopathy (DR); High glucose (HG); Human primary retinal pigment epithelium (RPE); Transcriptional patterns

DOI:  https://doi.org/10.1007/s11033-024-09479-5
Front Ophthalmol (Lausanne). 2024 ;pii: 1355379. [Epub ahead of print]4

Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease.

Michael Landowski, Purnima Gogoi, Sakae Ikeda, Akihiro Ikeda.

  Aging is the most significant risk factor for age-related diseases in general, which is true for age-related diseases in the eye including age-related macular degeneration (AMD). Therefore, in order to identify potential therapeutic targets for these diseases, it is crucial to understand the normal aging process and how its mis-regulation could cause age-related diseases at the molecular level. Recently, abnormal lipid metabolism has emerged as one major aspect of age-related symptoms in the retina. Animal models provide excellent means to identify and study factors that regulate lipid metabolism in relation to age-related symptoms. Central to this review is the role of transmembrane protein 135 (TMEM135) in the retina. TMEM135 was identified through the characterization of a mutant mouse strain exhibiting accelerated retinal aging and positional cloning of the responsible mutation within the gene, indicating the crucial role of TMEM135 in regulating the normal aging process in the retina. Over the past decade, the molecular functions of TMEM135 have been explored in various models and tissues, providing insights into the regulation of metabolism, particularly lipid metabolism, through its action in multiple organelles. Studies indicated that TMEM135 is a significant regulator of peroxisomes, mitochondria, and their interaction. Here, we provide an overview of the molecular functions of TMEM135 which is crucial for regulating mitochondria, peroxisomes, and lipids. The review also discusses the age-dependent phenotypes in mice with TMEM135 perturbations, emphasizing the importance of a balanced TMEM135 function for the health of the retina and other tissues including the heart, liver, and adipose tissue. Finally, we explore the potential roles of TMEM135 in human age-related retinal diseases, connecting its functions to the pathobiology of AMD.

Keywords:  AMD; DHA; RPE; TMEM135; lipid; mitochondria; peroxisomes; photoreceptors

DOI:  https://doi.org/10.3389/fopht.2024.1355379