bims-mideyd 2023-04-23 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2023‒04‒23
six papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Tricin attenuates diabetic retinopathy by inhibiting oxidative stress and angiogenesis through regulating Sestrin2/Nrf2 signaling.
Lyso-globotriaosylsphingosine induces endothelial dysfunction via autophagy-dependent regulation of necroptosis.
Stem cell-derived retinal pigment epithelium cell therapy: Past and future directions.
Alteration of the MEK1/2-ERK1/2 Signaling Pathway in the Retina Associated with Age and Development of AMD-Like Retinopathy.
FRIENDLY is required for efficient dark-induced mitophagy and controlled senescence in Arabidopsis.
Watching the human retina breath in real time and the slowing of mitochondrial respiration with age.

Hum Exp Toxicol. 2023 Jan-Dec;42:42 9603271231171642

Tricin attenuates diabetic retinopathy by inhibiting oxidative stress and angiogenesis through regulating Sestrin2/Nrf2 signaling.

Xueli Yang, Dalei Li.

  To explore the potential function of tricin in diabetic retinopathy (DR) and investigate whether Sestrin2 is closely involved in DR. A single intraperitoneal injection of streptozotocin-induced diabetes model in Sprague-Dawley rats and a high glucose-induced retinal epithelial cell model in ARPE-19 cells were established. The retinas were removed and examined by hematoxylin-eosin (HE) staining and dihydroethidium (DHE) staining. The proliferation ability and reactive oxygen species (ROS) level of ARPE-19 cells were detected by 5-ethynyl-2'-deoxyuridine (EdU) and flow cytometry. Then, the content of superoxide dismutase (SOD), malonaldehyde (MDA), and glutathione peroxidase (GSH-Px) in serum or cell supernatant was tested using enzyme linked immunosorbent assay (ELISA). In addition, the expression of Sestrin2, nuclear factor erythroid-2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), platelet endothelial cell adhesion molecule-1 (CD31), and vascular endothelial growth factor receptor 2 (VEGFR2) in retina tissue or ARPE-19 cells were validated through western blot and immunofluorescence assays. With the increase of MDA and ROS concentration, Sestrin2 expression was downregulated significantly, and Nrf2 and HO-1 expression was also reduced in retina tissue or ARPE-19 cells of model group, whereas CD31 and VEGFR2 expression was upregulated. However, tricin ameliorated the oxidative stress and angiogenesis and rectified the abnormal expression of Sestrin2/Nrf2 in diabetic retinopathy. Further mechanistic studies showed that silence Sestrin2 reduced the protective effect of tricin on ARPE-19 cells, as well as abolished its regulating effect on the Nrf2 pathway. These results suggested that tricin inhibits oxidative stress and angiogenesis in retinal epithelial cells of DR rats via reinforcing Sestrin2/Nrf2 signaling.

Keywords:  Sestrin2/Nrf2; angiogenesis; diabetic retinopathy; oxidative stress; tricin

DOI:  https://doi.org/10.1177/09603271231171642
Korean J Physiol Pharmacol. 2023 May 01. 27(3): 231-240

Lyso-globotriaosylsphingosine induces endothelial dysfunction via autophagy-dependent regulation of necroptosis.

Ae-Rang Hwang, Seonghee Park, Chang-Hoon Woo.

  Fabry disease is a lysosomal storage disorder characterized by the lysosomal accumulations of glycosphingolipids in a variety of cytotypes, which include endothelial cells. The disease is inherited and originates from an error in glycosphingolipid catabolism caused by insufficient α-galactosidase A activity, which causes uncontrolled progressive storage of intracellular globotriaosylceramide (Gb3) in the vasculature and extracellular accumulation of lyso-Gb3 (a deacetylated soluble form of Gb3). Necrosis can lead to inflammation, which exacerbates necrosis and creates a positive feedback loop that triggers necroinflammation. However, the role played by necroptosis, a form of programmed necrotic cell death, in the cell-to-cell inflammatory reaction between epithelial and endothelial cells is unclear. Thus, the present study was undertaken to determine whether lyso-Gb3 induces necroptosis and whether necroptosis inhibition protects endothelial dysfunction against lyso-Gb3 inflamed retinal pigment epithelial cells. We found lyso-Gb3 induced necroptosis of a retinal pigment epithelial cell line (ARPE-19) in an autophagy-dependent manner and that conditioned media (CM) from ARPE-19 cells treated with lyso-Gb3 induced the necroptosis, inflammation, and senescence of human umbilical vein endothelial cells. In addition, a pharmacological study showed CM from lyso-Gb3 treated ARPE-19 cells induced endothelial necroptosis, inflammation, and senescence were significantly inhibited by an autophagy inhibitor (3-MA) and by two necroptosis inhibitors (necrostatin and GSK-872), respectively. These results demonstrate lyso-Gb3 induces necroptosis via autophagy and suggest that lyso-Gb3 inflamed retinal pigment epithelial cells trigger endothelial dysfunction via the autophagy-dependent necroptosis pathway. This study suggests the involvement of a novel autophagy-dependent necroptosis pathway in the regulation of endothelial dysfunction in Fabry disease.

Keywords:  Autophagy; Cellular senescence; Glycosphingolipids; Inflammation; Necroptosis

DOI:  https://doi.org/10.4196/kjpp.2023.27.3.231
Front Cell Dev Biol. 2023 ;11 1098406

Stem cell-derived retinal pigment epithelium cell therapy: Past and future directions.

Landon J Rohowetz, Peter Koulen.

  The eyes are relatively immune privileged organs, making them ideal targets for stem cell therapy. Researchers have recently developed and described straightforward protocols for differentiating embryonic and induced pluripotent stem cells into retinal pigment epithelium (RPE), making diseases affecting the RPE, such as age-related macular degeneration (AMD), viable targets for stem cell therapy. With the advent of optical coherence tomography, microperimetry, and various other diagnostic technologies, the ability to document disease progression and monitor response to treatments such as stem cell therapy has been significantly enhanced in recent years. Previous phase I/II clinical trials have employed various cell origins, transplant methods, and surgical techniques to identify safe and efficacious methods of RPE transplantation, and many more are currently underway. Indeed, findings from these studies have been promising and future carefully devised clinical trials will continue to enhance our understanding of the most effective methods of RPE-based stem cell therapy, with the hope to eventually identify treatments for disabling and currently incurable retinal diseases. The purpose of this review is to briefly outline existing outcomes from initial clinical trials, review recent developments, and discuss future directions of clinical research involving stem-cell derived RPE cell transplantation for retinal disease.

Keywords:  Stargardt disease; age-related macular degeneration (AMD); embryonic stem cell (ES cell); iPSC (induced pluripotent stem cell); retina; retinal pigment epithelium

DOI:  https://doi.org/10.3389/fcell.2023.1098406
Biochemistry (Mosc). 2023 Feb;88(2): 179-188

Alteration of the MEK1/2-ERK1/2 Signaling Pathway in the Retina Associated with Age and Development of AMD-Like Retinopathy.

Natalia A Muraleva, Nataliya G Kolosova.

  Age-related macular degeneration (AMD) is a complex neurodegenerative disease and a major cause of irreversible visual impairment in patients in developed countries. Although age is the greatest risk factor in AMD, molecular mechanisms involved in AMD remain unknown. Growing evidence shows that dysregulation of MAPK signaling contributes to aging and neurodegenerative diseases; however, the information on the role of MAPK upregulation in these processes is controversial. ERK1 and ERK2 participate in the maintenance of proteostasis through the regulation of protein aggregation induced by the endoplasmic reticulum stress and other stress-mediated cell responses. To assess the contribution of alterations in the ERK1/2 signaling to the AMD development, we compared age-associated changes in the activity of ERK1/2 signaling pathway in the retina of Wistar rats (control) and OXYS rats that develop AMD-like retinopathy spontaneously. The activity of the ERK1/2 signaling increased during physiological aging in the retina of Wistar rats. The manifestation and progression of the AMD-like pathology in the retina of OXYS rats was accompanied by hyperphosphorylation of ERK1/2 and MEK1/2, the key kinases of the ERK1/2 signaling pathway. The progression of the AMD-like pathology was also associated with the ERK1/2-dependent tau protein hyperphosphorylation and increase in the ERK1/2-dependent phosphorylation of alpha B crystallin at Ser45 in the retina.

Keywords:  ERK1/2 signaling pathway; OXYS rat; age-related macular degeneration; aging; alpha B crystallin; phosphorylation; tau protein

DOI:  https://doi.org/10.1134/S0006297923020025
Free Radic Biol Med. 2023 Apr 19. pii: S0891-5849(23)00377-5. [Epub ahead of print]

FRIENDLY is required for efficient dark-induced mitophagy and controlled senescence in Arabidopsis.

Sylwia M Kacprzak, Olivier Van Aken.

  Mitochondria play essential roles in plant metabolism, supporting both development and stress responses. To maintain a healthy pool of mitochondria, several quality control systems are in place. Selected degradation of mitochondria by autophagy -mitophagy- has been extensively studied in yeast and animals, but information on mitophagy components in plants is limited. The 'Friendly Mitochondria' (FRIENDLY; FMT) protein, homologous to 'clustered mitochondria protein homolog' CLU in animals, was recently suggested to mediate mitophagy of depolarized mitochondria. In this study, we evaluated the role of FMT in carbon starvation- and dark senescence-induced mitophagy in Arabidopsis. Using mitophagy flux assays, we show that loss of FMT results in decreased mitophagy during dark-induced senescence. Mitophagy induced by inhibition of Target of Rapamycin (TOR) signalling is also partially impaired in fmt mutants. The FMT protein is mostly localised in the cytosol, but we show that during darkness FMT is redistributed into speckles, some of which associate with mitochondria. Fmt mutants were initially identified for their abnormal mitochondrial morphology, with mitochondria often forming clusters. We found that dark senescence strongly increases the number and size of mitochondrial clusters in fmt mutants. In agreement with a role for FMT in mitophagy, we show that fmt mutants show accelerated senescence phenotypes comparable to autophagy 11 (atg11) mutants, but less prominent than in atg5 mutants. Furthermore, FMT prevents excessive dark-induced cell death and hydrogen peroxide production, and supports mitophagy and greening in etiolated seedlings. Our findings thus indicate that FMT contributes to mitophagy and provide evidence that mitophagy is required for controlled senescence and prevention of accelerated cell death. We propose that FMT mediates efficient mitophagy by preventing mitochondrial clustering, thereby allowing mitochondria to be captured more effectively by autophagosomes, rather than by acting as a direct mitophagy receptor.

Keywords:  Arabidopsis; Autophagy; Clustered mitochondria; Mitochondria oxidative stress; Mitophagy; Senescence

DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.04.007
Sci Rep. 2023 Apr 20. 13(1): 6445

Watching the human retina breath in real time and the slowing of mitochondrial respiration with age.

Pardis Kaynezhad, Ilias Tachtsidis, Sobha Sivaprasad, Glen Jeffery.

The retina has the greatest metabolic demand in the body particularly in dark adaptation when its sensitivity is enhanced. This requires elevated level of perfusion to sustain mitochondrial activity. However, mitochondrial performance declines with age leading to reduced adaptive ability. We assessed human retina metabolism in vivo using broad band near-infrared spectroscopy (bNIRS), which records colour changes in mitochondria and blood as retinal metabolism shifts in response to changes in environmental luminance. We demonstrate a significant sustained rise in mitochondrial oxidative metabolism in the first 3 min of darkness in subjects under 50 years old. This was not seen in those over 50 years. Choroidal oxygenation declines in < 50 s as mitochondrial metabolism increases, but gradually rises in the > 50 s. Significant group differences in blood oxygenation are apparent in the first 6 min, consistent with mitochondrial demand leading hemodynamic changes. A greater coupling between mitochondrial oxidative metabolism with hemodynamics is revealed in subjects older than 50, possibly due to reduced capacity in the older retina. Rapid in vivo assessment of retinal metabolism with bNIRS provides a route to understanding fundamental physiology and early identification of retinal disease before pathology is established.

DOI: https://doi.org/10.1038/s41598-023-32897-7