bims-mideyd 2023-12-03 papers

Mitochondrion. 2023 Nov 27. pii: S1567-7249(23)00090-9. [Epub ahead of print]

Effect of Humanin G (HNG) on Angiogenesis and Neurodegeneration markers in Age-related Macular Degeneration (AMD).

Advanced stages of Age-related Macular Degeneration (AMD) are characterized by retinal neurodegeneration and aberrant angiogenesis, and mitochondrial dysfunction contributes to the pathogenesis of AMD. In this study, we tested the hypothesis that Humanin G (HNG), a cytoprotective Mitochondrial-Derived Peptide, positively regulates cell proliferation, cell death, and the protein levels of angiogenesis and neurodegeneration markers, in normal and AMD RPE transmitochondrial cybrid cells that had identical nuclei derived from mitochondria-deficient ARPE-19 cells but differed in mitochondrial DNA (mtDNA) content derived from clinically characterized AMD patients and normal (control) subjects. Cell lysates were extracted from untreated and HNG-treated AMD and normal (control) cybrids, and the Luminex XMAP multiplex assay was used to measure the protein levels of angiogenesis and neurodegeneration markers. HNG reduced Caspase-3/7-mediated apoptosis, improved cell proliferation, and normalized the protein levels of angiogenesis and neurodegeneration markers in AMD RPE cybrid cells, thereby suggesting its positive regulatory role in AMD.

Keywords: Age-relatedMacularDegeneration(AMD); Angiogenesis; Apoptosis; Humanin G; Neurodegeneration

DOI: https://doi.org/10.1016/j.mito.2023.11.001

Sci Rep. 2023 Nov 30. 13(1): 21143

Oxidative stress and docosahexaenoic acid injury lead to increased necroptosis and ferroptosis in retinal pigment epithelium.

Almar Neiteler, Anwar A Palakkan, Kevin M Gallagher, James A Ross.

Age-related macular degeneration (AMD) is a complex disease caused by different genetic and environmental risk factors leading to loss of cells in the central part of the retina. Oxidative stress appears to be an important environmental risk factor that contributes to both the initiation and progression of AMD. Retinal pigment epithelium (RPE) plays an important role in regulating oxidative stress in the retina and is one of the main retinal cell types affected in AMD. A main function of RPE is to phagocytose photoreceptor outer segments (POS) which are rich in the polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA), making this cell type potentially more susceptible to oxidative stress-induced lipid peroxidation which can lead to cell death. RPE is known to undergo necrotic cell death in response to oxidative stress. The aim of this study was to determine if DHA in POS can increase oxidative damage to RPE. It was found that RPE undergo increased lipid peroxidation and decreased cell viability when stressed with hydrogen peroxide in combination with DHA or POS. H2O2-induced oxidative stress was found to cause both ferroptosis and necroptosis. However, the ferroptosis regulator acyl-CoA synthetase long-chain family member 4 (ACSL4) was found to be downregulated in RPE exposed to H2O2 and this effect was exacerbated when the RPE cells were simultaneously treated with DHA. Together, these results show a response of RPE when stressed which will likely be overwhelmed under disease conditions such as AMD resulting in cell death.

DOI: https://doi.org/10.1038/s41598-023-47721-5

Front Cell Dev Biol. 2023 ;11 1244765

The many faces of SIRT6 in the retina and retinal pigment epithelium.

Jie Cheng, Casey J Keuthan, Noriko Esumi.

Sirtuin 6 (SIRT6) is a member of the mammalian sirtuin family of NAD+-dependent protein deacylases, homologues of the yeast silent information regulator 2 (Sir2). SIRT6 has remarkably diverse functions and plays a key role in a variety of biological processes for maintaining cellular and organismal homeostasis. In this review, our primary aim is to summarize recent progress in understanding SIRT6's functions in the retina and retinal pigment epithelium (RPE), with the hope of further drawing interests in SIRT6 to increase efforts in exploring the therapeutic potential of this unique protein in the vision field. Before describing SIRT6's role in the eye, we first discuss SIRT6's general functions in a wide range of biological contexts. SIRT6 plays an important role in gene silencing, metabolism, DNA repair, antioxidant defense, inflammation, aging and longevity, early development, and stress response. In addition, recent studies have revealed SIRT6's role in macrophage polarization and mitochondrial homeostasis. Despite being initially understudied in the context of the eye, recent efforts have begun to elucidate the critical functions of SIRT6 in the retina and RPE. In the retina, SIRT6 is essential for adult retinal function, regulates energy metabolism by suppressing glycolysis that affects photoreceptor cell survival, protects retinal ganglion cells from oxidative stress, and plays a role in Müller cells during early neurodegenerative events in diabetic retinopathy. In the RPE, SIRT6 activates autophagy in culture and protects against oxidative stress in mice. Taken together, this review demonstrates that better understanding of SIRT6's functions and their mechanisms, both in and out of the context of the eye, holds great promise for the development of SIRT6-targeted strategies for prevention and treatment of blinding eye diseases.

Keywords: SIRT6; glucose metabolism; oxidative stress; protein deacylase; retina; retinal pigment epithelium

DOI: https://doi.org/10.3389/fcell.2023.1244765

Regen Ther. 2023 Dec;24 592-601

Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy.

Saki Sakakura, Emi Inagaki, Tomoko Sayano, Risa Yamazaki, Noemi Fusaki, Shin Hatou, Masatoshi Hirayama, Kazuo Tsubota, Kazuno Negishi, Hideyuki Okano, Shigeto Shimmura.

Introduction: Fuchs endothelial corneal dystrophy (FECD) is the leading cause of corneal blindness in developed countries. Corneal endothelial cells in FECD are susceptive to oxidative stress, leading to mitochondrial dysfunction and cell death. Oxidative stress causes many forms of cell death including parthanatos, which is characterized by translocation of apoptosis-inducing factor (AIF) to the nucleus with upregulation of poly (ADP-ribose) polymerase 1 (PARP-1) and poly (ADP-ribose) (PAR). Although cell death is an important aspect of FECD, previous reports have often analyzed immortalized cell lines, making the evaluation of cell death difficult. Therefore, we established a new in vitro FECD model to evaluate the pathophysiology of FECD.
Methods: Corneal endothelial cells were derived from disease-specific induced pluripotent stem cells (iPSCs). Hydrogen peroxide (H2O2) was used as a source for oxidative stress to mimic the pathophysiology of FECD. We investigated the responses to oxidative stress and the involvement of parthanatos in FECD-corneal endothelial cells.
Results: Cell death ratio and oxidative stress level were upregulated in FECD with H2O2 treatment compared with non-FECD control, indicating the vulnerability of oxidative stress in FECD. We also found that intracellular PAR, as well as PARP-1 and AIF in the nucleus were upregulated in FECD. Furthermore, PARP inhibition, but not pan-caspase inhibition, rescued cell death, DNA double-strand breaks, mitochondrial membrane potential depolarization and energy depletion, suggesting that cell death was mainly due to parthanatos.
Conclusions: We report that parthanatos may be involved in the pathophysiology of FECD and targeting this cell death pathway may be a potential therapeutic approach for FECD.

Keywords: Cell death; Fuchs' endothelial corneal dystrophy; Induced pluripotent stem cells; Mitochondria; Oxidative stress; Parthanatos

DOI: https://doi.org/10.1016/j.reth.2023.11.001