bims-mideyd 2022-12-04 papers

bims-mideyd

Biomed News

on Mitochondrial dysfunction in eye diseases

Issue of 2022–12–04
seven papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Inhibition of cellular senescence hallmarks by mitochondrial transplantation in senescence-induced ARPE-19 cells.
Dissecting Regulators of Aging and Age-Related Macular Degeneration in the Retinal Pigment Epithelium.
Diosgenin protects retinal pigment epithelial cells from inflammatory damage and oxidative stress induced by high glucose by activating AMPK/Nrf2/HO-1 pathway.
Proteostasis in aging-associated ocular disease.
Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma.
Isozyme-specific histone deacetylase 1/2 inhibitor K560 attenuates oxidative stress-induced retinal cell death.
Noninvasive Delivery of Self-Regenerating Cerium Oxide Nanoparticles to Modulate Oxidative Stress in the Retina.

Neurobiol Aging. 2022 Nov 06. pii: S0197-4580(22)00231-7. [Epub ahead of print]121 157-165

Inhibition of cellular senescence hallmarks by mitochondrial transplantation in senescence-induced ARPE-19 cells.

Sung-Eun Noh, Seok Jae Lee, Tae Geol Lee, Kyu-Sang Park, Jeong Hun Kim.

  Retinal pigment epithelium (RPE) damage is a major factor in age-related macular degeneration (AMD). The RPE in AMD shows mitochondrial dysfunction suggesting an association of AMD with mitochondrial function. Therefore, exogenous mitochondrial transplantation for restoring and replacing dysfunctional mitochondria may be an effective therapeutic strategy for AMD. Here, we investigated the effects of extrinsic mitochondrial transplantation on senescence-induced ARPE-19 cells. We demonstrated mitochondrial dysfunction in replicative senescence-induced ARPE-19 cells after repeated passage. Imbalanced mitophagy and mitochondrial dynamics resulted in increased mitochondrial numbers and elevated levels of mitochondrial and intracellular reactive oxygen species. Exogenous mitochondrial transplantation improved mitochondrial dysfunction and alleviated cellular senescence hallmarks, such as increased cell size, increased senescence-associated β-galactosidase activity, augmented NF-κB activity, increased inflammatory cytokines, and upregulated the cyclin-dependent kinase inhibitors p21 and p16. Further, cellular senescence properties were improved by exogenous mitochondrial transplantation in oxidative stress-induced senescent ARPE-19 cells. These results indicate that exogenous mitochondrial transplantation modulates cellular senescence and may be considered a novel therapeutic strategy for AMD.

Keywords:  Age-related macular degeneration; Exogenous mitochondrial transplantation; Oxidative stress; Retinal pigment epithelium; Senescence

DOI:  https://doi.org/10.1016/j.neurobiolaging.2022.11.003
Oxid Med Cell Longev. 2022 ;2022 6009787

Dissecting Regulators of Aging and Age-Related Macular Degeneration in the Retinal Pigment Epithelium.

Pabalu P Karunadharma, Rebecca J Kapphahn, Madilyn R Stahl, Timothy W Olsen, Deborah A Ferrington.

Age-related macular degeneration (AMD), the leading cause of blindness in elderly populations, involves the loss of central vision due to progressive dysfunction of the retinal pigment epithelium (RPE) and subsequent loss of light-sensing photoreceptors. While age is a key risk factor, not every aged individual develops AMD. Thus, the critical question is what specific cellular changes tip the balance from healthy aging to disease. To distinguish between changes associated with aging and AMD, we compared the RPE proteome in human eye bank tissue from nondiseased donors during aging (n = 50, 29-91 years) and in donors with AMD (n = 36) compared to age-matched donors without disease (n = 28). Proteins from RPE cells were separated on two-dimensional gels, analyzed for content, and identified using mass spectrometry. A total of 58 proteins displayed significantly altered content with either aging or AMD. Proteins involved in metabolism, protein turnover, stress response, and cell death were altered with both aging and AMD. However, the direction of change was predominantly opposite. With aging, we detected an overall decrease in metabolism and reductions in stress-associated proteins, proteases, and chaperones. With AMD, we observed upregulation of metabolic proteins involved in glycolysis, TCA, and fatty acid metabolism, with a concurrent decline in oxidative phosphorylation, suggesting a reprogramming of energy utilization. Additionally, we detected upregulation of proteins involved in the stress response and protein turnover. Predicted upstream regulators also showed divergent results, with inhibition of inflammation and immune response with aging and activation of these processes with AMD. Our results support the idea that AMD is not simply advanced aging but rather the culmination of perturbed protein homeostasis, defective bioenergetics, and increased oxidative stress within the aging RPE, exacerbated by environmental factors and the genetic background of an individual.

DOI: https://doi.org/10.1155/2022/6009787
Immun Inflamm Dis. 2022 Dec;10(12): e698

Diosgenin protects retinal pigment epithelial cells from inflammatory damage and oxidative stress induced by high glucose by activating AMPK/Nrf2/HO-1 pathway.

Yang Hao, Xuefeng Gao.

   INTRODUCTION: Diosgenin is a natural steroidal compound with reported antidiabetic and many other protective properties. This study aimed to explore the protective effect of diosgenin on high-glucose (HG)-induced retinal pigment epithelial cells.
METHODS: HG-induced ARPE-19 cells were considered as a cell model of diabetic retinopathy (DR). The viability and apoptosis of ARPE-19 cells induced by HG treated with either diosgenin or Compound C (CC; dorsomorphin) were detected by Cell Counting Kit-8 assay and flow cytometric analysis. The expression of apoptosis-related proteins, inflammation-related proteins, and AMPK/Nrf2/HO-1 pathway-related proteins was detected by western blotting. The levels of inflammatory cytokines and detection of oxidative stress indexes were performed using the appropriate assay kits. The messenger RNA expression of inflammatory cytokines was detected by real-time quantitative polymerase chain reaction.
RESULTS: There was no obvious effect of diosgenin on the viability of ARPE-19 cells and the viability of ARPE-19 cells was significantly reduced after HG induction. However, diosgenin increased the viability, inhibited the apoptosis, and reduced the inflammatory response and oxidative stress of ARPE-19 cells induced by HG. In addition, diosgenin could activate the AMPK/Nrf2/HO-1 pathway. CC, an AMPK inhibitor, could reverse the above changes caused by diosgenin treatment in ARPE-19 cells induced by HG.
CONCLUSIONS: Diosgenin could protect ARPE-19 cells from inflammatory damage and oxidative stress induced by HG, by activating the AMPK/Nrf2/HO-1 pathway.

Keywords:  AMPK/Nrf2/HO-1 pathway; diosgenin; inflammatory damage; oxidative stress; retinal pigment epithelial cells

DOI:  https://doi.org/10.1002/iid3.698
Mol Aspects Med. 2022 Nov 29. pii: S0098-2997(22)00102-9. [Epub ahead of print]88 101157

Proteostasis in aging-associated ocular disease.

Jasper Weinberg, Mohita Gaur, Anand Swaroop, Allen Taylor.

  Vision impairment has devastating consequences for the quality of human life. The cells and tissues associated with the visual process must function throughout one's life span and maintain homeostasis despite exposure to a variety of insults. Maintenance of the proteome is termed proteostasis, and is vital for normal cellular functions, especially at an advanced age. Here we describe basic aspects of proteostasis, from protein synthesis and folding to degradation, and discuss the current status of the field with a particular focus on major age-related eye diseases: age-related macular degeneration, cataract, and glaucoma. Our intent is to allow vision scientists to determine where and how to harness the proteostatic machinery for extending functional homeostasis in the aging retina, lens, and trabecular meshwork. Several common themes have emerged despite these tissues having vastly different metabolisms. Continued exposure to insults, including chronic stress with advancing age, increases proteostatic burden and reduces the fidelity of the degradation machineries including the ubiquitin-proteasome and the autophagy-lysosome systems that recognize and remove damaged proteins. This "double jeopardy" results in an exponential accumulation of cytotoxic proteins with advancing age. We conclude with a discussion of the challenges in maintaining an appropriate balance of protein synthesis and degradation pathways, and suggest that harnessing proteostatic capacities should provide new opportunities to design interventions for attenuating age-related eye diseases before they limit sight.

Keywords:  Age-related macular degeneration; Aging; Autophagy; Cataract; Development; Diabetes; Glaucoma; Lens; Nutrition; Retina; Retinopathy; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.mam.2022.101157
J Clin Invest. 2022 Dec 01. pii: e156967. [Epub ahead of print]132(23):

Thrombospondin 1 missense alleles induce extracellular matrix protein aggregation and TM dysfunction in congenital glaucoma.

Haojie Fu, Owen M Siggs, Lachlan Sw Knight, Sandra E Staffieri, Jonathan B Ruddle, Amy E Birsner, Edward Ryan Collantes, Jamie E Craig, Janey L Wiggs, Robert J D'Amato.

  Glaucoma is a highly heritable disease that is a leading cause of blindness worldwide. Here, we identified heterozygous thrombospondin 1 (THBS1) missense alleles altering p.Arg1034, a highly evolutionarily conserved amino acid, in 3 unrelated and ethnically diverse families affected by congenital glaucoma, a severe form of glaucoma affecting children. Thbs1R1034C-mutant mice had elevated intraocular pressure (IOP), reduced ocular fluid outflow, and retinal ganglion cell loss. Histology revealed an abundant, abnormal extracellular accumulation of THBS1 with abnormal morphology of juxtacanalicular trabecular meshwork (TM), an ocular tissue critical for aqueous fluid outflow. Functional characterization showed that the THBS1 missense alleles found in affected individuals destabilized the THBS1 C-terminus, causing protein misfolding and extracellular aggregation. Analysis using a range of amino acid substitutions at position R1034 showed that the extent of aggregation was correlated with the change in protein-folding free energy caused by variations in amino acid structure. Extracellular matrix (ECM) proteins, especially fibronectin, which bind to THBS1, also accumulated within THBS1 deposits. These results show that missense variants altering THBS1 p.Arg1034 can cause elevated IOP through a mechanism involving impaired TM fluid outflow in association with accumulation of aggregated THBS1 in the ECM of juxtacanalicular meshwork with altered morphology.

Keywords:  Extracellular matrix; Ophthalmology

DOI:  https://doi.org/10.1172/JCI156967
Neurosci Lett. 2022 Nov 23. pii: S0304-3940(22)00539-0. [Epub ahead of print]793 136978

Isozyme-specific histone deacetylase 1/2 inhibitor K560 attenuates oxidative stress-induced retinal cell death.

Hiroshi Tawarayama, Yoshiyuki Hirata, Uchida Keiko, Noriko Himori, Shinichi Uesato, Toru Nakazawa.

  Oxidative stress-induced damage is an underlying mechanism in the pathogenesis of age-related retinal diseases. Here, we examined the effects of K560, a potential candidate drug for the treatment of these diseases, on oxidative stress-induced retinal cell death. K560 is a novel isozyme-specific inhibitor of histone deacetylase 1 and 2 (HDAC1/2). Histone acetylation in retinal lysates and dissociated retinal cells was detected with a western blot analysis and cell-based enzyme-linked immunosorbent assay (ELISA), respectively. The viability of mouse retinal cells was measured with an alamarBlue assay. We used immunohistochemistry for RNA binding protein with multiple splicing (RBPMS) to visualize the retinal ganglion cells (RGCs) of mice. An ELISA analysis indicated that histone acetylation was enhanced in dissociated mouse retinal cells treated with K560. The cell viability assay indicated that K560 attenuated both exogenous hydrogen peroxide-induced and endogenous oxidative stress-induced cell death in dissociated retinal cells. Western blot analysis indicated that intravitreal K560 administration enhanced the acetylation of histones H3 and H4 in mouse retinal lysates. To examine the effect of K560 on oxidative stress-induced RGC death, we performed whole-mount immunohistochemistry for RBPMS on retinas dissected from eyes treated with K560 or vehicle on day one, and K560 or vehicle and NMDA on day two. Quantification of RBPMS-immunopositive cells indicated that K560 attenuated NMDA-induced RGC death. Taken together, our findings suggest that administration of a HDAC1/2-specific inhibitor K560 may be effective in the treatment of oxidative stress-mediated retinal degeneration and have less cytotoxicity than other known HDAC inhibitors, which are known to target a wide range of HDAC family members.

Keywords:  HDAC1/2 inhibitor; K560; NMDA; Oxidative stress; Retinal cell death

DOI:  https://doi.org/10.1016/j.neulet.2022.136978
ACS Appl Bio Mater. 2022 Nov 28.

Noninvasive Delivery of Self-Regenerating Cerium Oxide Nanoparticles to Modulate Oxidative Stress in the Retina.

Crystal S Shin, Remya Ammassam Veettil, Tamil S Sakthivel, Aparna Adumbumkulath, Richard Lee, Mahira Zaheer, Elayaraja Kolanthai, Sudipta Seal, Ghanashyam Acharya.

  Diseases affecting the retina, such as age-related macular degeneration (AMD), diabetic retinopathy, macular edema, and retinal vein occlusions, are currently treated by the intravitreal injection of drug formulations. These disease pathologies are driven by oxidative damage due to chronic high concentrations of reactive oxygen species (ROS) in the retina. Intravitreal injections often induce retinal detachment, intraocular hemorrhage, and endophthalmitis. Furthermore, the severe eye pain associated with these injections lead to patient noncompliance and treatment discontinuation. Hence, there is a critical need for the development of a noninvasive therapy that is effective for a prolonged period for treating retinal diseases. In this study, we developed a noninvasive cerium oxide nanoparticle (CNP) delivery wafer (Cerawafer) for the modulation of ROS in the retina. We fabricated Cerawafer loaded with CNP and determined its SOD-like enzyme-mimetic activity and ability to neutralize ROS generated in vitro. We demonstrated Cerawafer's ability to deliver CNP in a noninvasive fashion to the retina in healthy mouse eyes and the CNP retention in the retina for more than a week. Our studies have demonstrated the in vivo efficacy of the Cerawafer to modulate ROS and associated down-regulation of VEGF expression in the retinas of very-low-density lipoprotein receptor knockout (vldlr-/-) mouse model. The development of a Cerawafer nanotherapeutic will fulfill a hitherto unmet need. Currently, there is no such therapeutic available, and the development of a Cerawafer nanotherapeutic will be a major advancement in the treatment of retinal diseases.

Keywords:  Cerium oxide; Macular degeneration; Nanoparticles; Nanowafer; Oxidative stress; Retina

DOI:  https://doi.org/10.1021/acsabm.2c00809