bims-mideyd 2024-09-01 papers

Issue of 2024‒09‒01
four papers selected by
Rajalekshmy “Raji” Shyam, Indiana University Bloomington

Int J Mol Sci. 2024 Aug 07. pii: 8626. [Epub ahead of print]25(16):

Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress.

Tsai-Hsuan Yang, Eugene Yu-Chuan Kang, Pei-Hsuan Lin, Benjamin Ben-Chi Yu, Jason Hung-Hsuan Wang, Vincent Chen, Nan-Kai Wang.

This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs' high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.

Keywords: antioxidants; autosomal dominant optic atrophy; gene therapy; glaucoma; metabolism; mitochondria; mitochondrial transplantation; oxidative stress; retinal ganglion cells; retinopathy

DOI: https://doi.org/10.3390/ijms25168626

Exp Eye Res. 2024 Aug 21. pii: S0014-4835(24)00277-X. [Epub ahead of print] 110056

MitoQ relieves mitochondrial dysfunction in UVA and cigarette smoke-induced Fuchs endothelial corneal dystrophy.

Sean T Bannon, Nathan Shatz, Raymond Wong, Mohit Parekh, Ula V Jurkunas.

Fuchs endothelial corneal dystrophy (FECD), a degenerative corneal condition, is characterized by the droplet-like accumulation of the extracellular matrix, known as guttae and progressive loss of corneal endothelial cells ultimately leading to visual distortion and glare. FECD can be influenced by environmental stressors and genetic conditions. However, the role of mitochondrial dysfunction for advancing FECD pathogenesis is not yet fully studied. Therefore, in the present study we sought to determine whether a combination of environmental stressors (ultraviolet-A (UVA) light and cigarette smoke condensate (CSC)) can induce mitochondrial dysfunction leading to FECD. We also investigated if MitoQ, a water-soluble antioxidant, can target mitochondrial dysfunction induced by UVA and CSC in human corneal endothelial cells mitigating FECD pathogenesis. We modeled the FECD by increasing exogenous oxidative stress with CSC (0.2%), UVA (25J/cm2) and a combination of UVA+CSC and performed a temporal analysis of their cellular and mitochondrial effects on HCEnC-21T immortalized cells in vitro before and after MitoQ (0.05 μM) treatment. Interestingly, we observed that a combination of UVA+CSC exposure increased mitochondrial ROS and fragmentation leading to a lower mitochondrial membrane potential and increased levels of cytochrome c release leading to apoptosis and cell death. MitoQ intervention successfully mitigated these effects and restored cell viability. The UVA+CSC model could be used to study stress induced mitochondrial dysfunction. Additionally, MitoQ can serve as a viable antioxidant in attenuating mitochondrial dysfunction, underscoring its potential as a molecular-focused treatment approach to combat FECD pathogenesis.

Keywords: Fuchs endothelial corneal dystrophy; MitoQ; cornea; corneal endothelium; eye; mitochondria

DOI: https://doi.org/10.1016/j.exer.2024.110056

Exp Eye Res. 2024 Aug 23. pii: S0014-4835(24)00281-1. [Epub ahead of print] 110060

The novel secretome ST266 activates Akt and protects against oxidative stress-mediated injury in human RPE and Müller cells.

Alan C Tang, Nicholas A Besley, Rose Trimpey-Warfhatig, Ping Yang, Howard Wessel, Larry Brown, Ziv Kirshner, Glenn J Jaffe.

Oxidative stress-mediated retinal pigment epithelial (RPE) cell damage is associated with age-related macular degeneration (AMD). ST266 is the biological secretome produced by a novel population of amnion-derived multipotent progenitor cells. Herein, we investigated the effect of ST266 on RPE cell injury induced by hydroquinone (HQ), a cigarette smoke related oxidant, hydrogen peroxide (H2O2) and all-trans retinal (atRal), a pro-oxidant component of the retinoid cycle. We additionally investigated its effect on Müller cell injury induced by H2O2. Cultured human RPE cells were pre-treated for 1 hour in the presence or absence of MK-2206, a protein kinase B (Akt) inhibitor, then treated with varying concentrations of HQ, H2O2, or atRal for 1.5 hours. Cultured human Müller cells (MIO-M1) were pre-treated for 1 hour in the presence or absence of MK-2206, then treated with varying concentrations of H2O2 for 1.5 hours. Media were then replaced with STM100 (control media into which the ST266 secretome proteins were collected) or ST266 at various times. Cell viability was determined with WST-1 reagent. Mitochondrial membrane potential (Δψm) was quantified by a fluorescence plate reader. The protein phosphorylation levels of Akt, glycogen synthase kinase 3 beta (GSK-3β), and p70 ribosomal S6 kinase (p70S6K) were measured by Western blot. ST266 significantly improved RPE and MIO-M1 cell viability that was reduced by oxidant exposure and improved oxidant-disrupted Δψm. In both cell types, ST266 induced phosphorylation of Akt, GSK-3β, and p70S6K. MK-2206 significantly eliminated ST266-mediated protein phosphorylation of Akt, GSK-3β, and p70S6K and abolished the ST266-protective effect on cell viability. In conclusion, ST266 activates Akt, protects against oxidative stress-mediated cell injury in an Akt-dependent manner, and improves Δψm, suggesting a potential role for ST266 therapy in treating retinal diseases such as AMD.

Keywords: Müller; age-related macular degeneration; all-trans retinal; hydrogen peroxide; hydroquinone; retinal pigment epithelial

DOI: https://doi.org/10.1016/j.exer.2024.110060

Biochem Biophys Res Commun. 2024 Aug 15. pii: S0006-291X(24)01094-5. [Epub ahead of print]739 150558

Sulindac prevents increased mitochondrial VDAC1 expression and cell surface mistargeting induced by pathological conditions in retinal cells.

Mohammad Tariq, Marie Sjögren, Albert Salehi.

Diabetic retinopathy (DR) continues to be the primary cause of vision loss in poorly controlled diabetic subjects. The molecular mechanisms underlying retinal pigment epithelium (RPE) cell dysfunction in DR still remain elusive. We investigated the role of mitochondrial volt-age-dependent anion channel 1 (VDAC1) in RPE dysfunction under glucotoxic and inflammatory conditions. Our results demonstrate that both glucotoxicity and cytokine treatment reduces cellular viability accompanied by increased VDAC1 and inducible nitric oxide synthase (iNOS) expression, concomitant with decreased expression of mitochondrial VDAC2 and constitutively ex-pressed endothelial NOS (eNOS). Increased VDAC1 expression during these conditions leads to its mistargeting to the cell surface, leading to ATP loss. Additionally, VDAC1 upregulation by glucotoxicity and inflammatory cytokines induces leakage of mitochondrial DNA (mtDNA) into the cytosol. Sulindac, a nonsteroidal anti-inflammatory agent, mitigates the adverse effects associated with increased VDAC1 level under pathophysiological conditions, by suppressing VDAC1 expression. The effect of sulindac on restoring cell viability could be comparably achieved only with VDAC1 inhibitor (VBIT-4) or VDAC1-specific antibody and not with the iNOS inhibitor aminoguanidine. Our findings suggest that sulindac's beneficial effects on ARPE-19 cell function are mediated by prevention of increased VDAC1 expression under pathological conditions, thus preventing mtDNA leakage and ATP loss, which are the key steps in induction of cellular inflammatory responses involved in the development of DR.

DOI: https://doi.org/10.1016/j.bbrc.2024.150558