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

• Published in: Biochemical and biophysical research communications Vol. 739; p. 150558
• Main Authors: Tariq, Mohammad, Sjögren, Marie, Salehi, Albert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.12.2024
• Subjects: Anti-Inflammatory Agents, Non-Steroidal - pharmacology; antibodies; Basic Medicine; Cell and Molecular Biology; Cell Line; Cell Survival - drug effects; cell viability; Cell- och molekylärbiologi; cytokines; cytosol; diabetic retinopathy; Diabetic Retinopathy - metabolism; Diabetic Retinopathy - pathology; DNA, Mitochondrial - genetics; DNA, Mitochondrial - metabolism; endothelial nitric oxide synthase; epithelium; Glucose - metabolism; Humans; inducible nitric oxide synthase; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; mitochondrial DNA; Nitric Oxide Synthase Type II - genetics; Nitric Oxide Synthase Type II - metabolism; nonsteroidal anti-inflammatory agents; Retinal Pigment Epithelium - cytology; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; vision; Voltage-Dependent Anion Channel 1 - genetics; Voltage-Dependent Anion Channel 1 - metabolism
• ISSN: 0006-291X; 1090-2104; 1090-2104
• DOI: 10.1016/j.bbrc.2024.150558

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. [Display omitted] •Hyperglycemia and inflammatory conditions leads to induction of iNOS expression and increased mitochondrial VDAC1 expression in ARPE-19 cells.•Increased VDAC1 expression leads to its cell surface mistargeting causing ATP loss and mitochondrial DNA (mtDNA) leakage in ARPE-19 cells.•Sulindac (a nonsteroidal anti-inflammatory agent) dose-dependently restored the decreased cell viability induced by glucotoxicity and inflammatory conditions in ARPE-19 cells.•Sulindac effectively prevented the rise in VDAC1 expression and its translocation to the cell membrane, thereby preventing ATP loss and mtDNA leakage under pathological conditions.•VDAC1 blockade by VBIT-4 or by VDAC1 specific antibody similar to sulindac restored the reduced cellular viability induced by glucotoxicity and inflammatory conditions.