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

Tariq, Mohammad LU ; Sjögren, Marie LU and Salehi, Albert LU orcid (2024) In Biochemical and Biophysical Research Communications 739.
Abstract

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... (More)

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.

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publication status
published
subject
in
Biochemical and Biophysical Research Communications
volume
739
article number
150558
publisher
Elsevier
external identifiers
  • scopus:85201778574
  • pmid:39181068
ISSN
0006-291X
DOI
10.1016/j.bbrc.2024.150558
language
English
LU publication?
yes
id
a1a907f4-465e-46be-9182-239101eddd54
date added to LUP
2024-10-28 13:21:34
date last changed
2025-07-08 11:30:51
@article{a1a907f4-465e-46be-9182-239101eddd54,
  abstract     = {{<p>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.</p>}},
  author       = {{Tariq, Mohammad and Sjögren, Marie and Salehi, Albert}},
  issn         = {{0006-291X}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Biochemical and Biophysical Research Communications}},
  title        = {{Sulindac prevents increased mitochondrial VDAC1 expression and cell surface mistargeting induced by pathological conditions in retinal cells}},
  url          = {{http://dx.doi.org/10.1016/j.bbrc.2024.150558}},
  doi          = {{10.1016/j.bbrc.2024.150558}},
  volume       = {{739}},
  year         = {{2024}},
}