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Optimized Automated Analysis of Live Neuronal Mitochondria Homeostasis Modulation by Isoform-Specific Retinoic Acid Receptors
Published on: July 28, 2023
Retinol induces permeability transition and cytochrome c release from rat liver mitochondria
Fábio Klamt1, Marcos Roberto de Oliveira, José Cláudio Fonseca Moreira
1Centro de Estudos em Estresse Oxidativo, Departamento de Bioquímica, ICBS/Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil. fklamt@terra.com.br
Abstract:
Biological actions of retinoids on modulation of cellular gene expression by nuclear receptors are widely known. Recently, extra-nuclear effects of retinoids have been proposed, but remain to be better elucidated. Considering that retinoids induce apoptosis in tumor cells by an unknown mechanism, and that mitochondria play a key role in controlling apoptosis via cytochrome c (cyt c) release, we exposed rat liver mitochondria to 3-40 microM of retinol (vitamin A), and observed that retinol causes mitochondrial permeability transition (MPT) and cyt c release, in a concentration-dependent pattern. Increased superoxide anion generation and lipoperoxidation were also observed. Cyclosporin A or trolox co-administration reverted all parameters tested. In view of these findings, we conclude that retinol induces mitochondria oxidative damage, leading to MPT and cyt c release by opening of the permeability transition pore, thus suggesting a putative mechanism of apoptosis activation by retinol.
Insights
Retinol (vitamin A) triggers cell death by damaging mitochondria, causing the release of cytochrome c. This suggests a new pathway for how vitamin A induces apoptosis in tumor cells.
Area of Science:
- Biochemistry
- Cell Biology
- Toxicology
Background:
- Retinoids are known for nuclear receptor-mediated gene expression.
- Extra-nuclear effects of retinoids, particularly in apoptosis, require further investigation.
- Mitochondria are critical in initiating apoptosis through cytochrome c release.
Purpose of the Study:
- To investigate the extra-nuclear effects of retinol on mitochondria.
- To elucidate the mechanism by which retinoids may induce apoptosis.
- To determine if retinol directly impacts mitochondrial function and integrity.
Main Methods:
- Isolated rat liver mitochondria were exposed to varying concentrations of retinol (3-40 microM).
- Mitochondrial permeability transition (MPT), cytochrome c release, superoxide anion generation, and lipoperoxidation were measured.
- Effects were assessed with and without co-administration of Cyclosporin A or trolox.
Main Results:
- Retinol induced MPT and cytochrome c release in a concentration-dependent manner.
- Increased superoxide anion generation and lipoperoxidation were observed with retinol exposure.
- Co-administration of Cyclosporin A or trolox prevented retinol-induced mitochondrial damage and cytochrome c release.
Conclusions:
- Retinol causes oxidative damage to mitochondria, leading to the opening of the permeability transition pore.
- This mitochondrial dysfunction and subsequent cytochrome c release suggest a mechanism for retinol-induced apoptosis.
- The findings highlight a potential extra-nuclear role for retinol in programmed cell death, particularly relevant for tumor cells.
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