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Regulation of the cardiac mitochondrial membrane potential by retinoids
Irina Korichneva1, John Waka, Ulrich Hammerling
1Program in Immunology, Sloan-Kettering Institute for Cancer Research, 1275 York Ave., New York, NY 10021, USA. korichni@mskcc.org
Abstract:
Cardiomyocytes suffering irreversible damage under oxidative stress during ischemia activate their suicide program. Mitochondria play a key role in this process, while they themselves are subject to regulation by a number of signaling pathways. We demonstrate here that retinoids influence mitochondrial function in cardiomyocytes. Depending on their chemical nature, retinoids can either ameliorate or exacerbate stress-related damage. Thus, vitamin A, retinol, was protective because retinol deprivation enhanced oxidative damage, as indicated by rapid loss of mitochondrial membrane potential. Supplementation with a physiological concentration of retinol reversed this effect. Anhydroretinol (AR), a known antagonist, which works by displacing retinol from the common binding sites on serine/threonine kinases, also caused mitochondrial membrane depolarization. The AR effect was both Ca(2+)-dependent and cyclosporin-sensitive, suggesting an upstream signaling mechanism rather than direct membrane effect. Our results agree with a model where retinol supports mitochondrial integrity by enabling upstream signaling processes. The consequences of disrupting these processes by AR are opening of the permeability transition pore, release of cytochrome c, and activation of the suicide program.
Insights
Retinoids impact heart cell mitochondria. Vitamin A (retinol) protects against oxidative stress, while anhydroretinol exacerbates damage by disrupting protective signaling pathways crucial for cell survival.
Area of Science:
- Cardiology
- Molecular Biology
- Cell Biology
Background:
- Oxidative stress during ischemia triggers cardiomyocyte apoptosis.
- Mitochondria are central to this process and are regulated by signaling pathways.
- Retinoids are known to influence cellular functions.
Purpose of the Study:
- To investigate the role of retinoids in regulating mitochondrial function in cardiomyocytes.
- To determine how different retinoids affect stress-induced damage in heart cells.
Main Methods:
- Assessment of mitochondrial membrane potential in cardiomyocytes under various retinoid conditions.
- Investigating the effects of retinol and anhydroretinol (AR) on oxidative stress.
- Examining calcium (Ca2+) dependence and cyclosporin sensitivity of AR effects.
Main Results:
- Retinol deprivation worsened oxidative damage and mitochondrial membrane potential loss.
- Physiological retinol concentrations protected against damage.
- Anhydroretinol caused mitochondrial depolarization, suggesting an upstream signaling disruption.
- AR's effects were Ca2+-dependent and cyclosporin-sensitive.
Conclusions:
- Retinol supports mitochondrial integrity in cardiomyocytes via upstream signaling.
- Anhydroretinol disrupts these pathways, leading to mitochondrial dysfunction and apoptosis.
- Retinoids represent a potential therapeutic target for managing ischemia-related heart damage.