Vitamin A and Retinoids as Mitochondrial Toxicants

Abstract

Vitamin A and its derivatives, the retinoids, are micronutrient necessary for the human diet in order to maintain several cellular functions from human development to adulthood and also through aging. Furthermore, vitamin A and retinoids are utilized pharmacologically in the treatment of some diseases, as, for instance, dermatological disturbances and some types of cancer. In spite of being an essential micronutrient with clinical application, vitamin A exerts several toxic effects regarding redox environment and mitochondrial function. Moreover, decreased life quality and increased mortality rates among vitamin A supplements users have been reported. However, the exact mechanism by which vitamin A elicits its deleterious effects is not clear yet. In this review, the role of mitochondrial dysfunction in the mechanism of vitamin A-induced toxicity is discussed.

Figure 1

A schematic diagram summarizing the effects of in vivo vitamin A supplementation on mitochondrial function regarding the mitochondrial electron transfer chain (METC) enzyme activity. Mitochondrial dysfunction may lead to increased O₂ ^−• production through electron leakage and partial reduction of O₂. Mn-SOD converts O₂ ^−• to H₂O₂ and, together with MAO, favors an increase in the levels of H₂O₂ in different cell types (please see text for details). H₂O₂ is able to react with iron ions generating ^•OH (the most powerful ROS) through Fenton chemistry reaction (not shown), for example, leading to widespread redox disturbances.

Figure 2

Unbalanced SOD/CAT ratio resulting in increased H₂O₂ production. Additionally, increased O₂ ^−• levels inhibit CAT enzyme activity allosterically leading to even more high H₂O₂ concentration due to accumulation of this ROS.

Figure 3

A general view of the effects of in vivo vitamin A supplementation in an animal experimental model. It has been hypothesized that vitamin A may induce mitochondrial dysfunction by different ways as follows: (1) by decreasing BDNF levels, (2) by inducing ER stress and calcium ion metabolism deregulation, and/or (3) by increasing α-synuclein levels. The increased O₂ ^−• levels may induce redox unbalance in the organelle that, in turn, may generate more O₂ ^−• in a vicious cycle. Increased H₂O₂ production (by Mn-SOD and MAO enzymes) may disseminate redox impairment from one region to another.

Figure 4

A general view of the consequences of in vivo vitamin A supplementation on the susceptibility of mitochondria to ex vivo challenges with different chemical agents. Mitochondria isolated from vitamin A-treated rats are more sensitive to different chemical insults including amyloid β, H₂O₂, and CaCl₂, as discussed in the text.