Arsenite impinges on endoplasmic reticulum-mitochondria crosstalk to elicit mitochondrial ROS formation and downstream toxicity. (November 2021)

• Record Type: Journal Article
• Authors: Cantoni, Orazio; Zito, Ester; Fiorani, Mara; Guidarelli, Andrea
• Is Part Of: Seminars in cancer biology. Volume 76(2021)
• Page Start: 132
• Page End: 138
• Publication Date: 2021-11
• Subjects: Arsenite -- Inositol-1, 4, 5-triphosphate receptor -- Ryanodine receptor -- Mitochondrial Ca2+ -- Mitochondrial superoxide; Cancer -- Periodicals; Neoplasms -- Periodicals; Review Literature; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.semcancer.2021.06.002
• Languages: English
• ISSNs: 1044-579X

Abstract

Abstract: Arsenite is an important carcinogen and toxic compound, causing various deleterious effects through multiple mechanisms. In this review, we focused on mitochondrial ROS (mitoROS) and discussed on the mechanisms mediating their formation. The metalloid promotes direct effects in mitochondria, resulting in superoxide formation only under conditions of increased mitochondrial Ca 2+ concentration ([Ca 2+ ]m ). In this perspective, the time of exposure and concentration requirements for arsenite were largely conditioned by other effects of the metalloid in specific sites of the endoplasmic reticulum (ER). Arsenite induced a slow and limited mobilization of Ca 2+ from IP3 R via a saturable mechanism, failing to increase the [Ca 2+ ]m . This effect was however associated with the triggering of an intraluminal crosstalk between the IP3 R and the ryanodine receptor (RyR), causing a large and concentration dependent release of Ca 2+ from RyR and a parallel increase in [Ca 2+ ]m . Thus, the Ca 2+ -dependent mitoO2 −. formation appears to be conditioned by the spatial/functional organization of the ER/mitochondria network and RyR expression. We also speculate on the possibility that the ER stress response might regulate the above effects on the intraluminal crosstalk between the IP3 R and the RyR via oxidation of critical thiols mediated by the H2 O2 locally released by oxidoreductin 1α.