title: The study of the mechanism of arsenite toxicity in respiration-deficient cells reveals that NADPH oxidase-derived superoxide promotes the same downstream events mediated by mitochondrial superoxide in respiration-proficient cells.
abstract: We herein report the results from a comparative study of arsenite toxicity in respiration-proficient (RP) and -deficient (RD) U937 cells. An initial characterization of these cells led to the demonstration that the respiration-deficient phenotype is not associated with apparent changes in mitochondrial mass and membrane potential. In addition, similar levels of superoxide (O2(.-)) were generated by RP and RD cells in response to stimuli specifically triggering respiratory chain-independent mitochondrial mechanisms or extramitochondrial, NADPH-oxidase dependent, mechanisms. At the concentration of 2.5μM, arsenite elicited selective formation of O2(.-) in the respiratory chain of RP cells, with hardly any contribution of the above mechanisms. Under these conditions, O2(.-) triggered downstream events leading to endoplasmic reticulum (ER) stress, autophagy and apoptosis. RD cells challenged with similar levels of arsenite failed to generate O2(.-) because of the lack of a functional respiratory chain and were therefore resistant to the toxic effects mediated by the metalloid. Their resistance, however, was lost after exposure to four fold greater concentrations of arsenite, coincidentally with the release of O2(.-) mediated by NADPH oxidase. Interestingly, extramitochondrial O2(.-) triggered the same downstream events and an identical mode of death previously observed in RP cells. Taken together, the results obtained in this study indicate that arsenite toxicity is strictly dependent on O2(.-) availability that, regardless of whether generated in the mitochondrial or extramitochondrial compartments, triggers similar downstream events leading to ER stress, autophagy and apoptosis.
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", 61029 Urbino, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Guidarelli
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", 61029 Urbino, Italy.
authors.forename: Mara
authors.initials: M
authors.lastname: Fiorani
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", 61029 Urbino, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Carloni
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", 61029 Urbino, Italy.
authors.forename: Liana
authors.initials: L
authors.lastname: Cerioni
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", 61029 Urbino, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Balduini
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", 61029 Urbino, Italy. Electronic address: orazio.cantoni@uniurb.it.
authors.forename: Orazio
authors.initials: O
authors.lastname: Cantoni
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018053:Arsenites / Q000633:toxicity*; D001343:Autophagy; D019069:Cell Respiration; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D010101:Oxygen Consumption; D013481:Superoxides / Q000378:metabolism*; D020298:U937 Cells
chemical_list: D018053:Arsenites; D013481:Superoxides; D019255:NADPH Oxidases; C015001:arsenite
keywords: Apoptosis; Arsenite; Autophagy; ER Stress; Mitochondria; NADPH Oxidase; Superoxide