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This study enhances our understanding of these mechanisms by demonstrating that exposure to 1 \u00b5M ATO initiates a biphasic Ca\n                    <jats:sup>2+<\/jats:sup>\n                    release: an initial flux from inositol 1,4,5-trisphosphate receptors (IP\u2083Rs), followed by a secondary release via ryanodine receptors (RyRs). Unlike IP\n                    <jats:sub>3<\/jats:sub>\n                    R-derived Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , the fraction of the cation released through RyRs is subsequently taken up by mitochondria. Notably, IP\n                    <jats:sub>3<\/jats:sub>\n                    R-derived Ca\n                    <jats:sup>2+<\/jats:sup>\n                    uniquely activates NADPH oxidase 2 (NOX 2), a key event leading to the downstream generation of mitochondrial superoxide\u00a0(mitoO\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>.\u2212<\/jats:sup>\n                    ). Importantly, mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    accumulation itself is not required for mitoO\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>.\u2212<\/jats:sup>\n                    emission. ATO-induced genomic DNA strand breaks are mediated by NOX 2-derived reactive oxygen species (ROS), both directly and indirectly, through the subsequent induction of mitochondrial ROS formation. Furthermore, mitochondrial uptake of RyR-derived Ca\n                    <jats:sup>2+<\/jats:sup>\n                    is essential for triggering the mitochondrial permeability transition and the ensuing apoptotic cell death. Although sodium arsenite elicited comparable effects on Ca\n                    <jats:sup>2+<\/jats:sup>\n                    homeostasis, it promoted mitoO\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>.\u2212<\/jats:sup>\n                    generation via a distinct, NOX 2-independent pathway that relied on RyR-mediated mitochondrial Ca\n                    <jats:sup>2+<\/jats:sup>\n                    accumulation. Thus, in NB4 cells, ATO exposure orchestrates a functional crosstalk between discrete Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sources to regulate a cascade of events culminating in NOX 2 activation, mitoO\n                    <jats:sub>2<\/jats:sub>\n                    <jats:sup>.\u2212<\/jats:sup>\n                    production, and initiation of the mitochondrial apoptotic pathway.\n                  <\/jats:p>","DOI":"10.1007\/s00204-026-04328-9","type":"journal-article","created":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T18:31:19Z","timestamp":1776105079000},"page":"2995-3010","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distinct Ca2+ pools regulate NADPH oxidase 2 activation driving Ca2+-independent mitochondrial ROS formation and mitochondrial permeability transition in arsenic trioxide-treated NB4 cells"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8621-3223","authenticated-orcid":false,"given":"Andrea","family":"Guidarelli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Spina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Buffi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mara","family":"Fiorani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orazio","family":"Cantoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"issue":"4","key":"4328_CR1","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1152\/physrev.00006.2016","volume":"96","author":"MJ Berridge","year":"2016","unstructured":"Berridge MJ (2016) The inositol trisphosphate\/calcium signaling pathway in health and disease. 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