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This is striking, given that both factors are involved in cancer cell regulation and metabolism. Mitochondria (mt) dysfunction is one of the main drivers of cancer, producing more mitochondria, higher cellular energy, and ROS that can enhance oxidative stress and stress tolerance responses. To study the effects of 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D on metabolic and mt dysfunction, we used the vitamin D receptor (VDR)\u2010sensitive MG\u201063 osteosarcoma cell model. Using biochemical approaches, 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D decreased mt ROS levels, membrane potential (\u0394\u03a8\n                    <jats:sub>mt<\/jats:sub>\n                    ), biogenesis, and translation, while enforcing endoplasmic reticulum\/mitohormetic stress adaptive responses. Using a mitochondria\u2010focused transcriptomic approach, gene set enrichment and pathway analyses show that 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D lowered mt fusion\/fission and oxidative phosphorylation (OXPHOS). By contrast, mitophagy, ROS defense, and epigenetic gene regulation were enhanced after 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D treatment, as well as key metabolic enzymes that regulate fluxes of substrates for cellular architecture and a shift toward non\u2010oxidative energy metabolism. ATACseq revealed putative oxi\u2010sensitive and tumor\u2010suppressing transcription factors that may regulate important mt functional genes such as the mTORC1 inhibitor,\n                    <jats:italic>DDIT4\/REDD1<\/jats:italic>\n                    . DDIT4\/REDD1 was predominantly localized to the outer mt membrane in untreated MG\u201063 cells yet sequestered in the cytoplasm after 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D and rotenone treatments, suggesting a level of control by membrane depolarization to facilitate its cytoplasmic mTORC1 inhibitory function. The results show that 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D activates distinct adaptive metabolic responses involving mitochondria to regain redox balance and control the growth of osteosarcoma cells. \u00a9 2021 The Authors.\n                    <jats:italic>JBMR Plus<\/jats:italic>\n                    published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.\n                  <\/jats:p>","DOI":"10.1002\/jbm4.10572","type":"journal-article","created":{"date-parts":[[2021,10,25]],"date-time":"2021-10-25T05:40:19Z","timestamp":1635140419000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Vitamin D Modulation of Mitochondrial Oxidative Metabolism and\n                    <scp>mTOR<\/scp>\n                    Enforces Stress Adaptations and Anticancer Responses"],"prefix":"10.1093","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5143-9879","authenticated-orcid":false,"given":"Mikayla","family":"Quigley","sequence":"first","affiliation":[{"name":"Biology Department University of Miami Coral Gables FL USA"},{"name":"Dana Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Rieger","sequence":"additional","affiliation":[{"name":"Biology Department University of Miami Coral Gables FL USA"},{"name":"Sylvester Comprehensive Cancer Center, Miller School of Medicine University of Miami Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Capobianco","sequence":"additional","affiliation":[{"name":"Institute for Data Science and Computing University of Miami Coral Gables FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Computer Science University of Miami Coral Gables FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengguang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Dermatology The First Affiliated Hospital of Chongqing Medical University Chongqing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5806-9690","authenticated-orcid":false,"given":"Martin","family":"Hewison","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems Research University of Birmingham Birmingham UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5557-3904","authenticated-orcid":false,"given":"Thomas S","family":"Lisse","sequence":"additional","affiliation":[{"name":"Biology Department 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