{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:27:50Z","timestamp":1785511670215,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"US Army Medical Research Command","award":["W81XWH2110402"],"award-info":[{"award-number":["W81XWH2110402"]}]},{"name":"Henry L. Brasza endowment at Wayne State University","award":["W81XWH2110402"],"award-info":[{"award-number":["W81XWH2110402"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The mitochondrial regulator MNRR1 is reduced in several pathologies, including the mitochondrial heteroplasmic disease MELAS, and genetic restoration of its level normalizes the pathological phenotype. Here, we investigate the upstream mechanism that reduces MNRR1 levels. We have identified the hypoxic regulator HIF2\u03b1 to bind the MNRR1 promoter and inhibit transcription by competing with RBPJ\u03ba. In MELAS cells, there is a pseudohypoxic state that transcriptionally induces HIF2\u03b1 and stabilizes HIF2\u03b1 protein. MELAS cybrids harboring the m.3243A &gt; G mutation display reduced levels of prolyl hydroxylase 3 (PHD3), which contributes to the HIF2\u03b1 stabilization. These results prompted a search for compounds that could increase MNRR1 levels pharmacologically. The screening of a 2400-compound library uncovered the antifungal drug nitazoxanide and its metabolite tizoxanide as enhancers of MNRR1 transcription. We show that treating MELAS cybrids with tizoxanide restores cellular respiration, enhances mitophagy, and, importantly, shifts heteroplasmy toward wild-type mtDNA. Furthermore, in fibroblasts from MELAS patients, the compound improves mitochondrial biogenesis, enhances autophagy, and protects from LPS-induced inflammation. Mechanistically, nitazoxanide reduces HIF2\u03b1 levels by increasing PHD3. Chemical activation of MNRR1 is thus a potential strategy to improve mitochondrial deficits seen in MELAS. Finally, our data suggests a broader physiological pathway wherein two proteins, induced under severe (1% O2; HIF2\u03b1) and moderate (4% O2; MNRR1) hypoxic conditions, regulate each other inversely.<\/jats:p>","DOI":"10.3390\/cells14141078","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:45:52Z","timestamp":1752572752000},"page":"1078","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pseudohypoxia-Stabilized HIF2\u03b1 Transcriptionally Inhibits MNRR1, a Druggable Target in MELAS"],"prefix":"10.3390","volume":"14","author":[{"given":"Neeraja","family":"Purandare","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3477-4659","authenticated-orcid":false,"given":"Vignesh","family":"Pasupathi","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram","family":"Rajan","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8472-7672","authenticated-orcid":false,"given":"Caleb","family":"Vegh","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Firestine","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamas","family":"Kozicz","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2046-1600","authenticated-orcid":false,"given":"Andrew M.","family":"Fribley","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"},{"name":"Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1059-9358","authenticated-orcid":false,"given":"Lawrence I.","family":"Grossman","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siddhesh","family":"Aras","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, MI 48201, USA"},{"name":"Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"},{"name":"Department of Obstetrics and Gynecology, School of Medicine, Wayne State University, Hutzel Women\u2019s Hospital 3990 John R. Street, 7 Brush North, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1083\/jcb.19.3.613","article-title":"Intramitochondrial Fibers with DNA Characteristics. Ii. Enzymatic and Other Hydrolytic Treatments","volume":"19","author":"Nass","year":"1963","journal-title":"J. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1083\/jcb.19.3.593","article-title":"Intramitochondrial Fibers with DNA Characteristics. I. Fixation and Electron Staining Reactions","volume":"19","author":"Nass","year":"1963","journal-title":"J. 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