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More than\u00a0300 mutations in\n                    <jats:italic>POLG<\/jats:italic>\n                    , the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists\n                    <jats:sup>2<\/jats:sup>\n                    . Here we report on the discovery and characterization of PZL-A, a first-in-class small-molecule activator of mtDNA synthesis that is capable of restoring function to the most common mutant variants of POL\u03b3. PZL-A binds to an allosteric site at the interface between the catalytic POL\u03b3A subunit and the proximal POL\u03b3B subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POL\u03b3 in vitro and activates mtDNA synthesis in cells from paediatric patients with lethal\n                    <jats:italic>POLG<\/jats:italic>\n                    disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. Our work demonstrates that a small molecule can restore function to mutant DNA polymerases, offering a promising avenue for treating\n                    <jats:italic>POLG<\/jats:italic>\n                    disorders and other severe conditions linked to depletion of mtDNA.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-08856-9","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T11:03:34Z","timestamp":1744196614000},"page":"501-507","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Small molecules restore mutant mitochondrial DNA polymerase activity"],"prefix":"10.1038","volume":"642","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5153-8431","authenticated-orcid":false,"given":"Sebastian","family":"Valenzuela","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefeng","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertil","family":"Macao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mattias","family":"Stamgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Geukens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul S.","family":"Charifson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunther","family":"Kern","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Hoberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Jenninger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3060-4107","authenticated-orcid":false,"given":"Anja V.","family":"Gruszczyk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seoeun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8992-7631","authenticated-orcid":false,"given":"Katarina A. 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M.F., C.M.G., B.M., X.Z. and N.-G.L. are shareholders of Pretzel Therapeutics and have received consulting fees. S.V. has received consulting fees from Pretzel Therapeutics. M.S., C.G., A.V.G., J.M.F., Y.S., S.J.K., L.A., G.M.B., S.E., C.P.-H., T.A.K., B.K.-M., C.P., J.E.J., X.X. and S.G. are full-time employees of Pretzel Therapeutics and may hold stock or stock options as part of their compensation. V.P. is a former employee of Pretzel Therapeutics. P.S.C., A.M.G., G.K. and J.G. are consultants for Pretzel Therapeutics and hold stock or stock options as part of their compensation. The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}