{"entity": "researcher", "timestamp": "2026-06-08T05:55:48.130Z", "family": "Valenzuela", "given": "Sebastian", "initials": "S", "orcid": "0000-0001-5153-8431", "affiliations": ["Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Medicinaregatan 9A, P.O. Box 440, 41390, Gothenburg, Sweden."], "links": {"self": {"href": "https://publications.scilifelab.se/researcher/16c5cd1a4e8a4d9389514f33049240a5.json"}, "display": {"href": "https://publications.scilifelab.se/researcher/16c5cd1a4e8a4d9389514f33049240a5"}}, "publications": [{"entity": "publication", "iuid": "c466edad3243407ba07ae58843066301", "links": {"self": {"href": "https://publications.scilifelab.se/publication/c466edad3243407ba07ae58843066301.json"}, "display": {"href": "https://publications.scilifelab.se/publication/c466edad3243407ba07ae58843066301"}}, "title": "Small molecules restore mutant mitochondrial DNA polymerase activity.", "authors": [{"family": "Valenzuela", "given": "Sebastian", "initials": "S", "orcid": "0000-0001-5153-8431", "researcher": {"href": "https://publications.scilifelab.se/researcher/16c5cd1a4e8a4d9389514f33049240a5.json"}}, {"family": "Zhu", "given": "Xuefeng", "initials": "X"}, {"family": "Macao", "given": "Bertil", "initials": "B"}, {"family": "Stamgren", "given": "Mattias", "initials": "M"}, {"family": "Geukens", "given": "Carol", "initials": "C"}, {"family": "Charifson", "given": "Paul S", "initials": "PS"}, {"family": "Kern", "given": "Gunther", "initials": "G"}, {"family": "Hoberg", "given": "Emily", "initials": "E"}, {"family": "Jenninger", "given": "Louise", "initials": "L"}, {"family": "Gruszczyk", "given": "Anja V", "initials": "AV", "orcid": "0000-0003-3060-4107", "researcher": {"href": "https://publications.scilifelab.se/researcher/57299dfd50ed45219e6d9f9765f6cd12.json"}}, {"family": "Lee", "given": "Seoeun", "initials": "S"}, {"family": "Johansson", "given": "Katarina A S", "initials": "KAS", "orcid": "0009-0005-8992-7631", "researcher": {"href": "https://publications.scilifelab.se/researcher/d3bac3ed243c4f0493e0d494f79a7ca2.json"}}, {"family": "Miralles Fust\u00e9", "given": "Javier", "initials": "J", "orcid": "0000-0001-8818-9650", "researcher": {"href": "https://publications.scilifelab.se/researcher/2dcf35ce5b204221b2167f281ce219b3.json"}}, {"family": "Shi", "given": "Yonghong", "initials": "Y"}, {"family": "Kerns", "given": "S Jordan", "initials": "SJ"}, {"family": "Arabanian", "given": "Laleh", "initials": "L"}, {"family": "Martinez Botella", "given": "Gabriel", "initials": "G"}, {"family": "Ekstr\u00f6m", "given": "Sofie", "initials": "S"}, {"family": "Green", "given": "Jeremy", "initials": "J", "orcid": "0000-0003-4544-6412", "researcher": {"href": "https://publications.scilifelab.se/researcher/91088e7b066944c7b415aa1b18632c44.json"}}, {"family": "Griffin", "given": "Andrew M", "initials": "AM"}, {"family": "Pardo-Hern\u00e1ndez", "given": "Carlos", "initials": "C"}, {"family": "Keating", "given": "Thomas A", "initials": "TA", "orcid": "0009-0009-1386-2471", "researcher": {"href": "https://publications.scilifelab.se/researcher/52c4d61c63fe4129b9d06c0758c6cef9.json"}}, {"family": "K\u00fcppers-Munther", "given": "Barbara", "initials": "B"}, {"family": "Larsson", "given": "Nils-G\u00f6ran", "initials": "NG", "orcid": "0000-0001-5100-996X", "researcher": {"href": "https://publications.scilifelab.se/researcher/1dc68aa2893a4ab8845fc32d8d6bc59a.json"}}, {"family": "Phan", "given": "Cindy", "initials": "C"}, {"family": "Posse", "given": "Viktor", "initials": "V", "orcid": "0000-0003-4936-4967", "researcher": {"href": "https://publications.scilifelab.se/researcher/2bd6a8d4e0f94ea090d12a376b17876a.json"}}, {"family": "Jones", "given": "Juli E", "initials": "JE"}, {"family": "Xie", "given": "Xie", "initials": "X"}, {"family": "Giroux", "given": "Simon", "initials": "S", "orcid": "0000-0003-1499-2576", "researcher": {"href": "https://publications.scilifelab.se/researcher/7dbcb75a94a24eff8dd3737366bb3423.json"}}, {"family": "Gustafsson", "given": "Claes M", "initials": "CM", "orcid": "0000-0003-3531-8468", "researcher": {"href": "https://publications.scilifelab.se/researcher/2851656430d147dab7a8a32e50fee7b7.json"}}, {"family": "Falkenberg", "given": "Maria", "initials": "M", "orcid": "0000-0001-8713-173X", "researcher": {"href": "https://publications.scilifelab.se/researcher/562109b99a5c4eb3bd8b92f30014828b.json"}}], "type": "journal article", "published": "2025-06-00", "journal": {"title": "Nature", "issn": "1476-4687", "volume": "642", "issue": "8067", "pages": "501-507", "issn-l": "0028-0836"}, "abstract": "Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase \u03b3 (POL\u03b3), a heterotrimeric complex consisting of a catalytic POL\u03b3A subunit and two accessory POL\u03b3B subunits1. More than 300 mutations in POLG, the gene encoding the catalytic subunit, have been linked to severe, progressive conditions with high rates of morbidity and mortality, for which no treatment exists2. 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 POLG 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 POLG disorders and other severe conditions linked to depletion of mtDNA.", "doi": "10.1038/s41586-025-08856-9", "pmid": "40205042", "labels": {"Integrated Microscopy Technologies Gothenburg": "Service", "Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12158775"}, {"db": "pii", "key": "10.1038/s41586-025-08856-9"}], "notes": [], "created": "2025-11-05T14:10:00.381Z", "modified": "2025-11-13T12:50:07.085Z"}, {"entity": "publication", "iuid": "499254acb4eb4139bf11f17fd8968652", "links": {"self": {"href": "https://publications.scilifelab.se/publication/499254acb4eb4139bf11f17fd8968652.json"}, "display": {"href": "https://publications.scilifelab.se/publication/499254acb4eb4139bf11f17fd8968652"}}, "title": "Modelling POLG mutations in mice unravels a critical role of POL\u03b3\u0392 in regulating phenotypic severity.", "authors": [{"family": "Corr\u00e0", "given": "Samantha", "initials": "S"}, {"family": "Zuppardo", "given": "Alessandro", "initials": "A", "orcid": "0000-0001-9601-3567", "researcher": {"href": "https://publications.scilifelab.se/researcher/308877ae9bac46328666ca4e56b73d26.json"}}, {"family": "Valenzuela", "given": "Sebastian", "initials": "S", "orcid": "0000-0001-5153-8431", "researcher": {"href": "https://publications.scilifelab.se/researcher/16c5cd1a4e8a4d9389514f33049240a5.json"}}, {"family": "Jenninger", "given": "Louise", "initials": "L"}, {"family": "Cerutti", "given": "Raffaele", "initials": "R"}, {"family": "Sillamaa", "given": "Sirelin", "initials": "S", "orcid": "0000-0001-8077-9963", "researcher": {"href": "https://publications.scilifelab.se/researcher/29a3fbab3f684386a2e08236bfd8674e.json"}}, {"family": "Hoberg", "given": "Emily", "initials": "E"}, {"family": "Johansson", "given": "Katarina A S", "initials": "KAS", "orcid": "0009-0005-8992-7631", "researcher": {"href": "https://publications.scilifelab.se/researcher/d3bac3ed243c4f0493e0d494f79a7ca2.json"}}, {"family": "Rovsnik", "given": "Urska", "initials": "U"}, {"family": "Volta", "given": "Sara", "initials": "S"}, {"family": "Silva-Pinheiro", "given": "Pedro", "initials": "P", "orcid": "0000-0002-0872-5749", "researcher": {"href": "https://publications.scilifelab.se/researcher/bbc93779b0704e55a91eb4d755255aed.json"}}, {"family": "Davis", "given": "Hannah", "initials": "H"}, {"family": "Trifunovic", "given": "Aleksandra", "initials": "A", "orcid": "0000-0002-5472-3517", "researcher": {"href": "https://publications.scilifelab.se/researcher/bf7d2fa56e714134bc66ca5884b8e86b.json"}}, {"family": "Minczuk", "given": "Michal", "initials": "M", "orcid": "0000-0001-8242-1420", "researcher": {"href": "https://publications.scilifelab.se/researcher/8f03f6f8725149c6938067d043ca4f7f.json"}}, {"family": "Gustafsson", "given": "Claes M", "initials": "CM", "orcid": "0000-0003-3531-8468", "researcher": {"href": "https://publications.scilifelab.se/researcher/2851656430d147dab7a8a32e50fee7b7.json"}}, {"family": "Suomalainen", "given": "Anu", "initials": "A", "orcid": "0000-0003-4833-5195", "researcher": {"href": "https://publications.scilifelab.se/researcher/6625705a6d4246c3a5f397008173899f.json"}}, {"family": "Zeviani", "given": "Massimo", "initials": "M"}, {"family": "Macao", "given": "Bertil", "initials": "B", "orcid": "0000-0001-6511-6125", "researcher": {"href": "https://publications.scilifelab.se/researcher/b5445196c3234bdb8686e85f77a66f3f.json"}}, {"family": "Zhu", "given": "Xuefeng", "initials": "X", "orcid": "0000-0002-4759-4446", "researcher": {"href": "https://publications.scilifelab.se/researcher/eebd5f32ac0c48869c90ba2d2ba94fa9.json"}}, {"family": "Falkenberg", "given": "Maria", "initials": "M", "orcid": "0000-0001-8713-173X", "researcher": {"href": "https://publications.scilifelab.se/researcher/562109b99a5c4eb3bd8b92f30014828b.json"}}, {"family": "Viscomi", "given": "Carlo", "initials": "C", "orcid": "0000-0001-6050-0566", "researcher": {"href": "https://publications.scilifelab.se/researcher/e84ba370ae594e6db85d338ab69a02df.json"}}], "type": "journal article", "published": "2025-05-23", "journal": {"title": "Nat Commun", "issn": "2041-1723", "volume": "16", "issue": "1", "pages": "4782", "issn-l": "2041-1723"}, "abstract": "DNA polymerase \u03b3 (POL\u03b3), responsible for mitochondrial DNA replication, consists of a catalytic POL\u03b3A subunit and two accessory POL\u03b3B subunits. Mutations in POLG, which encodes POL\u03b3A, lead to various mitochondrial diseases. We investigated the most common POLG mutations (A467T, W748S, G848S, Y955C) by characterizing human and mouse POL\u03b3 variants. Our data reveal that these mutations significantly impair POL\u03b3 activities, with mouse variants exhibiting milder defects. Cryogenic electron microscopy highlighted structural differences between human and mouse POL\u03b3, particularly in the POL\u03b3B subunit, which may explain the higher activity of mouse POL\u03b3 and the reduced severity of mutations in mice. We further generated a panel of mouse models mirroring common human POLG mutations, providing crucial insights into the pathogenesis of POLG-related disorders and establishing robust models for therapeutic development. Our findings emphasize the importance of POL\u03b3B in modulating the severity of POLG mutations.", "doi": "10.1038/s41467-025-60059-y", "pmid": "40404629", "labels": {"Integrated Microscopy Technologies Gothenburg": "Service", "Cryo-EM": "Service"}, "xrefs": [{"db": "pmc", "key": "PMC12098916"}, {"db": "pii", "key": "10.1038/s41467-025-60059-y"}], "notes": [], "created": "2025-11-05T13:48:13.014Z", "modified": "2025-11-13T12:47:34.901Z"}]}