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Small molecules restore mutant mitochondrial DNA polymerase activity.

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Τίτλος: Small molecules restore mutant mitochondrial DNA polymerase activity.
Συγγραφείς: Valenzuela S; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Zhu X; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Macao B; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Stamgren M; Pretzel Therapeutics, Mölndal, Sweden., Geukens C; Pretzel Therapeutics, Mölndal, Sweden., Charifson PS; Pretzel Therapeutics, Waltham, MA, USA., Kern G; Pretzel Therapeutics, Waltham, MA, USA., Hoberg E; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Jenninger L; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Gruszczyk AV; Pretzel Therapeutics, Mölndal, Sweden., Lee S; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Johansson KAS; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden., Miralles Fusté J; Pretzel Therapeutics, Mölndal, Sweden., Shi Y; Pretzel Therapeutics, Mölndal, Sweden., Kerns SJ; Pretzel Therapeutics, Waltham, MA, USA., Arabanian L; Pretzel Therapeutics, Mölndal, Sweden., Martinez Botella G; Pretzel Therapeutics, Waltham, MA, USA., Ekström S; Pretzel Therapeutics, Mölndal, Sweden., Green J; Pretzel Therapeutics, Waltham, MA, USA., Griffin AM; Pretzel Therapeutics, Waltham, MA, USA., Pardo-Hernández C; Pretzel Therapeutics, Mölndal, Sweden., Keating TA; Pretzel Therapeutics, Waltham, MA, USA., Küppers-Munther B; Pretzel Therapeutics, Mölndal, Sweden., Larsson NG; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden., Phan C; Pretzel Therapeutics, Mölndal, Sweden., Posse V; Pretzel Therapeutics, Mölndal, Sweden., Jones JE; Pretzel Therapeutics, Waltham, MA, USA., Xie X; Pretzel Therapeutics, Mölndal, Sweden., Giroux S; Pretzel Therapeutics, Waltham, MA, USA. sgiroux@pretzeltx.com., Gustafsson CM; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden. claes.gustafsson@medkem.gu.se., Falkenberg M; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden. maria.falkenberg@medkem.gu.se.
Πηγή: Nature [Nature] 2025 Jun; Vol. 642 (8067), pp. 501-507. Date of Electronic Publication: 2025 Apr 09.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE
Imprint Name(s): Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.
Ιατρικοί όροι (MeSH): DNA, Mitochondrial*/biosynthesis , DNA, Mitochondrial*/genetics , Mutation*/genetics , DNA-Directed DNA Polymerase*/metabolism , DNA-Directed DNA Polymerase*/genetics , DNA-Directed DNA Polymerase*/chemistry , Mitochondria*/enzymology , Mitochondria*/drug effects , Mitochondria*/genetics , Mitochondria*/metabolism , Mutant Proteins*/metabolism , Mutant Proteins*/genetics , Mutant Proteins*/chemistry, DNA Polymerase gamma/metabolism ; DNA Polymerase gamma/genetics ; DNA Polymerase gamma/chemistry ; Oxidative Phosphorylation/drug effects ; Catalytic Domain/drug effects ; Allosteric Site/drug effects ; Cell Respiration/drug effects ; DNA Replication/drug effects ; Mitochondrial Diseases/drug therapy ; Mitochondrial Diseases/genetics ; Mitochondrial Diseases/enzymology ; Humans ; Models, Molecular ; Animals ; Child ; Mice
Περίληψη: Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB 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 POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ 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.
(© 2025. The Author(s).)
Competing Interests: Competing interests: M.F., C.M.G., G.M.B. and N.-G.L. are co-founders of Pretzel Therapeutics. 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.
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Grant Information: University of Gothenburg
Substance Nomenclature: EC 2.7.7.7 (DNA Polymerase gamma)
0 (DNA, Mitochondrial)
EC 2.7.7.7 (DNA-Directed DNA Polymerase)
EC 2.7.7.7 (POLG protein, human)
0 (Mutant Proteins)
Entry Date(s): Date Created: 20250409 Date Completed: 20250611 Latest Revision: 20260413
Update Code: 20260414
PubMed Central ID: PMC12158775
DOI: 10.1038/s41586-025-08856-9
PMID: 40205042
Βάση Δεδομένων: MEDLINE
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  Data: Small molecules restore mutant mitochondrial DNA polymerase activity.
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  Data: <searchLink fieldCode="AU" term="%22Valenzuela+S%22">Valenzuela S</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.<br /><searchLink fieldCode="AU" term="%22Zhu+X%22">Zhu X</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.<br /><searchLink fieldCode="AU" term="%22Macao+B%22">Macao B</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.<br /><searchLink fieldCode="AU" term="%22Stamgren+M%22">Stamgren M</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Geukens+C%22">Geukens C</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Charifson+PS%22">Charifson PS</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Kern+G%22">Kern G</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Hoberg+E%22">Hoberg E</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.<br /><searchLink fieldCode="AU" term="%22Jenninger+L%22">Jenninger L</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.<br /><searchLink fieldCode="AU" term="%22Gruszczyk+AV%22">Gruszczyk AV</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Lee+S%22">Lee S</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.<br /><searchLink fieldCode="AU" term="%22Johansson+KAS%22">Johansson KAS</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.<br /><searchLink fieldCode="AU" term="%22Miralles+Fusté+J%22">Miralles Fusté J</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Shi+Y%22">Shi Y</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Kerns+SJ%22">Kerns SJ</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Arabanian+L%22">Arabanian L</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Martinez+Botella+G%22">Martinez Botella G</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Ekström+S%22">Ekström S</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Green+J%22">Green J</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Griffin+AM%22">Griffin AM</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Pardo-Hernández+C%22">Pardo-Hernández C</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Keating+TA%22">Keating TA</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Küppers-Munther+B%22">Küppers-Munther B</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Larsson+NG%22">Larsson NG</searchLink>; Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.<br /><searchLink fieldCode="AU" term="%22Phan+C%22">Phan C</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Posse+V%22">Posse V</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Jones+JE%22">Jones JE</searchLink>; Pretzel Therapeutics, Waltham, MA, USA.<br /><searchLink fieldCode="AU" term="%22Xie+X%22">Xie X</searchLink>; Pretzel Therapeutics, Mölndal, Sweden.<br /><searchLink fieldCode="AU" term="%22Giroux+S%22">Giroux S</searchLink>; Pretzel Therapeutics, Waltham, MA, USA. sgiroux@pretzeltx.com.<br /><searchLink fieldCode="AU" term="%22Gustafsson+CM%22">Gustafsson CM</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden. claes.gustafsson@medkem.gu.se.<br /><searchLink fieldCode="AU" term="%22Falkenberg+M%22">Falkenberg M</searchLink>; Department of Medical Biochemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden. maria.falkenberg@medkem.gu.se.
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– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Mammalian mitochondrial DNA (mtDNA) is replicated by DNA polymerase γ (POLγ), a heterotrimeric complex consisting of a catalytic POLγA subunit and two accessory POLγB subunits<superscript>1</superscript>. 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 exists<superscript>2</superscript>. 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 POLγ. PZL-A binds to an allosteric site at the interface between the catalytic POLγA subunit and the proximal POLγB subunit, a region that is unaffected by nearly all disease-causing mutations. The compound restores wild-type-like activity to mutant forms of POLγ 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.<br /> (© 2025. The Author(s).)
– Name: Abstract
  Label: Competing Interests
  Group: Ab
  Data: Competing interests: M.F., C.M.G., G.M.B. and N.-G.L. are co-founders of Pretzel Therapeutics. 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.
– Name: Ref
  Label: References
  Group: RefInfo
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  Data: EC 2.7.7.7 (DNA Polymerase gamma)<br />0 (DNA, Mitochondrial)<br />EC 2.7.7.7 (DNA-Directed DNA Polymerase)<br />EC 2.7.7.7 (POLG protein, human)<br />0 (Mutant Proteins)
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  Data: 10.1038/s41586-025-08856-9
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