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1.	Jiang, S, et al. (author) Inhibition of mammalian mtDNA transcription acts paradoxically to reverse diet-induced hepatosteatosis and obesity 2024 In: Nature metabolism. - 2522-5812. Journal article (peer-reviewed)
2.	Bonekamp, N. A., et al. (author) Small-molecule inhibitors of human mitochondrial DNA transcription 2020 In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588, s. 712-716 Journal article (peer-reviewed)abstract Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system(1-6). The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease. Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.

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Type of publication: journal article (2)

Type of content: peer-reviewed (2)

Author/Editor: Unger, A (2); Bergbrede, T. (2); Di Lucrezia, R. (2); Giavalisco, P. (2); Yuan, T. (1); Krook, A (1); show more...; Zierath, JR (1); Borg, M (1); Mann, M (1); Larsson, NG (1); Wibom, R (1); Peter, Bradley (1); Falkenberg, Maria, 1 ... (1); Alsina, D (1); Atanassov, I (1); Koolmeister, C (1); Andersson, O (1); de Angelis, MH (1); Li, X. P. (1); Gustafsson, Claes M, ... (1); Cramer, P (1); Mourier, A (1); Larsson, N. G. (1); Ren, L. (1); Filograna, R (1); Bonekamp, N. A. (1); Hillen, H. S. (1); Felser, A. (1); Choidas, A. (1); Horn, M. (1); Koch, U. (1); Menninger, S. (1); Boros, J. (1); Habenberger, P. (1); Denzel, M. S. (1); Nussbaumer, P. (1); Klebl, B. (1); Jiang, S. (1); Mennuni, M (1); Kremer, LS (1); Hansen, FM (1); Misic, J (1); Rosenberger, FA (1); Dragano, NRV (1); Rubalcava-Gracia, D (1); Papadea, P (1); show less...

University: Karolinska Institutet (2); University of Gothenburg (1)

Language: English (2)

Research subject (UKÄ/SCB): Natural sciences (1); Medical and Health Sciences (1)

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