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- Bonekamp, N. A., et al.
(författare)
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Small-molecule inhibitors of human mitochondrial DNA transcription
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 588, s. 712-716
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Tidskriftsartikel (refereegranskat)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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| 5. |
- Mourier, A, et al.
(författare)
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Mitofusin 2 is required to maintain mitochondrial coenzyme Q levels
- 2015
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Ingår i: The Journal of cell biology. - : Rockefeller University Press. - 1540-8140 .- 0021-9525. ; 208:4, s. 429-442
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondria form a dynamic network within the cell as a result of balanced fusion and fission. Despite the established role of mitofusins (MFN1 and MFN2) in mitochondrial fusion, only MFN2 has been associated with metabolic and neurodegenerative diseases, which suggests that MFN2 is needed to maintain mitochondrial energy metabolism. The molecular basis for the mitochondrial dysfunction encountered in the absence of MFN2 is not understood. Here we show that loss of MFN2 leads to impaired mitochondrial respiration and reduced ATP production, and that this defective oxidative phosphorylation process unexpectedly originates from a depletion of the mitochondrial coenzyme Q pool. Our study unravels an unexpected and novel role for MFN2 in maintenance of the terpenoid biosynthesis pathway, which is necessary for mitochondrial coenzyme Q biosynthesis. The reduced respiratory chain function in cells lacking MFN2 can be partially rescued by coenzyme Q10 supplementation, which suggests a possible therapeutic strategy for patients with diseases caused by mutations in the Mfn2 gene.
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| 8. |
- Atanassov, A, et al.
(författare)
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Grazing incident asymmetric X-ray diffraction of beta-FeSi2 layers, produced by ion beam synthesis
- 2004
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Ingår i: Vacuum. - : Elsevier BV. - 0042-207X .- 1879-2715. ; 76:02-Mar, s. 277-280
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Tidskriftsartikel (refereegranskat)abstract
- The crystal structure of beta-FeSi2 phase, prepared by ion beam synthesis (IBS) method, followed by rapid thermal annealing (RTA) is investigated by grazing incident asymmetric X-ray diffraction (GIAXRD). The X-ray spectra, obtained at different grazing angles, indicated that the beta-FeSi2 phase is formed in the whole implantation range. From the comparison of the reflections intensities ratios, it is found that in the metal-deficient regions, where the beta-FeSi2 phase is present in the form of precipitates, the crystallites orientation is influenced by the one of the silicon substrates, while the orientation in the metal-rich region is different and depends on the annealing temperature. (C) 2004 Elsevier Ltd. All rights reserved.
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| 9. |
- Bonekamp, NA, et al.
(författare)
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High levels of TFAM repress mammalian mitochondrial DNA transcription in vivo
- 2021
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Ingår i: Life science alliance. - : Life Science Alliance, LLC. - 2575-1077. ; 4:11
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Tidskriftsartikel (refereegranskat)abstract
- Mitochondrial transcription factor A (TFAM) is compacting mitochondrial DNA (dmtDNA) into nucleoids and directly controls mtDNA copy number. Here, we show that the TFAM-to-mtDNA ratio is critical for maintaining normal mtDNA expression in different mouse tissues. Moderately increased TFAM protein levels increase mtDNA copy number but a normal TFAM-to-mtDNA ratio is maintained resulting in unaltered mtDNA expression and normal whole animal metabolism. Mice ubiquitously expressing very high TFAM levels develop pathology leading to deficient oxidative phosphorylation (OXPHOS) and early postnatal lethality. The TFAM-to-mtDNA ratio varies widely between tissues in these mice and is very high in skeletal muscle leading to strong repression of mtDNA expression and OXPHOS deficiency. In the heart, increased mtDNA copy number results in a near normal TFAM-to-mtDNA ratio and maintained OXPHOS capacity. In liver, induction of LONP1 protease and mitochondrial RNA polymerase expression counteracts the silencing effect of high TFAM levels. TFAM thus acts as a general repressor of mtDNA expression and this effect can be counterbalanced by tissue-specific expression of regulatory factors.
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