Small-molecule inhibitors of human mitochondrial DNA transcription

Bonekamp, Nina A.; Peter, Bradley; Hillen, Hauke S.; Felser, Andrea; Bergbrede, Tim; Choidas, Axel; Horn, Moritz; Unger, Anke; Lucrezia, Raffaella Di; Atanassov, Ilian; Li, Xinping; Koch, Uwe; Menninger, Sascha; Boros, Joanna; Habenberger, Peter; Giavalisco, Patrick; Cramer, Patrick; Denzel, Martin S.; Nußbaumer, Peter; Klebl, Bert; Falkenberg, Maria; Gustafsson, Claes M.; Larsson, Nils‐Göran

doi:10.1038/s41586-020-03048-z

Cited by 129 publications

(198 citation statements)

References 51 publications

Supporting

Mentioning

189

Contrasting

Order By: Relevance

“…Mitochondria are responsible for providing cellular energy through the well-known oxidative phosphorylation (OXPHOS) system whereby energy is converted to adenosine 5′-triphosphate [ 10 – 14 ]. This will require transcription and expressions of mitochondrial DNA (mtDNA) [ 12 , 15 – 17 ]. Indeed, mtDNA encodes at least 13 essential subunits of the OXPHOS system, 2 mitochondrial ribosomal RNAs, and 22 transfer RNAs [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…Increased mtDNA transcription for the biogenesis of the OXPHOS system is vital for the growth of rapidly dividing cancer cells [ 12 , 23 , 24 ]. Conversely, targeting OXPHOS in mitochondria should be an important strategy to inhibit cancer cell growth [ 10 , 12 , 15 , 25 ]. Studies have shown that POLRMT could be an important metabolic oncogene, promoting OXPHOS progression and cancer cell growth [ 15 , 25 – 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…Conversely, targeting OXPHOS in mitochondria should be an important strategy to inhibit cancer cell growth [ 10 , 12 , 15 , 25 ]. Studies have shown that POLRMT could be an important metabolic oncogene, promoting OXPHOS progression and cancer cell growth [ 15 , 25 – 27 ]. Its expression and potential functions in NSCLC are examined in the present study.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

et al. 2021

View full text Add to dashboard Cite

POLRMT (RNA polymerase mitochondrial) is responsible for the transcription of mitochondrial genome encoding key components of oxidative phosphorylation. This process is important for cancer cell growth. The current study tested expression and potential functions of POLRMT in non-small cell lung cancer (NSCLC). TCGA cohorts and the results from the local lung cancer tissues showed that POLRMT is overexpressed in human lung cancer tissues. In both primary human NSCLC cells and A549 cells, POLRMT silencing (by targeted lentiviral shRNAs) or knockout (through CRSIPR/Cas9 gene editing method) potently inhibited cell viability, proliferation, migration, and invasion, and induced apoptosis activation. On the contrast, ectopic overexpression of POLRMT using a lentiviral construct accelerated cell proliferation and migration in NSCLC cells. The mtDNA contents, mRNA levels of mitochondrial transcripts, and subunits of respiratory chain complexes, as well as S6 phosphorylation, were decreased in POLRMT-silenced or -knockout NSCLC cells, but increased after ectopic POLRMT overexpression. In vivo, intratumoral injection of POLRMT shRNA adeno-associated virus (AAV) potently inhibited NSCLC xenograft growth in severe combined immune deficiency mice. The mtDNA contents, mRNA levels of mitochondria respiratory chain complex subunits, and S6 phosphorylation were decreased in POLRMT shRNA AAV-injected NSCLC xenograft tissues. These results show that POLRMT is a novel and important oncogene required for NSCLC cell growth in vitro and in vivo.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Previous studies [17][18][19][20][21] found that, even when there was plenty of oxygen, most tumor cells still choose glycolysis rather than oxidative phosphorylation, a feature called the Warburg effect, which was classi ed as one of the top ten characteristics of tumors in 2011 [22]. Although the Warburg effect has been veri ed in many tumors, recent studies have shown that mitochondrial-dependent energy synthesis plays a key role in tumor growth and proliferation [23][24][25][26]. Not all tumor cells perform glycolysis, as reported in this study, but are divided into glycolysis and oxidative phosphorylation [27].…”

Section: Discussionmentioning

confidence: 99%

PFKFB4 Interference Regulates Mitochondrial Membrane Fusion and Affects Glioma Proliferation and Apoptosis

Kai¹,

Yu²,

Luo³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Fructose-2,6-biphosphatase 4 (PFKFB4) is a key enzyme in glucose metabolism, and its differential expression is closely related to the occurrence and development of tumors. However, the related molecular mechanisms in glioblastoma(GBM) remain unclear. Methods: Firstly, the expression of PFKFB4 in normal and GBM tissues was analyzed by bioinformatics in The Cancer Genome Atlas (TCGA) database, and the relationship between PFKFB4 and survival was analyzed. Then detected the expression of PFKFB4 in tissues and cells of glioma. After PFKFB4 Interference, observed the proliferation by CCK8 and EDU, apoptosis of U87 cells by flow cytometry. the content of ATP and mitochondrial membrane function were detected. The possible interaction mechanism between PFKFB4 and mitochondria was analyzed by bioinformatics and verified by qPCR and Western blotting(WB). Finally, the experiment of subcutaneous tumor formation in nude mice was verified.Results: Our study found that PFKFB4 is highly expressed in glioma tissues and cell lines. High expression levels are associated with a poor prognosis. In addition, PFKFB4 inhibition attenuates the proliferation and mitochondrial function of cancer cells promotes apoptosis, and can also reduce ATP levels. Further studies showed that PFKFB4 affects the metabolic reprogramming of gliomas by regulating mitochondrial membrane fusion, Regulating the protein expression of mitofusin 1(MFN1), mitofusin 2(MFN2), opticatrophy-1(OPA1). Animal studies verify these results.Conclusion: PFKFB4 may be a potential therapeutic target for glioma.

show abstract

“…Mitochondria possess their own DNA and translation machinery. Diseases of mtDNA have first been described not so long ago (Wallace et al, 1988), and a new frontier is the manipulation of mtDNA, which holds great promise for a future correction of mtDNA diseases (Gammage et al, 2018) and possibly to treat cancer (Bonekamp et al, 2020). It is remarkable that only 13 out of the roughly 1,100 proteins found in mitochondria are encoded by mtDNA (Rath et al, 2020).…”

Section: Mitochondrial Dnamentioning

confidence: 99%

Looking Back to the Future of Mitochondrial Research

Bernardi

2021

Front. Physiol.

View full text Add to dashboard Cite

Small-molecule inhibitors of human mitochondrial DNA transcription

Cited by 129 publications

References 51 publications

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

The requirement of mitochondrial RNA polymerase for non-small cell lung cancer cell growth

PFKFB4 Interference Regulates Mitochondrial Membrane Fusion and Affects Glioma Proliferation and Apoptosis

Looking Back to the Future of Mitochondrial Research

Contact Info

Product

Resources

About