Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

Mennuni, Mara; Filograna, Roberta; Felser, Andrea; Bonekamp, Nina A.; Giavalisco, Patrick; Lytovchenko, Oleksandr; Larsson, Nils‐Göran

doi:10.15252/embr.202153054

Cited by 22 publications

(13 citation statements)

References 83 publications

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“…To further support our hypothesis, we showed that IMT1, a first-in-class specific and noncompetitive POLRMT inhibitor [ 9 , 30 ], robustly suppressed proliferation (Fig. 3G ) and migration (Fig.…”

Section: Resultsmentioning

confidence: 55%

The mitochondrial RNA polymerase POLRMT promotes skin squamous cell carcinoma cell growth

Wang

et al. 2022

Cell Death Discov.

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RNA polymerase mitochondrial (POLRMT) expression and the potential biological functions in skin squamous cell carcinoma (SCC) were explored. We showed that POLRMT is significantly elevated in skin SCC. Genetic depletion of POLRMT, using shRNA-induced knockdown or CRISPR/Cas9-mediated knockout (KO), resulted in profound anti-skin SCC cell activity. In patient-derived primary skin SCC cells or immortalized lines (A431 and SCC-9), POLRMT shRNA or KO potently suppressed mitochondrial DNA (mtDNA) transcription and suppressed cell viability, proliferation and migration. POLRMT shRNA or KO impaired mitochondrial functions in different skin SCC cells, leading to production of ROS (reactive oxygen species), depolarization of mitochondria and depletion of ATP. Moreover, mitochondrial apoptosis cascade was induced in POLRMT-depleted skin SCC cells. IMT1, a POLRMT inhibitor, largely inhibited proliferation and migration, while inducing depolarization of mitochondria and apoptosis in primary skin SCC cells. Contrarily, ectopic overexpression of POLRMT increased mtDNA transcription and augmented skin SCC cell growth. Importantly, POLRMT shRNA adeno-associated virus injection robustly hindered growth of the subcutaneous A431 xenografts in mice. In the POLRMT shRNA virus-treated A431 xenograft tissues, POLRMT depletion, mtDNA transcription inhibition, cell apoptosis, lipid peroxidation and ATP depletion were detected. Together, overexpressed POLRMT increases mtDNA transcription and promotes skin SCC growth.

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Section: Resultsmentioning

confidence: 55%

The mitochondrial RNA polymerase POLRMT promotes skin squamous cell carcinoma cell growth

Wang

et al. 2022

Cell Death Discov.

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“…NSUN2 knocked-out HEK293T cell line [ 149 – 151 ], YARS2 knocked-out HeLa cell line [ 152 ], and yars2 −/− zebrafish, nsun2 −/− mice [ 150 ] model). At the same time, the CRISPR technique is used in the development of Genomic-Wide Screening Libraries to identify essential genes in different pathways such as oxidative phosphorylation [ 153 ], ATP-modulating [ 154 ], cell death [ 155 ], metabolic resistance [ 156 ], adenine nucleotide translocator—ANT functions [ 157 ], or knock-out screen to identify how mitochondrial stress is relayed to ATF4 [ 158 ].…”

Section: Clinical Applications Of the Crispr Systemmentioning

confidence: 99%

An Update on the Application of CRISPR Technology in Clinical Practice

et al. 2023

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The CRISPR/Cas system, an innovative gene-editing tool, is emerging as a promising technique for genome modifications. This straightforward technique was created based on the prokaryotic adaptive immune defense mechanism and employed in the studies on human diseases that proved enormous therapeutic potential. A genetically unique patient mutation in the process of gene therapy can be corrected by the CRISPR method to treat diseases that traditional methods were unable to cure. However, introduction of CRISPR/Cas9 into the clinic will be challenging because we still need to improve the technology's effectiveness, precision, and applications. In this review, we first describe the function and applications of the CRISPR–Cas9 system. We next delineate how this technology could be utilized for gene therapy of various human disorders, including cancer and infectious diseases and highlight the promising examples in the field. Finally, we document current challenges and the potential solutions to overcome these obstacles for the effective use of CRISPR–Cas9 in clinical practice.

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“…Again, exploiting the OXPHOS dependence of cancer cell populations, the inhibition of cell growth was demonstrated in numerous cancer cell lines. Importantly, not all cell lines were responsive to IMTs, and resistance was shown to develop via a loss of genes intrinsic to mammalian target of rapamycin complex 1 (mTORC1) and von Hippel–Lindau (VHL) pathways in addition to an increased expression of mtDNA [155].…”

Section: Mitochondria and Malignancymentioning

confidence: 99%

Mitochondrial DNA mutations in ageing and cancer

2022

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Advancing age is a major risk factor for malignant transformation and the development of cancer. As such, over 50% of neoplasms occur in individuals over the age of 70. The pathologies of both ageing and cancer have been characterized by respective groups of molecular hallmarks, and while some features are divergent between the two pathologies, several are shared. Perturbed mitochondrial function is one such common hallmark, and this observation therefore suggests that mitochondrial alterations may be of significance in age-related cancer development. There is now considerable evidence documenting the accumulation of somatic mitochondrial DNA (mtDNA) mutations in ageing human postmitotic and replicative tissues. Similarly, mutations of the mitochondrial genome have been reported in human cancers for decades. The plethora of functions in which mitochondria partake, such as oxidative phosphorylation, redox balance, apoptosis and numerous biosynthetic pathways, manifests a variety of ways in which alterations in mtDNA may contribute to tumour growth. However, the specific mechanisms by which mtDNA mutations contribute to tumour progression remain elusive and often contradictory. This review aims to consolidate current knowledge and describe future direction within the field.

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Metabolic resistance to the inhibition of mitochondrial transcription revealed by CRISPR‐Cas9 screen

Cited by 22 publications

References 83 publications

The mitochondrial RNA polymerase POLRMT promotes skin squamous cell carcinoma cell growth

The mitochondrial RNA polymerase POLRMT promotes skin squamous cell carcinoma cell growth

An Update on the Application of CRISPR Technology in Clinical Practice

Mitochondrial DNA mutations in ageing and cancer

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