The mitochondria DNA (mtDNA) editing tool, zinc finger nucleases (ZFNs), transcription activator-like effector nuclease (TALENs), and clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) system, is a promising approach for the treatment of mtDNA diseases by eliminating mutant mitochondrial genomes. However, there have been no reports of repairing the mutant mtDNA with homologous recombination strategy to date. Here, we show a mito-CRISPR/Cas9 system that mito-Cas9 protein can specifically target mtDNA and reduce mtDNA copy number in both human cells and zebrafish. An exogenous single-stranded DNA with short homologous arm was knocked into the targeting loci accurately, and this mutagenesis could be steadily transmitted to F1 generation of zebrafish. Moreover, we found some major factors involved in nuclear DNA repair were upregulated significantly by the mito-CRISPR/Cas9 system. Taken together, our data suggested that the mito-CRISPR/Cas9 system could be a useful method to edit mtDNA by knock-in strategy, providing a potential therapy for the treatment of inherited mitochondrial diseases.

Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance is a major obstacle in the treatment of non-small cell lung cancer (NSCLC). Epigenetic alterations have been shown to be involved in NSCLC oncogenesis; however, their function in EGFR-TKI resistance remains uncharacterized. Here, we found that an EHMT2 inhibitor, UNC0638, can significantly inhibit cell growth and induce apoptosis in EGFR-TKI-resistant NSCLC cells. Additionally, we also found that EHMT2 expression and enzymatic activity levels were elevated in EGFR-TKI-resistant NSCLC cells. Moreover, we determined that genetic or pharmacological inhibition of EHMT2 expression enhanced TKI sensitivity and suppressed migration and tumor sphere formation in EGFR-TKI-resistant NSCLC cells. Further investigation revealed that EHMT2 contributed to PTEN transcriptional repression and thus facilitated AKT pathway activation. The negative relationship between EHMT2 and PTEN was confirmed by our clinical study. Furthermore, we determined that combination treatment with the EHMT2 inhibitor and Erlotinib resulted in enhanced antitumor effects in a preclinical EGFR-TKI-resistance model. We also found that high EHMT2 expression along with low PTEN expression can predict poor overall survival in patients with NSCLC. In summary, our findings showed that EHMT2 facilitated EGFR-TKI resistance by regulating the PTEN/AKT pathway in NSCLC cells, suggesting that EHMT2 may be a target in the clinical treatment of EGFR-TKI-resistant NSCLC.

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One of the most sustainable and promising approaches for hydrogen peroxide (H2O2) production in a low‐cost and environment‐friendly way is photosynthesis, which, however, suffers from poor carrier utilization and low H2O2 productivity. The addition of proton donors such as isopropanol or ethanol can increase H2O2 production, which, unfortunately, will inevitably elevate the entire cost while wasting the oxidizing power of holes (h+). Herein, the tetrahydroisoquinolines (THIQs) is employed as a distinctive proton donor for the thermodynamically feasible and selective semi‐dehydrogenation reaction to highly valuable dihydroisoquinolines (DHIQs), and meanwhile, to couple with and promote H2O2 generation in one photoredox reaction under the photocatalysis by dual‐functional Zn3In2S6 photocatalyst. Surprisingly, the suitably defective Zn3In2S6 offers an excellent and near‐stoichiometric co‐production performance of H2O2 and DHIQs at unprecedentedly high rates of 66.4 and 62.1 mmol h‐1 g‐1 under visible light (λ ≥ 400 nm), respectively, which outperforms all the previously available reports even though sacrificial agents were employed in those reports. Additionally, photocatalytic redox reaction mechanism demonstrates that H2O2 can be generated through multiple pathways, highlighting the synergistic effect among ROS (·O2‐ and 1O2), h+ and proton donor, which has been ignored in previous studies.

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