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SMIP004-7 is a small molecule inhibitor of mitochondrial respiration with selective in vivo anti-cancer activity through an as-yet unknown molecular target. We demonstrate here that SMIP004-7 targets drug-resistant cancer cells with stem-like features by inhibiting mitochondrial respiration complex I (NADH:ubiquinone oxidoreductase, complex I [CI]). Instead of affecting the quinone-binding site targeted by most CI inhibitors, SMIP004-7 and its cytochrome P450-dependent activated metabolite(s) have an uncompetitive mechanism of inhibition involving a distinct N-terminal region of catalytic subunit NDUFS2 that leads to rapid disassembly of CI. SMIP004-7 and an improved chemical analog selectively engage NDUFS2 in vivo to inhibit the growth of triple-negative breast cancer transplants, a response mediated at least in part by boosting CD4+ and CD8+ T cell-mediated immune surveillance. Thus, SMIP004-7 defines an emerging class of ubiquinone uncompetitive CI inhibitors for cell autonomous and microenvironmental metabolic targeting of mitochondrial respiration in cancer. [Display omitted] • SMIP004 compounds inhibit NADH:ubiquinone oxidoreductase (complex I) • Unique ubiquinone uncompetitive mechanism of inhibition • In vivo target engagement involves complex I subunit NDUFS2 • Complex I inhibition reverses hypoxia and promotes cancer immune surveillance Mitochondrial complex I is identified as the target of cancer selective cytotoxic agent SMIP004-7. Jain et al. show that anti-tumor activity involves ubiquinone uncompetitive inhibition of complex I, leading to a reversal of tumor hypoxia and promotion of tumor immune surveillance. [ABSTRACT FROM AUTHOR]

eIF3, a multi-subunit complex with numerous functions in canonical translation initiation, is known to interact with 40S and 60S ribosomal proteins and translation elongation factors, but a direct involvement in translation elongation has never been demonstrated. We found that eIF3 deficiency reduced early ribosomal elongation speed between codons 25 and 75 on a set of ∼2,700 mRNAs encoding proteins associated with mitochondrial and membrane functions, resulting in defective synthesis of their encoded proteins. To promote elongation, eIF3 interacts with 80S ribosomes translating the first ∼60 codons and serves to recruit protein quality-control factors, functions required for normal mitochondrial physiology. Accordingly, eIF3e+/− mice accumulate defective mitochondria in skeletal muscle and show a progressive decline in muscle strength. Hence, eIF3 interacts with 80S ribosomes to enhance, at the level of early elongation, the synthesis of proteins with membrane-associated functions, an activity that is critical for mitochondrial physiology and muscle health. • eIF3—via eIF3e—promotes mRNA selective early translation elongation • eIF3e-dependent mRNAs encode membrane, secretory, and organelle targeted proteins • eIF3 travels with 80S ribosomes until nascent chains emerge for subcellular targeting • In vivo , eIF3e promotes mitochondrial function and skeletal muscle health Lin et al. discovered that, in addition to its function in canonical translation initiation, multi-subunit eIF3 migrates with post-initiation 80S ribosomes to promote early translation elongation of mRNAs encoding organellar, secretory, and membrane-targeted proteins. Loss of eIF3's elongation and subcellular targeting activity leads to mitochondrial and skeletal muscle dysfunction. [ABSTRACT FROM AUTHOR]

∼30% of clear cell renal cell carcinoma (ccRCC) patients present with metastatic disease at the time of diagnosis, causing a dire 5-year survival rate of 13%. Although anti-PD-1 immunotherapy has improved survival, a strong need remains for new therapeutic options. Using integrated network analysis, we identified the mitotic regulator NDC80 as a predictor of ccRCC progression. Overexpression of NDC80 fosters the malignant phenotype by promoting cell cycle progression through S phase as well as boosting glycolysis and mitochondrial respiration. Despite high levels of immune infiltration, particularly derived from tumor resident CD8 + T cells with an exhausted phenotype, NDC80 defines a class of ccRCCs that poorly respond to immune checkpoint blockade. Instead, bioinformatics identified NDC80-high ccRCCs as sensitive to inhibitors of mitotic kinases, PLK1 and AURK, therapeutic approaches we validated in cell lines and mouse xenograft studies. Thus, NDC80 status pinpoints mitotic kinase inhibitors as promising therapeutic options in difficult-to-treat ccRCCs., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Mammalian COP9 signalosome (CSN) exists as two variant complexes containing either CSN7A or CSN7B paralogs of unknown functional specialization. Constructing knockout cells, we found that CSN7A and CSN7B have overlapping functions in the deneddylation of cullin-RING ubiquitin ligases. Nevertheless, CSN CSN7B has a unique function in DNA double-strand break (DSB) sensing, being selectively required for ataxia telangiectasia mutated (ATM)-dependent formation of NBS1 S343p and γH2AX as well as DNA-damage-induced apoptosis triggered by mitomycin C and ionizing radiation. Live-cell microscopy revealed rapid recruitment of CSN7B but not CSN7A to DSBs. Resistance of CSN7B knockout cells to DNA damage is explained by the failure to deneddylate an upstream DSB signaling component, causing a switch in DNA repair pathway choice with increased utilization of non-homologous end joining over homologous recombination. In mice, CSN7B knockout tumors are resistant to DNA-damage-inducing chemotherapy, thus providing an explanation for the poor prognosis of tumors with low CSN7B expression., Competing Interests: Declaration of Interests D.A.W. is a part-time resident in medical genetics at MGZ Medical Genetics Center, Munich, Germany. The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)