A major impediment to the characterization of mtDNA repair mechanisms in comparison to nuclear DNA repair mechanisms is the difficulty of specifically addressing mitochondrial damage. Using a mitochondria-penetrating peptide, we can deliver DNA-damaging agents directly to mitochondria, bypassing the nuclear compartment. Here, we describe the use of an mtDNA-damaging agent in tandem with CRISPR/Cas9 screening for the genome-wide discovery of factors essential for mtDNA damage response. Using mitochondria-targeted doxorubicin (mtDox), we generate mtDNA double-strand breaks (mtDSBs) specifically in this organelle. Combined with an untargeted doxorubicin (Dox) screen, we identify genes with significantly greater essentiality during mitochondrial versus nuclear DNA damage. We characterize the essentiality of our top hit, WRNIP1─observed here for the first time to respond to mtDNA damage. We further investigate the mitochondrial role of WRNIP1 in innate immune signaling and nuclear genome maintenance, outlining a model that experimentally supports mitochondrial turnover in response to mtDSBs.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acschembio.3c00620 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Discovery of novel dual tubulin and MMPs inhibitors for the treatment of lung cancer and overcoming drug resistance.
Eur J Med Chem
January 2025
State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin, 541004, China; National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Institute of Green Chemistry and Process Enhancement Technology, Huaiyin Institute of Technology, Huai'an, 223003, China. Electronic address:
Nowadays, hybrid molecule with dual targets activity or effect is regarded as an effective strategy for combating the drug resistance development in cancer therapy. Herein, novel of bifunctional conjugates targeting tubulin and MMPs inhibitors were synthesized. Among them, 15j exhibited robust anticancer activity in vitro and in vivo, with IC values of 0.
View Article and Find Full Text PDFMitochondrial Mayhem: How cigarette smoke induces placental dysfunction through MMS19 degradation.
Ecotoxicol Environ Saf
January 2025
Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang 110004, PR China. Electronic address:
Cigarette smoke (CS) has detrimental effects on placental growth and embryo development, but the underlying mechanisms remain unclear. This study aims to investigate the impact of CS on trophoblast cell proliferation and regulated cell death (RCD) by examining its interference with iron-sulfur cluster (ISC) proteins and the CIA pathway. Exposure to CS disrupted the cytosolic ISC assembly (CIA) pathway, downregulated ISC proteins, and decreased ISC maturation in the placenta of rats exposed to passive smoking.
View Article and Find Full Text PDFCobalt oxide nanoparticles induce cytotoxicity and excessive ROS mediated mitochondrial dysfunction and p53-independent apoptosis in melanoma cells.
Sci Rep
January 2025
Faculty of Biotechnology, October University for Modern Sciences and Arts (MSA), 6th of October City, Egypt.
Nanotherapy has emerged as a promising strategy for the targeted and efficient treatment of melanoma, the most aggressive and lethal form of skin cancer, with minimized systemic toxicity. However, the therapeutic efficacy of cobalt oxide nanoparticles (CoONPs) in melanoma treatment remains unexplored. This study aimed to assess the therapeutic potential of CoONPs in melanoma treatment by evaluating their impact on cell viability, genomic DNA and mitochondrial integrity, reactive oxygen species (ROS) generation and apoptosis induction in melanoma A-375 cells.
View Article and Find Full Text PDFSingle-cell transcriptomic analysis reveals characteristic feature of macrophage reprogramming in liver Mallory-Denk bodies pathogenesis.
J Transl Med
January 2025
The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China; The Qingyuan Affiliated Hospital of Guangzhou Medical University, Qingyuan People's hospital, Qingyuan, China.
Chronic liver diseases are highly linked with mitochondrial dysfunction and macrophage infiltration. Mallory-Denk bodies (MDBs) are protein aggregates associated with hepatic inflammation, and MDBs pathogenesis could be induced in mice by feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Here, we investigate the macrophage heterogeneity and the role of macrophage during MDBs pathogenesis on DDC-induced MDBs mouse model by single-nucleus RNA sequencing (snRNA-seq).
View Article and Find Full Text PDFSelf-Cascaded Pyroptosis-STING Initiators for Catalytic Metalloimmunotherapy.
J Am Chem Soc
January 2025
Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China.
Gasdermin (GSDM)-mediated pyroptosis involves the induction of mitochondrial damage and the subsequent release of mitochondrial DNA (mtDNA), which is anticipated to activate the cGAS-STING pathway, thereby augmenting the antitumor immune response. However, challenges lie in effectively triggering pyroptosis in cancer cells and subsequently enhancing the cGAS-STING activation with specificity. Herein, we developed intelligent self-cascaded pyroptosis-STING initiators of cobalt fluoride (CoF) nanocatalysts for catalytic metalloimmunotherapy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!