ArticleCell death & disease2016
DDX3 DEAD-box RNA helicase plays a central role in mitochondrial protein quality control in Leishmania.
Article in Cell death & disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 43 citations in OpenAlex.
- Mitochondrial Localization and Abundance of Leishmania Cytochrome c Oxidase Subunit IV Is Maintained Following Loss of Mitochondrial Membrane Potential Associated With Mammalian Temperature.Molecular microbiology · 2026Article
- Oxidative Stress and Survival ofExpert reviews in molecular medicine · 2025Review
- Molecular docking ofIn silico pharmacology · 2025Article
- Ddx3xa mutations drive cardiac defects in a zebrafish model via dysregulation of wnt/β-catenin signaling.Frontiers in molecular biosciences · 2025Article
- Identification of novel inhibitors from3 Biotech · 2025Article
- Deciphering the relationship between temperature and immunity.Discovery immunology · 2024Review
- Quantitative proteomics of sperm tail in asthenozoospermic patients: exploring the molecular pathways affecting sperm motility.Cell and tissue research · 2023Article
- Expanded Proteomic Survey of the Human Parasite Leishmania major Focusing on Changes in Null Mutants of the Golgi GDP-Mannose/Fucose/Arabinopyranose TransporterMicrobiology spectrum · 2022Article
- Distinct mRNA and protein interactomes highlight functional differentiation of major eIF4F-like complexes fromFrontiers in molecular biosciences · 2022Article
- Genetic depletion of the RNA helicase DDX3 leads to impaired elongation of translating ribosomes triggering co-translational quality control of newly synthesized polypeptides.Nucleic acids research · 2021Article
- TheGenes · 2021Article
- SystematicFrontiers in chemistry · 2021Article
- DDX3 DEAD-box RNA helicase (Hel67) gene disruption impairs infectivity of Leishmania donovani and induces protective immunity against visceral leishmaniasis.Scientific reports · 2020Article
- The AAA + ATPase valosin-containing protein (VCP)/p97/Cdc48 interaction network in Leishmania.Scientific reports · 2020Article
- Unravelling the proteomic signature of extracellular vesicles released by drug-resistant Leishmania infantum parasites.PLoS neglected tropical diseases · 2020Article
- PRMT7 regulates RNA-binding capacity and protein stability in Leishmania parasites.Nucleic acids research · 2020Article
- The mRNA-bound Proteome ofMolecular & cellular proteomics : MCP · 2019Article
- Targeting mitochondrial translation by inhibiting DDX3: a novel radiosensitization strategy for cancer treatment.Oncogene · 2018Article
- The Pumilio-domain protein PUF6 contributes to SIDER2 retroposon-mediated mRNA decay inRNA (New York, N.Y.) · 2017Article
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Authors and funding
7 authors at 3 institutions in 3 countries.
Funding
Abstract
DDX3 is a highly conserved member of ATP-dependent DEAD-box RNA helicases with multiple functions in RNA metabolism and cellular signaling. Here, we describe a novel function for DDX3 in regulating the mitochondrial stress response in the parasitic protozoan Leishmania. We show that genetic inactivation of DDX3 leads to the accumulation of mitochondrial reactive oxygen species (ROS) associated with a defect in hydrogen peroxide detoxification. Upon stress, ROS production is greatly enhanced, causing mitochondrial membrane potential loss, mitochondrial fragmentation, and cell death. Importantly, this phenotype is exacerbated upon oxidative stress in parasites forced to use the mitochondrial oxidative respiratory machinery. Furthermore, we show that in the absence of DDX3, levels of major components of the unfolded protein response as well as of polyubiquitinated proteins increase in the parasite, particularly in the mitochondrion, as an indicator of mitochondrial protein damage. Consistent with these findings, immunoprecipitation and mass-spectrometry studies revealed potential interactions of DDX3 with key components of the cellular stress response, particularly the antioxidant response, the unfolded protein response, and the AAA-ATPase p97/VCP/Cdc48, which is essential in mitochondrial protein quality control by driving proteosomal degradation of polyubiquitinated proteins. Complementation studies using DDX3 deletion mutants lacking conserved motifs within the helicase core support that binding of DDX3 to ATP is essential for DDX3's function in mitochondrial proteostasis. As a result of the inability of DDX3-depleted Leishmania to recover from ROS damage and to survive various stresses in the host macrophage, parasite intracellular development was impaired. Collectively, these observations support a central role for the Leishmania DDX3 homolog in preventing ROS-mediated damage and in maintaining mitochondrial protein quality control.
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