A5026492423- Cell death mechanisms and regulation
- interferon and immune responses
- Mitochondrial Function and Pathology
- Ubiquitin and proteasome pathways
- Inflammasome and immune disorders
- ATP Synthase and ATPases Research
- Autophagy in Disease and Therapy
- DNA Repair Mechanisms
- Cancer Mechanisms and Therapy
- PI3K/AKT/mTOR signaling in cancer
- RNA Interference and Gene Delivery
- Microtubule and mitosis dynamics
- Nanoplatforms for cancer theranostics
- Bioactive Compounds and Antitumor Agents
- Viral Infections and Outbreaks Research
- RNA regulation and disease
- Peptidase Inhibition and Analysis
- Extracellular vesicles in disease
- Heat shock proteins research
- Phagocytosis and Immune Regulation
- Cancer-related molecular mechanisms research
- Cancer-related Molecular Pathways
- Immune cells in cancer
- NF-κB Signaling Pathways
- Histone Deacetylase Inhibitors Research
Cancer Research UK Scotland Institute
2015-2024
University of Glasgow
2015-2024
Innsbruck Medical University
2022-2024
Universität Innsbruck
2022-2024
Cancer Research UK
2015-2024
Queen's University Belfast
2012-2020
Article26 July 2018Open Access Source DataTransparent process Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis Joel S Riley orcid.org/0000-0001-9170-5716 Cancer Research UK Beatson Institute, Glasgow, Institute of Sciences, University Search for more papers by this author Giovanni Quarato orcid.org/0000-0003-1167-3422 Department Immunology, St. Jude Children's Hospital, Memphis, TN, USA Catherine Cloix Jonathan Lopez orcid.org/0000-0003-3768-2378 Jim...
During apoptosis, the mitochondrial outer membrane is permeabilized, leading to release of cytochrome c that activates downstream caspases. Mitochondrial permeabilization (MOMP) has historically been thought occur synchronously and completely throughout a cell, rapid caspase activation apoptosis. Using new imaging approach, we demonstrate MOMP not an all-or-nothing event. Rather, find minority mitochondria can undergo in stress-regulated manner, phenomenon term "minority MOMP." Crucially,...
Mitophagy is an evolutionarily conserved process that selectively targets impaired mitochondria for degradation. Defects in mitophagy are often associated with diverse pathologies, including cancer. Because the main known regulators of frequently inactivated cancer cells, mechanisms regulate cells not fully understood. Here, we identified E3 ubiquitin ligase (ARIH1/HHARI) triggers a PINK1-dependent manner. We found ARIH1/HHARI polyubiquitinates damaged mitochondria, leading to their removal...
Abstract Senescent cells drive age-related tissue dysfunction partially through the induction of a chronic senescence-associated secretory phenotype (SASP) 1 . Mitochondria are major regulators SASP; however, underlying mechanisms have not been elucidated 2 often essential for apoptosis, cell fate distinct from cellular senescence. During widespread mitochondrial outer membrane permeabilization (MOMP) commits to die 3 Here we find that MOMP occurring in subset mitochondria is feature This...
Mitochondrial dysfunction is interconnected with cancer. Nevertheless, how defective mitochondria promote cancer poorly understood. We find that mitochondrial promotes DNA damage under conditions of increased apoptotic priming. Underlying this process, we reveal a key role for dynamics in the regulation and genome instability. The ability to regulate oncogenic centers upon control minority outer membrane permeabilization (MOMP), process enables non-lethal caspase activation leading damage....
Abstract Mitochondrial outer membrane permeabilisation (MOMP) is often essential for apoptosis, by enabling cytochrome c release that leads to caspase activation and rapid cell death. Recently, MOMP has been shown be inherently pro-inflammatory with emerging cellular roles, including its ability elicit anti-tumour immunity. Nonetheless, how triggers inflammation the regulates this remains poorly defined. We find upon MOMP, many proteins localised either inner or mitochondrial membranes are...
The cystine-glutamate antiporter, xCT, supports a glutathione synthesis program enabling cancer cells to cope with metabolically stressful microenvironments. Up-regulated in combination glutaminolysis, leads increased extracellular glutamate, which promotes invasive behavior by activating metabotropic glutamate receptor 3 (mGluR3). Here we show that activation of mGluR3 breast activates Rab27-dependent release vesicles (EVs), can transfer characteristics “recipient” tumor cells. These EVs...
Abstract Mitofusins reside on the outer mitochondrial membrane and regulate fusion, a physiological process that impacts diverse cellular processes. are activated by conformational changes subsequently oligomerize to enable fusion. Here, we identify small molecules directly increase or inhibit mitofusins activity modulating mitofusin conformations oligomerization. We use these better understand role of in function, signaling. find activation increases, whereas inhibition decreases fusion...
Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression FLIP, which blocks extrinsic apoptotic pathway inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression NSCLC effect HDAC inhibitors on expression, activation drug resistance normal line models. Immunohistochemical analysis cytoplasmic nuclear protein was carried out using a novel digital pathology approach. Both...
Most apoptotic stimuli require mitochondrial outer membrane permeabilization (MOMP) in order to execute cell death. As such, MOMP is subject tight control by Bcl-2 family proteins. We have developed a powerful new technique investigate Bcl-2-mediated regulation of MOMP. This method, called mito-priming, uses co-expression pro- and anti-apoptotic proteins engineer addiction. On addition targeting BH3 mimetics, mito-primed cells undergo apoptosis rapid synchronous manner. Using this method we...
Small interfering RNAs (siRNAs) are widely used in biomedical research and clinical trials. Here, we demonstrate that siRNA treatment is commonly associated with significant sensitization to ferroptosis, independently of the target protein knockdown. Genetically targeting mitochondrial antiviral-signaling (MAVS) reversed siRNA-mediated sensitizing effect, but no activation canonical MAVS signaling, which involves phosphorylation IkBα interferon regulatory transcription factor 3 (IRF3), was...
Death Receptor 5 (DR5) is a pro-apoptotic cell-surface receptor that potential therapeutic target in cancer. Despite the potency of DR5-targeting agents preclinical models, translation these effects into clinic remains disappointing. Herein, we report an alternative approach to exploiting DR5 tumor expression using antibody-targeted, chemotherapy-loaded nanoparticles. We describe development optimized polymer-based nanotherapeutic incorporating both functionalized polyethylene glycol (PEG)...
TRAIL-R2 (DR5) is a clinically-relevant therapeutic target and key for immune effector cells. Herein, we identify novel interaction between the Skp1-Cullin-1-F-box (SCF) Cullin-Ring E3 Ubiquitin Ligase complex containing Skp2 (SCFSkp2). We find that SCFSkp2 can interact with both TRAIL-R2's pre-ligand association (PLAC) ligand-activated death-inducing signalling (DISC). Moreover, Cullin-1 interacts in its active NEDDylated form. Inhibiting Cullin-1's DISC recruitment using NEDDylation...
Centrosomes are membrane-less organelles that orchestrate a wide array of biological functions by acting as microtubule organizing centers. Here, we report caspase-2-driven apoptosis is elicited in blood cells failing cytokinesis and extra centrosomes necessary to trigger this cell death. Activation caspase-2 depends on the PIDDosome multi-protein complex priming PIDD1 at for pathway. Accordingly, loss its centrosomal adapter, ANKRD26, allows survival unrestricted polyploidization response...
Centrosomes are membrane-less organelles that orchestrate a wide array of biological functions by acting as microtubule organizing centers. Here, we report caspase-2–driven apoptosis is elicited in blood cells failing cytokinesis and extra centrosomes necessary to trigger this cell death. Activation caspase-2 depends on the PIDDosome multi-protein complex, priming PIDD1 at for pathway activation. Accordingly, loss its centrosomal adapter, ANKRD26, allows survival unrestricted...
Abstract Mitochondria are often essential for apoptosis through mitochondrial outer membrane permeabilization (MOMP). This central event enables cytochrome c release leading to caspase activation and rapid cell death. Recently, MOMP has been shown be inherently pro-inflammatory, instance, by enabling DNA-dependent of cGAS-STING signalling. Alongside having emerging functions in health disease, associated inflammation can also elicit anti-tumour immunity. Nonetheless, how triggers the...