A5089346626- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- PI3K/AKT/mTOR signaling in cancer
- Parkinson's Disease Mechanisms and Treatments
- Ion channel regulation and function
- Metabolism and Genetic Disorders
- Computational Drug Discovery Methods
- Cell Image Analysis Techniques
- Liver Disease Diagnosis and Treatment
- Autophagy in Disease and Therapy
- Pharmacological Receptor Mechanisms and Effects
- Lung Cancer Treatments and Mutations
- Neuroscience and Neuropharmacology Research
- Pharmacogenetics and Drug Metabolism
- Hepatitis B Virus Studies
- Schizophrenia research and treatment
- CAR-T cell therapy research
- Lysosomal Storage Disorders Research
- Viral Infectious Diseases and Gene Expression in Insects
- Hepatitis C virus research
- Coenzyme Q10 studies and effects
- Metabolomics and Mass Spectrometry Studies
- Protein Kinase Regulation and GTPase Signaling
- CRISPR and Genetic Engineering
MRC Toxicology Unit
2020-2023
University of Cambridge
2020-2023
AstraZeneca (United Kingdom)
2022
University College London
2016
Wellcome Trust
2008-2011
MRC Mitochondrial Biology Unit
2010
Medical Research Council
2008-2010
University of Leeds
2008
Institute of Structural and Molecular Biology
2008
ROS (reactive oxygen species) are considered to be a major cause of cellular oxidative stress, linked neuromuscular diseases and aging. Complex I (NADH:ubiquinone oxidoreductase) is one the main contributors superoxide production by mitochondria, knowledge its mechanism O2 reduction required for formulation causative connections between complex defects pathological effects. There evidence two distinct (but not mutually exclusive) sites I. Studies isolated enzyme largely support participation...
NADH:ubiquinone oxidoreductase (complex I) is a major source of reactive oxygen species in mitochondria and contributor to cellular oxidative stress. In isolated complex I the reduced flavin known react with molecular form predominantly superoxide, but studies using intact contend that superoxide may result from semiquinone responds proton-motive force (Δp) also. Here, we use bovine heart submitochondrial particles show single mechanism describes production by under all conditions (during...
Mitochondrial fission is essential for the degradation of damaged mitochondria. It currently unknown how dynamin-related protein 1 (DRP1)-associated machinery selectively targeted to segregate We show that PTEN-induced putative kinase (PINK1) serves as a pro-fission signal, independently Parkin. Normally, scaffold AKAP1 recruits A (PKA) outer mitochondrial membrane phospho-inhibit DRP1. reveal after damage, PINK1 triggers PKA displacement from A-kinase anchoring 1. By ejecting PKA, ensures...
Mitochondrial dysfunction is implicated in numerous neurodegenerative disorders and Parkinson's disease (PD) particular. PINK1 Parkin gene mutations are causes of autosomal recessive PD, these respective proteins function cooperatively to degrade depolarized mitochondria (mitophagy). It widely assumed that impaired mitophagy as toxic reactive oxygen species (ROS)-producing accumulate progressively drive neurodegeneration. Instead, we report a LON-ClpP proteolytic quality control axis...
PROteolysis TArgeting Chimeras (PROTACs) use the ubiquitin–proteasome system to degrade a protein of interest for therapeutic benefit. Advances made in targeted degradation technology have been remarkable, with several molecules having moved into clinical studies. However, robust routes assess and better understand safety risks PROTACs need be identified, which is an essential step toward delivering efficacious safe compounds patients. In this work, we used Cell Painting, unbiased...
Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies other prevalent psychiatric conditions, including bipolar disorder major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority patients. The majority antipsychotic function dopamine receptor antagonists brain while most recent 'third'-generation, aripiprazole, act partial agonists. Despite showing good clinical...
Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac disproportionately targeted by toxins resulting in a loss function. An analysis the effects mubritinib showed this drug did not inhibit HER2 as reported, but directly inhibits respiratory complex I, reducing cardiac-cell beat rate, with prolonged exposure cell death. We used library chemical variants and modifying...
GB virus B (GBV-B) is the closest relative to hepatitis C (HCV) with which it shares a common genome organization, however, unlike HCV in humans, generally causes an acute resolving New World monkeys. It important understand factors regulating different disease profiles of two viruses and this regard, as well playing key role viral RNA replication, NS5A non-structural protein modulates variety host-cell signalling pathways. We have shown previously that NS5A, expressed either alone, or...
The integrated-stress-response (ISR) and AMPK are core regulators of adaptive mammalian biology. Here, we examined how mitochondrial stress connects with the ISR (mt-ISR), mTORC1-eIF4F translation apparatus if/how concurrent activation controls this signalling circuit. We show inhibited electron-transfer-chain (ETC) activity, a hyper-fission morphology, stimulated potent ISR/ATF4-driven adaption whilst preserving even in presence activated AMPK. axis was essential to execute ATF4-adaptive...
Summary Antipsychotic drugs are the mainstay of treatment for schizophrenia and provide adjunct therapies other prevalent psychiatric conditions, including bipolar disorder major depressive disorder. However, they also induce debilitating extrapyramidal syndromes (EPS), such as Parkinsonism, in a significant minority patients. The majority antipsychotic function dopamine receptor antagonists brain while most recent ‘third’-generation, aripiprazole, act partial agonists. Despite showing good...