Mitochondria and Cell Death Regulation following toxic injury

Lead Research Organisation: MRC Toxicology Unit

Abstract

Tissue homeostasis relies on the tightly controlled removal of excessive cells normally through a form of cell suicide termed apoptosis. Whereas an aberrant resistance to apoptosis participates in the development of cancer, excessive cell death, contributes to neurodegenerative diseases like Parkinson’s disease. Mitochondria, essential cellular components responsible for converting the energy in food into fuel for the cells, have been recently found to be key regulators of cell death. Our research focuses on understanding how mitochondria regulate cell death and how this process can be impaired in cancer cells. Additionally, given that we have established a link between specific mitochondrial proteins and Parkinson’s disease, we are interested in determining how defects in these proteins contribute to this neurodegenerative disease. Parkinson’s disease occurs when certain nerve cells, or neurons, in an area of the brain known as the substantia nigra become impaired or die. These neurons normally produce a chemical messenger called dopamine, which is responsible for transmitting signals that ensure smooth, purposeful muscle activity. The loss of dopamine causes the nerve cells to fire out of control, preventing patients from directing or controlling their movements in a normal manner. Some toxic substances in the environment, as well as some illicit drugs can affect mitochondrial function giving rise to parkinsonism in some individuals. We believe that our research might provide links between susceptibility to toxic agents that contribute to Parkinson’s disease and mutations in some of the proteins we are characterizing.

Technical Summary

The focus of our research is to better understand the control of cellular death processes in normal cells and in pathological states with alterations of these processes. Our aim is to achieve a better understanding of the regulatory mechanisms controlling cell death. Understanding the basic biology of these processes can provide insights that are aimed to deliver field-changing mechanistic insights into toxicology and disease.
Part of our research addresses the function of mitochondrial proteins such as the protease HtrA2 and PINK1 and their role in stress responses. Mutations in HtrA2 and PINK1 are linked to Parkinson’s disease and we identified a mitochondrial stress-sensing pathway that involves the interaction between these two proteins.
Our work focuses on mitochondrial signaling pathways of toxicity associated with neurodegenerative diseases. The aim of this work is to target these pathways to improve neuronal health in models of Parkinson’s disease and other diseases related to mitochondrial dysfunction. We use the fruit fly as a model system to study organs and tissues with high energetic demand, such as the brain and muscles, that are susceptible to toxic insults.

Publications

10 25 50
 
Title Controlling genes to reverse the symptoms of Parkinson's disease 
Description Published on Feb 6, 2017 http://dx.doi.org/10.1038/cdd.2016.158 
Type Of Art Film/Video/Animation 
Year Produced 2017 
Impact Exceeds 500 views on YouTube 
URL https://youtu.be/cFJJm2YZKKM
 
Title Fly models of Parkinson's disease point way to new therapies 
Description Published on Jun 23, 2016 http://dx.doi.org/10.1038/cddis.2016.173 Celardo et al. "Mitofusin-mediated ER stress triggers neurodegeneration in pink1/parkin models of Parkinson's disease" 
Type Of Art Film/Video/Animation 
Year Produced 2016 
Impact More than 2000 views on YouTube 
URL https://youtu.be/13oA5eiH-8s
 
Title Niacin is neuroprotective in a fly model of Parkinson's disease 
Description Published on Dec 28, 2016 doi.org/10.1242/bio.022186 
Type Of Art Film/Video/Animation 
Year Produced 2006 
Impact More than 700 views on YouTube 
URL https://youtu.be/1e4oWI50IWg
 
Title E-MTAB-1406 
Description Transcription profiling by array of Drosophila melanogaster park25 (parkin) and pink1 (Pink1) mutants to identify neuron-specific transcriptional changes that may be relevant to Parkinson's disease 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact Stats: 80 views, 2 downloads 
 
Description EUROSKILLS - Leonardo da Vinci 
Organisation WorldSkills Europe
Country Netherlands 
Sector Charity/Non Profit 
PI Contribution 1. Development of skills in semi-quantitative PCR assays 2. Development of skills in quantitative PCR (qPCR) assays 3. Establishment of an assay for the detection of somatic mutations in formalin-fixed, paraffin- embedded (FFPE) cancer tissues, employing the Ion AmpliSeq Comprehensive Cancer Panel and Ion Torrent Semi-Conductor-based sequencing. This involves ultra-high multiplex PCR combined with targeted sequencing library construction for full exon coverage of 409 genes encompassing over 50% of the Wellcome Trust Sanger Institute Cancer Gene Census 4. Development of an assay for the qPCR validation of single-nucleotide variants (SNVs) detected by Ion Torrent sequencing
Collaborator Contribution Provided trainees
Impact Competence is Next Generation Sequencing technology for the trainees.
Start Year 2013
 
Description HOPE Grant (Pancreatic cancer) 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution Outline the research proposal and generated pilot data
Collaborator Contribution Co-writers of the research proposal
Impact Funding for this research proposal
Start Year 2013
 
Description LLP-ERASMUS 
Organisation University of Naples
Country Italy 
Sector Academic/University 
PI Contribution Hosting and training European Students
Collaborator Contribution Contribute to research conducted in our laboratory
Impact xx
Start Year 2013
 
Description Nick Wood 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to data and significant intellectual input into collaborator/partners research.
Collaborator Contribution Access to data and significant intellectual input into your collaborator/partners research.
Impact 17906618 19023330
 
Description Pancreatic cancer UK Grant 
Organisation University of Leicester
Department Department of Cancer Studies
Country United Kingdom 
Sector Academic/University 
PI Contribution Generated pilot data and outlined research proposal
Collaborator Contribution Co-writers of the research proposal
Impact Funding for this research project
Start Year 2013
 
Description Roy Castle Grant 
Organisation University of Leicester
Department Department of Cancer Studies
Country United Kingdom 
Sector Academic/University 
PI Contribution Molecular profiling of cancer genes present in circulating free DNA (cfDNA) of lung cancer patients
Collaborator Contribution Insolation of cfDNA from human plasma
Impact Grant award from the Roy Castle Lung Cancer Foundation (http://www.roycastle.org)
Start Year 2012
 
Description Synta ENCHANT Trial (9090-11) 
Organisation Synta Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Next generation sequencing of DNA from cancer patients
Collaborator Contribution Designed clinical trial and collected samples
Impact VCF files
Start Year 2013
 
Description Synta GALAXY Trial 
Organisation Synta Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Next generation sequencing of DNA from cancer patients
Collaborator Contribution Designed clinical trial and obtained samples
Impact VCF files
Start Year 2012
 
Title Addgene 
Description DNA plasmids used in our publications are available through addgene.org 
IP Reference  
Protection Protection not required
Year Protection Granted
Licensed Yes
Impact Total number of distributed plasmids to date: 119
 
Title Analysis pipeline to explore links between air pollution and COVID-19 
Description Analysis pipeline for links between air pollution and COVID-19 
Type Of Technology Webtool/Application 
Year Produced 2020 
Open Source License? Yes  
Impact The main aims of this analysis pipeline are as follows: 1. Determine a relationship between air pollutants and COVID-19-associated deaths/cases in England 2. Investigate whether any relationship between air pollution and COVID-19 remains significant in the presence of confounding factors at the regional and subregional level 3. Determine the effect of air pollutants on infectivity at individual levels. 
URL https://m1gus.github.io/AirPollutionCOVID19/
 
Company Name Cancer Diagnostics 
Description We are now offering a diagnostic test for cancer, which profiles the DNA of the cancer. This test is available to selected oncologists and pharmaceutical companies. 
Year Established 2012 
Impact Development of new blood-based cancer diagnostic tools
Website http://cancerdiagnostics.org
 
Description A study finds evidence of pre-cancerous lung tumours in mice using blood tests 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact A series of activities designed to explain our research to the general public. This included social media posts and a video on YouTube
Year(s) Of Engagement Activity 2019
URL https://cambridgerepository.altmetric.com/details/55350312
 
Description An article in the "research highlights" section of Nature Chemical Biology 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Dissemination of our work
Year(s) Of Engagement Activity 2014
URL http://www.nature.com/nchembio/journal/v10/n3/full/nchembio.1469.html
 
Description Article in BioWorld by Sharon Kingman. This focuses on our recent work focusing on nucleotide metabolism. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Increase awareness of our work

ds
Year(s) Of Engagement Activity 2014
URL http://www.bioworld.com/content/nucleotide-metabolism-key-parkinson's-disease-study-shows
 
Description Article in the Science section of Público 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Many direct enquiries about the therapeutic implications of our work

Direct enquiries
Year(s) Of Engagement Activity 2014
URL http://www.publico.pt/ciencia/noticia/uma-dieta-rica-em-acido-folico-podera-prevenir-ou-retardar-a-d...
 
Description Blood test can predict lung cancer before it is a killer 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact A blood test has been developed that could save countless lives by improving early detection of lung cancer.
Year(s) Of Engagement Activity 2019
URL https://www.independent.ie/life/health-wellbeing/blood-test-can-predict-lung-cancer-before-it-is-a-k...
 
Description Blood test could bring new hope for early lung cancer detection 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Researchers used a CT scan and blood test to detect how many cancer cells DNA molecules would shed inside of the lungs of lab mice, according to a study published Tuesday in Disease Models and Mechanisms.
Year(s) Of Engagement Activity 2019
URL https://www.upi.com/Health_News/2019/02/13/Blood-test-could-bring-new-hope-for-early-lung-cancer-det...
 
Description EARLY DIAGNOSIS SAVES LIVES Simple blood test could spot deadly lung cancer BEFORE it disease starts growing 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Scientists found that as the devastating disease spreads it sheds its own DNA into the blood, which could help detect it in its earliest stages.
Year(s) Of Engagement Activity 2019
URL https://www.thesun.co.uk/fabulous/8409719/lung-cancer-simple-blood-test-red-flags/
 
Description EMRSN Researchers Meeting 2016 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A meeting of Parkinson's researches with members of the Parkinson's East Midlands Research Support Network, including those patients with Parkinson's disease. This includes science seminars, visits to the labs and an informal lunch.
Year(s) Of Engagement Activity 2016
 
Description Interview by ITV Central 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Increased awareness of our research
Year(s) Of Engagement Activity 2014
URL http://www.itv.com/news/central/story/2014-02-04/parkinsons-disease-big-breakthrough/
 
Description Lung cancer could be detected with a BLOOD TEST raising hopes of diagnosing the deadly disease early 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact British researchers have created a new type of screening which can identify early stages of the disease - and even predict where pre-cancerous tumours may develop
Year(s) Of Engagement Activity 2019
URL https://www.dailymail.co.uk/health/article-6695307/Early-stages-lung-cancer-detected-simple-blood-te...
 
Description MRC Centenary Presentation 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Sparked questions and discussions afterwards

School pupils asked for lab visits
Year(s) Of Engagement Activity 2013
 
Description Micro-CT Captures Lung Cancer Biomarkers 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact New research led by scientists at the MRC Toxicology Unit suggests that by analysing levels of DNA in the blood, the early detection of lung cancer could be improved.
Year(s) Of Engagement Activity 2019
URL https://www.technologynetworks.com/tn/news/micro-ct-captures-lung-cancer-biomarkers-315414
 
Description New research suggests a simple blood test could improve the early detection of lung cancer 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact New research has suggested that the early detection of lung cancer could be improved through the analysis of DNA levels in the blood.
Year(s) Of Engagement Activity 2019
URL https://ecancer.org/news/15412-new-research-suggests-a-simple-blood-test-could-improve-the-early-det...
 
Description New research suggests a simple blood test could improve the early detection of lung cancer 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact New research led by scientists at the Medical Research Council (MRC) Toxicology Unit suggests that by analysing levels of DNA in the blood, the early detection of lung cancer could be improved.
Year(s) Of Engagement Activity 2019
URL https://www.eurekalert.org/pub_releases/2019-02/mrc-nrs020619.php
 
Description New research suggests a simple blood test could improve the early detection of lung cancer 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact New research led by scientists at the Medical Research Council (MRC) Toxicology Unit suggests that by analysing levels of DNA in the blood, the early detection of lung cancer could be improved.
Year(s) Of Engagement Activity 2019
URL https://medicalxpress.com/news/2019-02-simple-blood-early-lung-cancer.html
 
Description Simple Blood Test to Improve the Early Lung Cancer Detection 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact In mice, pre-cancerous lung tests can be analyzed using blood-based tests, revealed research led by scientists at the Medical Research Council (MRC) Toxicology Unit. The findings of the study are published in the journal Disease Models and Mechanism.
Year(s) Of Engagement Activity 2019
URL https://www.medindia.net/news/simple-blood-test-to-improve-the-early-lung-cancer-detection-185827-1....
 
Description Study gives Parkinson's cure hope 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact http://news.bbc.co.uk/1/hi/england/leicestershire/7023096.stm

Increased awareness of research into the mechanisms of Parkinson's disease
Year(s) Of Engagement Activity 2007
URL http://news.bbc.co.uk/1/hi/england/leicestershire/7023096.stm