Mitochondria and cell death regulation following toxic injury
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
Our organs comprise millions of cells that work together in concert for those tissues to carry out their functions. In each cell, there are tiny structures called mitochondria that act as powerhouses.
They carry out many fundamental jobs, from turning the food we eat into energy, to killing cells when they have become old or damaged. As a result, a wide range of diseases can occur when they go wrong. Mitochondrial disorders appear in almost any organ, can occur at any age, and are incurable. Their social and economic impact is enormous.
Mitochondrial defects can be modelled in animals such as the fruit fly. We use flies engineered to carry mitochondrial defects. We found that defective mitochondria send-out messages to another tiny structure in the cell called the endoplasmic reticulum (ER). The outcome of this process is cell death. We want to understand the nature of the signal transmitted between the mitochondria and the ER that causes cell death. Understanding this process will lead to new strategies, designed to alter this communication, restoring cell heath. This can be important to protect certain tissues and organs with high energetic demands such as the brain and heart.
They carry out many fundamental jobs, from turning the food we eat into energy, to killing cells when they have become old or damaged. As a result, a wide range of diseases can occur when they go wrong. Mitochondrial disorders appear in almost any organ, can occur at any age, and are incurable. Their social and economic impact is enormous.
Mitochondrial defects can be modelled in animals such as the fruit fly. We use flies engineered to carry mitochondrial defects. We found that defective mitochondria send-out messages to another tiny structure in the cell called the endoplasmic reticulum (ER). The outcome of this process is cell death. We want to understand the nature of the signal transmitted between the mitochondria and the ER that causes cell death. Understanding this process will lead to new strategies, designed to alter this communication, restoring cell heath. This can be important to protect certain tissues and organs with high energetic demands such as the brain and heart.
Technical Summary
Mitochondria are cellular organelles that provide the main source of energy to cells. They are critical to the health of tissues with high energetic demand such as the brain and heart. Mitochondrial toxicity, resulting from both genetic and environmental factors leads to tissue damage and diseases in humans. Our aim is to increase mechanistic knowledge of adverse outcome pathways (AOPs) linked to mitochondrial toxicity. We use the fruit fly (Drosophila melanogaster) as an in vivo model system to study AOPs associated with mitochondrial liability. Fruit flies have short lifespan and powerful genetics. Further, the majority of human disease-causing genes have functional homologs in flies. Using a systems-based approach, combining transcriptomics, proteomics and metabolomics, we have identified new AOPs triggered by mitochondrial toxicity. These activate stress in the endoplasmic reticulum and immunity pathways. Our current work focuses on increasing knowledge on the mechanism through which mitochondrial toxicity triggers these adverse outcomes and how their manipulation can restore mitochondrial health. This knowledge, derived from in vivo studies, is essential to improve drug safety and human health.
Our work is unravelling two novel AOPs identified by our team: activation of endoplasmic reticulum stress caused by direct contacts with mitochondria and activation of innate immune response pathways.
Our work is unravelling two novel AOPs identified by our team: activation of endoplasmic reticulum stress caused by direct contacts with mitochondria and activation of innate immune response pathways.
Organisations
People |
ORCID iD |
L. Miguel Martins (Principal Investigator) |
Publications
Rakhit CP
(2019)
Early detection of pre-malignant lesions in a KRASG12D-driven mouse lung cancer model by monitoring circulating free DNA.
in Disease models & mechanisms
Garrido-Maraver J
(2019)
Enhancing folic acid metabolism suppresses defects associated with loss of Drosophila mitofusin.
in Cell death & disease
Garrido-Maraver J
(2019)
Enhancing folic acid metabolism suppresses defects associated with loss of Drosophila mitofusin.
Garrido-Maraver J
(2020)
Forcing contacts between mitochondria and the endoplasmic reticulum extends lifespan in a Drosophila model of Alzheimer's disease.
in Biology open
Scialò F
(2020)
Mitochondrial complex I derived ROS regulate stress adaptation in Drosophila melanogaster.
in Redox biology
Travaglio M
(2020)
Links between air pollution and COVID-19 in England
Travaglio M
(2021)
Links between air pollution and COVID-19 in England.
Leal NS
(2021)
Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases.
in Biomedicines
Yu Y
(2021)
Alzheimer's and Parkinson's Diseases Predict Different COVID-19 Outcomes: A UK Biobank Study.
in Geriatrics (Basel, Switzerland)
Popovic R
(2021)
Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways.
in International journal of molecular sciences
Yu Y
(2021)
Parp mutations protect from mitochondrial toxicity in Alzheimer's disease.
in Cell death & disease
Travaglio M
(2021)
Links between air pollution and COVID-19 in England.
in Environmental pollution (Barking, Essex : 1987)
Georgiou M
(2022)
ATR and CDK4/6 inhibition target the growth of methotrexate-resistant choriocarcinoma.
in Oncogene
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_UU_00025/1 | 01/04/2018 | 31/07/2020 | £1,680,000 | ||
MC_UU_00025/2 | Transfer | MC_UU_00025/1 | 01/04/2018 | 30/09/2020 | £3,488,000 |
MC_UU_00025/3 | Transfer | MC_UU_00025/2 | 01/04/2018 | 31/03/2024 | £2,873,000 |
MC_UU_00025/4 | Transfer | MC_UU_00025/3 | 01/04/2018 | 31/03/2024 | £3,108,000 |
MC_UU_00025/5 | Transfer | MC_UU_00025/4 | 01/04/2018 | 31/03/2024 | £2,200,000 |
MC_UU_00025/6 | Transfer | MC_UU_00025/5 | 01/04/2018 | 31/05/2019 | £76,000 |
MC_UU_00025/7 | Transfer | MC_UU_00025/6 | 01/04/2018 | 31/03/2024 | £2,547,000 |
MC_UU_00025/8 | Transfer | MC_UU_00025/7 | 01/10/2019 | 31/03/2024 | £2,438,000 |
MC_UU_00025/9 | Transfer | MC_UU_00025/8 | 01/09/2019 | 31/03/2024 | £1,721,000 |
Description | Informed policy for the US Centers for Disease Control and Prevention on links between wildfire smoke and COVID-19 |
Geographic Reach | North America |
Policy Influence Type | Citation in other policy documents |
URL | https://stacks.cdc.gov/view/cdc/88968 |
Description | Interview by Green Party |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.youtube.com/watch?v=XM45qVmw6No&feature=youtu.be |
Description | Interview with BBC India |
Geographic Reach | Asia |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.bbc.co.uk/news/world-asia-india-54596245 |
Description | Interview with BBC radio Cambridgeshire |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Contribution to a national consultation/review |
Description | Interview with European Hospitals |
Geographic Reach | Europe |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://healthcare-in-europe.com/en/news/air-pollution-linked-to-higher-covid-19-mortality.html |
Description | Interview with Italian national news outlet Il Messaggero |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.ilmessaggero.it/salute/ricerca/coronavirus_smog_inquinamento_citta-5202505.html |
Description | Interview with The Guardian |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.theguardian.com/environment/2020/apr/20/air-pollution-may-be-key-contributor-to-covid-19... |
Description | Interview with Times of India |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://timesofindia.indiatimes.com/india/air-pollution-may-hinder-indias-fight-against-covid-19-say... |
Description | Interview with the Financial Times |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.ft.com/content/21f4ff6f-57ac-43cc-ae5b-602a127553de |
Description | Interview with the New Scientist |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.newscientist.com/article/2241778-are-you-more-likely-to-die-of-covid-19-if-you-live-in-a... |
Description | Live participation to France24 News |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.france24.com/en/video/20200427-preliminary-study-links-severity-of-illness-to-air-pollut... |
Description | Participation in a national consultation - Submitted advice to the House of Commons' Environment, Food & Rural Affairs Committee Inquiry on Air Quality |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://committees.parliament.uk/call-for-evidence/174/air-quality/ |
Description | Participation to the Naked Scientist podcast |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://www.thenakedscientists.com/articles/interviews/air-pollution-and-coronavirus |
Description | Submitted advice to the UK All-Party Parliamentary Group on Air Pollution |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
URL | https://appgairpollution.org |
Title | mRNA transcription profiling by array of adult flies expressing a artificial construct designed to bring mitochondria and the endoplasmic reticulum in close proximity |
Description | Microarray dataset |
Type Of Material | Database/Collection of data |
Year Produced | 2020 |
Provided To Others? | Yes |
Impact | Microarray data openly available to the scientific community |
URL | http://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-8468 |
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/ |
Title | Bioinformatic data analysis of outputs associated with enhanced contacts between mitochondria and the endoplasmic reticulum |
Description | Bioinformatic data analysis. |
Type Of Technology | Webtool/Application |
Year Produced | 2020 |
Impact | Identification of pathways associated with increased contacts between mitochondria and the endoplasmic reticulum |
URL | https://m1gus.github.io/Garrido_Maraver_MERCS/ |
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 | 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 | 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 | 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 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 | 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 | Parkinson's East Midlands Research Support Network, 7th Researchers Meeting 29th June 2019 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | A meeting between researchers, Parkinson's patients and Parkinson's UK. This included a series of short talks and a visit to our laboratory |
Year(s) Of Engagement Activity | 2019 |
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.... |