Mitochondrial oxidative damage and human diseases
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
A number of human diseases are associated with increased cell death caused by free radicals. These include degenerative diseases such as Parkinson's disease, Friedreich's ataxia and diabetes. Free radicals are reactive by-products of normal metabolism that damage cell components thereby disrupting normal function and leading to cell death. Mitochondria are the major source of free radicals within cells. These free radicals are formed as mitochondria consume the oxygen we breathe to make energy available to the cell. Mitochondria are also central to determining how cells die, consequently free radical damage to mitochondria is an important cause of cell death. We have developed procedures to target novel molecules to mitochondria. The hope is that these new molecules will enable us to elucidate the mechanisms by which free radicals damage mitochondria and increase cell death in human diseases. Some of these molecules are antioxidants that should block the effects of free radicals. Therefore this approach may also lead to novel therapies to decrease mitochondrial oxidative stress in human diseases such as Alzheimer's Disease and Parkinson's Disease.
Technical Summary
Mitochondria are central to the function of human cells because they make energy available to the cell in a usable form and because they are central to a number of pathways of cell death. Consequently it is unsurprising that defects in mitochondrial function contribute to a number of human diseases, including neurodegenerative diseases such as Parkinson's disease and Friedreich's ataxia. Damage to mitochondria also contributes to the pathophysiology of heart attack, stroke and diabetes. In this project my group are developing new tools to target molecules to mitochondria in order to understand the processes by which mitochondrial damage occurs and to develop ways in which this damage can be prevented or repaired in human diseases. In carrying out this work we seek to understand how mitochondrial damage occurs in yeast, cultured mammalian cells and in rodent models of mitochondrial damage. One of the most important causes of mitochondrial damage is thought to be the formation of free radicals by mitochondria as a byproduct of their normal function. These short lived but reactive species cause damage to mitochondria DNA, proteins and lipids thereby disrupting normal mitochondrial function. A consequence of this damage is that it causes cells to undergo cell death by both apoptotic and necrotic pathways. We are particularly interested in understanding the links between mitochondrial damage and increased cell death. To unravel the role of mitochondrial free radicals in cell death requires a range of techniques from molecular biology, cell biology and biochemistry. In addition to these standard approaches, we are also developing a strategy that is proving to be particularly useful. This is the selective targeting of molecules to mitochondria within cells. To do this we use the large membrane potential across the mitochondrial inner member to drive the uptake of lipophilic cations to which we have attached biologically active molecules. These active molecules include antioxidants and reporter molecules designed to respond to free radicals. By using these molecules we are able to both estimate and block mitochondrial oxidative damage, and thereby infer its role in cell death. In related work we are also developing strategies to direct large molecules such as proteins and nucleic acids to mitochondria in order to repair the damage caused to mitochondria by free radicals. The approaches we are developing may allow us to measure or manipulate mitochondria processes independently of the rest of the cell. This has scientific potential in helping us understand the roles of mitochondria within the cell. As some of the molecules being developed may prevent or repair mitochondrial damage they may lead to improved therapies for human diseases involving mitochondrial dysfunction. These include degenerative diseases such as Parkinson's disease and diabetes and the general pathological changes associated with ageing.
People |
ORCID iD |
Michael Murphy (Principal Investigator) |
Publications
Abe J
(2024)
Malonate given at reperfusion prevents post-myocardial infarction heart failure by decreasing ischemia/reperfusion injury.
in Basic research in cardiology
Antonucci S
(2019)
Selective mitochondrial superoxide generation in vivo is cardioprotective through hormesis.
in Free radical biology & medicine
Beach TE
(2020)
Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury.
in Redox biology
Bjedov I
(2020)
Fine-tuning autophagy maximises lifespan and is associated with changes in mitochondrial gene expression in Drosophila.
in PLoS genetics
Description | Bradley-NIHR |
Organisation | University of Cambridge |
Department | Department of Surgery |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Lead of cross cutting Theme 8: "Mitochondrial Biology". |
Collaborator Contribution | Lead of cross cutting Theme 8: "Mitochondrial Biology". |
Impact | . |
Start Year | 2014 |
Description | Evelyn Trust |
Organisation | University of Cambridge |
Department | Department of Surgery |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Scientific and technical expertise in the collaboration "Antioxidant therapy after renal transplantation". |
Collaborator Contribution | Dr Kourosh Saeb-Parsy, Department of Surgery, University of Cambridge. Clinical expertise in the collaboration "Antioxidant therapy after renal transplantation". |
Impact | doi: 10.1016/j.redox.2015.04.008; |
Start Year | 2014 |
Title | MITOCHONDRIA-TARGETED DICARBONYL SEQUESTERING COMPOUNDS |
Description | The invention relates to compounds having Formula (1): A-L-B or pharmaceutically acceptable salts thereof, wherein: A is a dicarbonyl sequestering moiety comprising a substituted aryl group or a substituted heteroaryl group; L is an optional linker moiety; and B is a mitochondrial targeting moiety. The invention also relates to pharmaceutical compositions containing such compounds and salts, and to the use of such compounds and salts for treating diabetes, preferably hyperglycaemic diabetes. A m |
IP Reference | ZA201603129 |
Protection | Patent granted |
Year Protection Granted | 2018 |
Licensed | No |
Impact | The invention relates to compounds having Formula (1): A-L-B or pharmaceutically acceptable salts thereof, wherein: A is a dicarbonyl sequestering moiety comprising a substituted aryl group or a substituted heteroaryl group; L is an optional linker moiety; and B is a mitochondrial targeting moiety. The invention also relates to pharmaceutical compositions containing such compounds and salts, and to the use of such compounds and salts for treating diabetes, preferably hyperglycaemic diabetes. A m |
Description | "Saturday Morning" Radio Show (NZ) |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I talked on a NZ radio show about the development of anti-oxidants that fight aging. Impact: increased awareness |
Year(s) Of Engagement Activity | 2018 |
Description | Big Biology Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | Members of the MRC MBU participated in the Big Biology Day 2017 at Hills Road Sixth Form College. Scientists explained the Unit's research with hands-on activities. These included experiments using Drosophila melanogaster - with fluorescent markings and temperature sensitivity, our "Find the mutant fly" game, colouring books and posters. BBD 2019 included further hands-on activities to showcase the Unit's research. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.hillsroad.ac.uk/college-life/events/2017/10/14/default-calendar/big-biology-day |
Description | Big Biology Day 2022 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Hands on, interactive activities showcasing the MBU's research on mitochondria, careers advice. Activities will include our MITOTrumps card game, demonstrations using fruit flies and mitochondrial pinball. |
Year(s) Of Engagement Activity | 2022 |
Description | Czech TV Channel CT24 |
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 | Interview with Mike Murphy explaining how succinate accumulation drives ischaemia-reperfusion injury during organ transplantation. Impact: increased awareness. |
Year(s) Of Engagement Activity | 2019 |
Description | Dissemination of scientific achievements via the internet |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Dissemination of scientific achievements to the general public, scientists and others via the Unit's website, Twitter and Facebook. https://www.facebook.com/mrc.mbu/ Twitter - @MRC_MBU https://www.mrc-mbu.cam.ac.uk https://www.mrc-mbu.cam.ac.uk/research-groups/murphy-group |
Year(s) Of Engagement Activity | 2021,2022 |
URL | https://www.mrc-mbu.cam.ac.uk/research-groups/murphy-group |
Description | Dissemination of scientific achievements via the internet |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Dissemination of scientific achievements to the general public, scientists and others via the Unit's website, Alpha Galileo, Twitter and Facebook. https://www.facebook.com/mrc.mbu/ Twitter - @MRC_MBU http://www.mrc-mbu.cam.ac.uk http://www.alphagalileo.org http://www.mrc-mbu.cam.ac.uk/people/mike-murphy |
Year(s) Of Engagement Activity | 2015,2016,2017,2018,2019,2020,2021 |
URL | http://www.mrc-mbu.cam.ac.uk/people/mike-murphy |
Description | Goop Newsletter |
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 | Article for Goop Newsletter, "Why Your Mitochondrial Health Matters". |
Year(s) Of Engagement Activity | 2018 |
URL | https://goop.com/wellness/health/why-your-mitochondrial-health-matters/ |
Description | I'm A Scientist - Stay at Home |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Schools |
Results and Impact | Online annual event hosted by the MRC to facilitate interactive discussions with school students. |
Year(s) Of Engagement Activity | 2020 |
URL | https://imascientist.org.uk/ |
Description | MRC MBU Annual Open Day/MRC Festival of Medical Research |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Overview of work at the MRC MBU; explanations of how mitochondrial dysfunction causes mitochondrial diseases. Audience: Secondary school students, tutors, general public and scientists from neighbouring institutes. Impact: increased awareness. Impact: request to visit schools in Hertfordshire. |
Year(s) Of Engagement Activity | 2015,2016,2017 |
URL | http://www.mrc-mbu.cam.ac.uk/news/2335/open-day-2015 |
Description | Mayfield Primary School Science Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | Members of the MBU visited Mayfield Primary School, Cambridge to participate in their Science Day. This was a classroom based event, with students in Reception (aged 4 and 5 years) rotating around the room. After a short talk, the children interacted with Lego models, pipetting and colouring. |
Year(s) Of Engagement Activity | 2017 |
Description | Queen Edith's Primary School |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Members of the MBU visited Queen Edith's Primary School, Cambridge to participate in their Science Day. This was a carousel-type event, with students in years 1-4 rotating around the room. The demonstrations included Lego models, computer games, pipetting and DNA sequencing puzzles. Feedback: Thank you so much for coming here today. The children have not stopped talking about it since leaving the room. |
Year(s) Of Engagement Activity | 2017 |
Description | RAREfest 2022 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | MBU volunteers showcased the Unit's research via posters, discussions and hands-on activities. The event was organised by the Rare Disease Network. It is held every two years and is aimed at providing a platform of communication for patients, their families and carers, healthcare professionals/providers and researchers. Video footage is available here: https://www.youtube.com/@mrcmitochondrialbiologyun i211/playlists |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.camraredisease.org/rarefest22/ |
Description | Radio documentary (Ireland) |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | I talked on a radio show about the development of anti-oxidants that fight aging. Feedback - increased awareness. |
Year(s) Of Engagement Activity | 2018 |
Description | University of Cambridge Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Demonstrating how mitochondrial dysfunction leads to illness and giving insight into the work of the MBU. Interest in attending the Unit's open day in June; requests for summer studentships and work experience visits. |
Year(s) Of Engagement Activity | 2015,2016,2017 |
URL | http://www.sciencefestival.cam.ac.uk/about/past-festivals/2015-cambridge-science-festival |
Description | Website and social media |
Form Of Engagement Activity | Engagement focused website, blog or social media channel |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | My research is promoted on the MBU's website and via social media channels, such as Facebook and Twitter. This leads to various forms of engagement - increased awareness, requests for further information, potential collaborations etc. |
Year(s) Of Engagement Activity | 2022,2023,2024 |
URL | https://www.mrc-mbu.cam.ac.uk/research-groups/murphy-group |
Description | Women in Science at Comberton Village College |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | The aim of the event was to encourage female students to consider sciences/technology and engineering as a career option available to them. It is hoped that the students who attended the event will be better informed to make career choices and motivated succeed in the coming months. Our scientists took a presentation, along with Lego models and DNA sequencing puzzles, and the students were heavily engaged in dialogue during the event. |
Year(s) Of Engagement Activity | 2017 |
Description | Work experience visit |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | An A level student visited my lab for a work experience visit and shadowed researchers to get a feel for laboratory research work. |
Year(s) Of Engagement Activity | 2022 |