Investigation of the function of the ER/mitochondria contact sites in cell physiology and disease
Lead Research Organisation:
University of Cambridge
Department Name: UNLISTED
Abstract
Mitochondria are highly dynamic organelles essential for the survival of the cell. Mitochondrial dynamics has been linked to different physiological functions, and contacts with other organelles are required for specific metabolic activity and mitochondrial behaviour. Indeed, endoplasmic reticulum and mitochondria work together and their closed juxtaposition is considered as a signalling platform for metabolite flux. Alteration of these contacts has been associated with defects in cellular homeostasis and with human disease. The goal of our group is to characterise the architecture and understand the associated functions of these inter-organelle contacts. Using biochemical, molecular and cell biological approaches, we want to investigate the function of the mitochondria/endoplasmic reticulum contact sites in different cell physiology processes including cell death, lipid and calcium fluxes and cell migration. This work will lead us to obtaining new insights into the importance of mitochondria and mitochondria/ER contacts in cellular signalling pathways, and to better understanding the pathomechanisms underpinning human diseases associated with defects in their regulation and dynamics.
Technical Summary
Mitochondria are complex organelles that provide essentially all of the energy, mainly through ATP synthesis, required for normal physiological function in nearly all cells of the body. They also play a central role in a number of cell signaling pathways, including cell death and regulation of the intracellular calcium homeostasis. Mitochondria are highly dynamic organelles that can adapt their network in response to specific cellular needs. Indeed, they are able to constantly fuse and divide, and these events are intimately related to their metabolic functions and cellular stress signals. Impairment of mitochondrial physiology is linked to human diseases including neurodegenerative and metabolic disorders such as Parkinson’s disease and diabetes, and also in the progression of certain forms of cancer. It has become clear recently that mitochondria do not function in isolation, but establish direct contact and communication with other cellular organelles to exchange metabolites and signals converging on, or streaming from, mitochondria. For instance, mitochondria are physically coupled to the endoplasmic reticulum through contact sites that act as a signaling platform. These are called mitochondria-associated membranes (MAM), and are essential for a number of processes, including intracellular calcium homeostasis, lipid exchange, mitochondrial dynamics and motility, ROS production and apoptosis. Studies performed in the last decade have identified several proteins which directly tether the two organelles in MAMs and proteins enriched in these contact sites that play highly specialised homeostatic or execution roles. However, the biogenesis, regulation and precise molecular mechanisms associated with these signaling platforms are still poorly understood. The goal of our lab is to understand the physiological importance of these inter-organelle contacts in specific cellular contexts, including metabolite flux during steady state, and in response to specific triggers, particularly during cell death or cell migration. Using molecular biological and biochemical approaches we will focus on the characterisation of proteins localised at the interface of the mito/ER contacts sites, their potential role in the stability of the MAM structures, and their functions in lipid and calcium fluxes during the execution of the cell death programme. We will couple these techniques with the state-of-the-art advanced microscopic analysis, including spinning disc and scanning confocal systems, super-resolution microscopy, and electron microscopy. To unravel the function of mito/ER contacts sites on cell physiology, live cell imaging will be performed to study organelle movements during cell migration. The precise localisation of target proteins will be studied by the emergent super-resolution microscopy techniques. Finally, we are also interested in understanding the relevance of mitochondrial dynamics and MAMs in the context of mitochondrial disease. We will study the mitochondrial biology, in different cellular models derived from patients, to characterize how mitochondrial morphology and inter-organelle contacts are affected by different gene mutations, and how this contributes to disease progression.
People |
ORCID iD |
| Julien Prudent (Principal Investigator) |
Publications
Chinnery PF
(2019)
De-fusing mitochondria defuses the mtDNA time-bomb.
in Cell research
Agip A
(2019)
Mammalian Respiratory Complex I Through the Lens of Cryo-EM
in Annual Review of Biophysics
Robb E
(2019)
Correction: Control of mitochondrial superoxide production by reverse electron transport at complex I.
in Journal of Biological Chemistry
Von Stockum S
(2019)
Inhibition of the deubiquitinase USP8 corrects a Drosophila PINK1 model of mitochondria dysfunction.
in Life science alliance
Hirst J
(2019)
Comment on "Protein assemblies ejected directly from native membranes yield complexes for mass spectrometry".
in Science (New York, N.Y.)
Hoitzing H
(2019)
Energetic costs of cellular and therapeutic control of stochastic mitochondrial DNA populations
in PLOS Computational Biology
Van Der Lee SJ
(2019)
A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer's disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity.
in Acta neuropathologica
Signes A
(2019)
APOPT1/COA8 assists COX assembly and is oppositely regulated by UPS and ROS.
in EMBO molecular medicine
Van Haute L
(2019)
NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs.
Andreazza S
(2019)
Mitochondrially-targeted APOBEC1 is a potent mtDNA mutator affecting mitochondrial function and organismal fitness in Drosophila.
in Nature communications
Zhang A
(2019)
The structure of the catalytic domain of the ATP synthase from Mycobacterium smegmatis is a target for developing antitubercular drugs
in Proceedings of the National Academy of Sciences
Rebelo-Guiomar P
(2019)
The mammalian mitochondrial epitranscriptome
in Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Saoura M
(2019)
Mutations in ELAC2 associated with hypertrophic cardiomyopathy impair mitochondrial tRNA 3'-end processing.
in Human mutation
Costa R
(2019)
Impaired Mitochondrial ATP Production Downregulates Wnt Signaling via ER Stress Induction.
in Cell reports
Ng Y
(2019)
Pathogenic variants in MT-ATP6 : A United Kingdom-based mitochondrial disease cohort study
in Annals of Neurology
Gammage P
(2019)
Mitochondrial DNA: the overlooked oncogenome?
Gammage P
(2019)
Mitochondrial DNA: the overlooked oncogenome?
in BMC Biology
Van Haute L
(2019)
NSUN2 introduces 5-methylcytosines in mammalian mitochondrial tRNAs
Sommerville E
(2019)
Identification of a novel heterozygous guanosine monophosphate reductase ( GMPR ) variant in a patient with a late-onset disorder of mitochondrial DNA maintenance
in Clinical Genetics
Musumeci O
(2019)
Lipomatosis Incidence and Characteristics in an Italian Cohort of Mitochondrial Patients
in Frontiers in Neurology
Viscomi C
(2019)
Breathe: Your Mitochondria Will Do the Rest If They Are Healthy!
in Cell metabolism
Guyatt AL
(2019)
A genome-wide association study of mitochondrial DNA copy number in two population-based cohorts.
in Human genomics
Tavoulari S
(2019)
The yeast mitochondrial pyruvate carrier is a hetero-dimer in its functional state
in The EMBO Journal
Oláhová M
(2019)
Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease.
in Human molecular genetics
Nissanka N
(2019)
Mechanisms of Mitochondrial DNA Deletion Formation.
Ruprecht J
(2019)
Editorial overview: COSB Membranes.
in Current opinion in structural biology
Nissanka N
(2019)
Mechanisms of Mitochondrial DNA Deletion Formation.
in Trends in genetics : TIG
Wei W
(2019)
Germline selection shapes human mitochondrial DNA diversity.
in Science (New York, N.Y.)
Haute L
(2019)
METTL15 introduces N4-methylcytidine into human mitochondrial 12S rRNA and is required for mitoribosome biogenesis
in Nucleic Acids Research
Izreig S
(2020)
Repression of LKB1 by miR-17~92 Sensitizes MYC-Dependent Lymphoma to Biguanide Treatment.
in Cell reports. Medicine
Ruprecht JJ
(2020)
The SLC25 Mitochondrial Carrier Family: Structure and Mechanism.
in Trends in biochemical sciences
Schon K
(2020)
Mitochondrial Diseases: A Diagnostic Revolution
in Trends in Genetics
Bridges HR
(2020)
Structure of inhibitor-bound mammalian complex I.
in Nature communications
Steele H
(2020)
Metabolic effects of bezafibrate in mitochondrial disease
in EMBO Molecular Medicine
Kunji E
(2020)
The SLC25 Carrier Family: Important Transport Proteins in Mitochondrial Physiology and Pathology
in Physiology
Kunji ERS
(2020)
The mitochondrial ADP/ATP carrier exists and functions as a monomer.
in Biochemical Society transactions
Desai N
(2020)
Elongational stalling activates mitoribosome-associated quality control
in Science
He J
(2020)
Assembly of the peripheral stalk of ATP synthase in human mitochondria
in Proceedings of the National Academy of Sciences
Wei W
(2020)
Author Correction: Nuclear-mitochondrial DNA segments resemble paternally inherited mitochondrial DNA in humans
in Nature Communications
Cortese A
(2020)
Cerebellar ataxia, neuropathy, vestibular areflexia syndrome due to RFC1 repeat expansion.
in Brain : a journal of neurology
Prole D
(2020)
Visualizing, quantifying, and manipulating mitochondrial DNA in vivo
in Journal of Biological Chemistry
| Description | Daiichi Sankyo Foundation of Life Science fellowship programme |
| Amount | £40,125 (GBP) |
| Organisation | Daiichi Sankyo Company |
| Sector | Private |
| Country | Japan |
| Start | 08/2017 |
| End | 09/2019 |
| Description | Isaac Newton Trust / Wellcome Trust ISSF / University of Cambridge Joint Research |
| Amount | £85,000 (GBP) |
| Organisation | University of Edinburgh |
| Department | Institutional Strategic Support Fund |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2018 |
| End | 03/2020 |
| Description | Postdoctoral Marie Sklodowska-Curie fellowship 2017 |
| Amount | £183,455 (GBP) |
| Funding ID | MITODYN |
| Organisation | Marie Sklodowska-Curie Actions |
| Sector | Charity/Non Profit |
| Country | Global |
| Start | 06/2017 |
| End | 07/2019 |
| Description | Ramon Areces Foundation postdoctoral fellowship |
| Amount | € 48,000 (EUR) |
| Organisation | Ramón Areces Foundation |
| Sector | Charity/Non Profit |
| Country | Spain |
| Start | 09/2019 |
| End | 10/2021 |
| Description | Characterization of TMEM63C |
| Organisation | University of Exeter |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | With Pr. Andrew Crosby and Dr. Emma Baple (University of Exeter, UK), we have identified and characterized TMEM63C as a new disease gene involved in hereditary Spastic Paraplegia. Co-lead the project, Scientific expertize, intellectual input, exchange of ideas, perform experiments. |
| Collaborator Contribution | Co-lead the project, Scientific expertize, intellectual input, exchange of ideas, perform experiments. |
| Impact | Manuscript just accepted for publication in Brain. |
| Start Year | 2019 |
| Description | Detection of membrane contact sites |
| Organisation | University of Cambridge |
| Department | Department of Clinical Neurosciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Collaboration with Pr. Patrick Yu Wai Man (Clinical neurosciences, University of Cambridge) on the contribution of MERCs to optic neuropathies. Scientific expertize, intellectual input, exchange of ideas, perform experiments, sharing of reagents, host student |
| Collaborator Contribution | Initiate the project, Scientific expertize, intellectual input, exchange of ideas, perform experiments. |
| Impact | Publication: PMID: 34656549 |
| Start Year | 2017 |
| Description | Linking mTOR signalling, mitochondrial dynamics and cell survival |
| Organisation | McGill University |
| Country | Canada |
| Sector | Academic/University |
| PI Contribution | In this collaboration, I provided scientific expertise, intellectual input and performed experiments for our publication. |
| Collaborator Contribution | Collaborators designed the project, contributed to scientific expertize and intellectual input, allowed facility access and performed the experiments. |
| Impact | Publication: doi: 10.1016/j.molcel.2017.08.013. PMID: 28918902. |
| Start Year | 2014 |
| Description | Mitochondria and CTL killing capacities |
| Organisation | University of Cambridge |
| Department | Cambridge Institute for Medical Research (CIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Scientific expertize, intellectual input, exchange of ideas, sharing of reagents, perform experiments |
| Collaborator Contribution | Our collaborator has established, developed and performed the project |
| Impact | Multi-disciplinary project from Immunology to cell biology and mitochondrial biology. This collaboration let to a scientific publication (PMID: 34648346). |
| Start Year | 2018 |
| Description | Mitochondrial calcium and cancer cell migration |
| Organisation | Claude Bernard University Lyon 1 (UCBL) |
| Country | France |
| Sector | Academic/University |
| PI Contribution | I contributed to design and start the project, scientific expertize and intelectual input. |
| Collaborator Contribution | They performed all the experiements and contributed to scientific expertize |
| Impact | Publications: doi: 10.1038/srep36570. PMID: 27827394 DOI: 10.5772/intechopen.74494 |
| Start Year | 2012 |
| Description | Mitochondrial dynamics and contact sites |
| Organisation | McGill University |
| Department | Montreal Neurological Institute and Hospital |
| Country | Canada |
| Sector | Hospitals |
| PI Contribution | Scientific expertize, intellectual input, exchange of ideas |
| Collaborator Contribution | Scientific expertize, intellectual input, exchange of ideas |
| Impact | Publication: doi: 10.1016/j.ceb.2017.03.007. PMID: 28391089 |
| Start Year | 2013 |
| Description | Mitofusins and metabolism |
| Organisation | University of Cambridge |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | In collaboration with Pr. David Savage from the Metabolic Research Laboratories, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, UK, and Pr. R Semple (University of Edinburgh, UK) we explore how mutant/loss of Mitofusins and mitochondrial fusion affect adipogenesis. In my lab, we investigate how mutation or the loss in Mfns control different mitochondrial functions, including bioenergetics, morphology and membrane contact sites with other organelles, using a specific mice model with Mfn2 mutation or in vitro models, generated by the lab of Pr. David Savage. |
| Collaborator Contribution | Pr D.Savage and R. Semple has generated and characterised different models of mitochondrial dysfunction, including Mfn2 mutant KI mice or different in vitro cell models, top investigate how Mfns and mitochondrial fusion control Adipocyte biology and metabolism. They are leading the collaboration. |
| Impact | This a multi-disciplenary project combining in vivo, metabolism adipocytes biology, mitochondria, bioenergetics and microscopy. This collaboration let to two publications, one published in elife and one in Biorxiv. |
| Start Year | 2020 |
| Description | Access Students from Cambridge Regional College |
| 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 | 11 Access students from Cambridge Regional College visited the MBU for a "Biology Masterclass", a visit to the fly laboratory and a "meet the scientists" session, where hands-on "festival" activities were available. |
| Year(s) Of Engagement Activity | 2022 |
| 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. Feedback: Interesting, fun, enjoyable. 2019: Members of the MBU took Mito-gami, "Destroying Mutant Mitochondrial DNA", DNA sequencing puzzles and colouring/activity books. There was much conversation about the science and career options. |
| Year(s) Of Engagement Activity | 2017,2018,2019 |
| URL | http://www.hillsroad.ac.uk/college-life/events/2017/10/14/default-calendar/big-biology-day |
| Description | Big Biology Day 2022, 2023, 2024 |
| 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 | 2022,2024 |
| URL | https://www.mrc-mbu.cam.ac.uk/news/mrc-mbu-big-biology-day-2022 |
| Description | Dissemination of scientific achievements via the Unit's 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 | https://www.facebook.com/mrc-mbu Twitter - @LabPrudent and @MRC_MBU https://www.mrc-mbu.cam.ac.uk/research-groups/prudent-group https://www.mrc-mbu.cam.ac.uk |
| Year(s) Of Engagement Activity | 2017,2018,2019,2020,2021,2022 |
| URL | https://www.mrc-mbu.cam.ac.uk/research-groups/prudent-group |
| Description | The Big Bang Fair London - Newham |
| 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 | Demonstration of genetic influence on body characteristics in Drosophila, "Find My Mutant Fly" game, posters explaining the science, movies. |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://nearme.thebigbangfair.co.uk/london/ |
| 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 | Up close and personal with fluorescent fruit flies. Members of the MBU showcased the Unit's research using fluorescent fruit flies - examined under a microscope. Temperature sensitive fruit flies were also used to demonstrate the effects of Parkinson's disease. Other activities included movies, posters, a game of elimination and an MRC Cambridge colouring book. 2019: Further showcasing of the Unit's research through the use of hands-on games and activities, discussions and explanations. |
| Year(s) Of Engagement Activity | 2017,2018,2019 |
| 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 | 2022,2023,2024,2025 |
| URL | https://www.mrc-mbu.cam.ac.uk/research-groups/prudent-group |
| Description | YSGOL John Bright Comprehensive School: Virtual Biology Masterclass |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | A level Biology students at YSGOL John Bright Comprehensive School, in Llandudno (North Wales) received a "Biology Masterclass" from Jordan Morris (a PhD student in my research group), who discussed with them the many roles of mitochondria in the cell, and how his work on the fundamental principles of mitochondrial biology has implications for the treatment of cancer. Feedback from tutor: The students really engaged with Jordan's excellent presentation; it was well linked to their A level studies, allowing them to engage with concepts they have begun to understand, whilst challenging them to think about the bigger picture of how their studies are relevant and applicable to current research. It has generated a good deal of discussion about mitochondria and cell biology, and started conversations about students' choices for their own future careers. We are grateful to Jordan for taking the time to join us, and it was especially welcome at this time where our students' expected journey through their education has been disrupted. The A level students will be carrying out work based on what they learnt from Jordan's talk, and how it fits in with the work they do in A level Biology. |
| Year(s) Of Engagement Activity | 2020 |