Mitochondria are double-membrane-bound organelles that are essential for cellular energy production. A fundamental question in eukaryotic cell biology is how the biogenesis of mitochondria is achieved and regulated
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
Mitochondria are key parts of the cell whose central role is to produce energy in a suitable form for many biological processes. They are also involved in programmed cell death, and in maintaining appropriate levels of calcium in cells. These activities require mitochondria to communicate with the cell nucleus. Disruption of mitochondrial function can lead to a broad range of human diseases including diabetes, neurodegenerative disorders, obesity, cancer and premature ageing. Therefore, a full understanding of the basic processes in mitochondria is needed to identify the causes and consequences of mitochondrial malfunction and to enable us to design new therapies that compensate for or correct such faults. This programme will study how mitochondria are made and how their function responds to the changing requirements of the cell during growth and development.
Technical Summary
Mitochondria are double-membrane-bound organelles that are essential for cellular energy production. A fundamental question in eukaryotic cell biology is how the biogenesis of mitochondria is achieved and regulated. The process requires the targeting, import and assembly of over 1500 proteins encoded in nuclear DNA. Because mitochondria also contain their own DNA (mtDNA), which in human contributes 13 key components of the energy production apparatus, bidirectional communication between the nucleus and the mitochondria is essential to produce the desired mitochondrial activity. Our knowledge of nucleus to mitochondria (anterograde) signalling pathways coordinating mitochondrial biogenesis is expanding rapidly, and is known to involve the actions of three factors: AMP kinase, Sirt1 and PGC1a. In contrast, the characterization of the key mitochondrial factors that contribute to the regulation of biogenesis, as well as factors involved in the retrograde response (signalling from mitochondria to the nucleus) is much more limited.
Recently my group has discovered a mitochondrial protein, MPV17, with the intrinsic capacity to stimulate mitochondrial function. MPV17 is an inner mitochondrial membrane protein of unknown function, which belongs to a small family of conserved proteins. In 2006, the identification of MPV17 as the gene responsible for a form of mitochondrial DNA depletion syndrome (MDS) linked its protein product to mtDNA maintenance in vivo. Mitochondrial DNA defects were established as a cause of human disease 25 years ago, and yet there is still much that remains obscure about mtDNA maintenance. In animals and plants almost nothing is known about the anchoring, segregation or transmission of mtDNA. Furthermore, mitochondrial (DNA) dysfunction is also implicated in several common disorders, such as neurodegenerative disease, metabolic syndrome and obesity. Thus the functional characterization of proteins causing mitochondrial disease, such as MPV17, is critical to a full understanding of the role of mitochondria in human health, and the design of rational therapeutic strategies. An ability to stimulate mitochondrial biogenesis is widely recognised as the best immediate prospect for treating mitochondrial dysfunction. Hence, the new finding of MPV17’s effect on mitochondrial biogenesis provides a major new target for this approach, which will be best exploited with knowledge of its mechanism of action.
The plan is to elucidate MPV17’s mechanism of action by dissecting the protein and its partners, studying its pathological variants and the regulation of MPV17 gene expression. Specific aims are: 1) To determine the functional and physiological impacts of MPV17 ablation and mutation via proteomic and metabolite profiling of mutant cell lines and an Mpv17 knockout mouse. Fibroblast deficient cell lines, DG75 mutant and a knockout mouse model for MPV17 are already providing us with material for analysis, and they will be used in the future for transcriptomic, proteomic and metabolomic analyses, and for interventions designed to ameliorate its loss. 2) To characterize MPV17’s protein partners by affinity purification and use truncated forms of the protein to identify the key elements needed for these protein-protein interactions. 3) To dissect the stimulatory effects of MPV17 on mitochondrial biogenesis via metabolic, proteomic, and ultrastructure analyses.
Our studies of MPV17 have led to the realization that the metabolic conditions for cell growth have a major impact on mitochondrial function. We have identified nutrient growth regimes that stimulate mitochondrial protein synthesis while repressing protein synthesis in the cytosol. Therefore we predict that some mechanisms of stimulating mitochondrial capacity will repress cytosolic protein synthesis and thereby arrest cell growth and division.
Recently my group has discovered a mitochondrial protein, MPV17, with the intrinsic capacity to stimulate mitochondrial function. MPV17 is an inner mitochondrial membrane protein of unknown function, which belongs to a small family of conserved proteins. In 2006, the identification of MPV17 as the gene responsible for a form of mitochondrial DNA depletion syndrome (MDS) linked its protein product to mtDNA maintenance in vivo. Mitochondrial DNA defects were established as a cause of human disease 25 years ago, and yet there is still much that remains obscure about mtDNA maintenance. In animals and plants almost nothing is known about the anchoring, segregation or transmission of mtDNA. Furthermore, mitochondrial (DNA) dysfunction is also implicated in several common disorders, such as neurodegenerative disease, metabolic syndrome and obesity. Thus the functional characterization of proteins causing mitochondrial disease, such as MPV17, is critical to a full understanding of the role of mitochondria in human health, and the design of rational therapeutic strategies. An ability to stimulate mitochondrial biogenesis is widely recognised as the best immediate prospect for treating mitochondrial dysfunction. Hence, the new finding of MPV17’s effect on mitochondrial biogenesis provides a major new target for this approach, which will be best exploited with knowledge of its mechanism of action.
The plan is to elucidate MPV17’s mechanism of action by dissecting the protein and its partners, studying its pathological variants and the regulation of MPV17 gene expression. Specific aims are: 1) To determine the functional and physiological impacts of MPV17 ablation and mutation via proteomic and metabolite profiling of mutant cell lines and an Mpv17 knockout mouse. Fibroblast deficient cell lines, DG75 mutant and a knockout mouse model for MPV17 are already providing us with material for analysis, and they will be used in the future for transcriptomic, proteomic and metabolomic analyses, and for interventions designed to ameliorate its loss. 2) To characterize MPV17’s protein partners by affinity purification and use truncated forms of the protein to identify the key elements needed for these protein-protein interactions. 3) To dissect the stimulatory effects of MPV17 on mitochondrial biogenesis via metabolic, proteomic, and ultrastructure analyses.
Our studies of MPV17 have led to the realization that the metabolic conditions for cell growth have a major impact on mitochondrial function. We have identified nutrient growth regimes that stimulate mitochondrial protein synthesis while repressing protein synthesis in the cytosol. Therefore we predict that some mechanisms of stimulating mitochondrial capacity will repress cytosolic protein synthesis and thereby arrest cell growth and division.
Organisations
- University College London (Fellow, Lead Research Organisation)
- Francis Crick Institute (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- University College London (Collaboration)
- Zogenix Inc (Collaboration)
- Newcastle University (Collaboration)
- Ospedale Pediatrico Bambino Gesu (OPBG) (Collaboration)
- Centre for Cooperative Research in Biomaterials (CIC BiomaGUNE) (Collaboration)
- The Lily Foundation (Collaboration)
- Helmholtz Association of German Research Centres (Collaboration)
Publications
Akman G
(2016)
Pathological ribonuclease H1 causes R-loop depletion and aberrant DNA segregation in mitochondria.
in Proceedings of the National Academy of Sciences of the United States of America
Malena A
(2016)
Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA.
in Autophagy
Dalla Rosa I
(2016)
MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria.
in PLoS genetics
Bugiardini E
(2017)
Clinicopathologic and molecular spectrum of RNASEH1-related mitochondrial disease.
in Neurology. Genetics
Moss C
(2017)
Aberrant ribonucleotide incorporation and multiple deletions in mitochondrial DNA of the murine MPV17 disease model
in Nucleic Acids Research
Desai R
(2017)
ATAD3 gene cluster deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism.
in Brain : a journal of neurology
Frazier AE
(2017)
Reply: Genotype-phenotype correlation in ATAD3A deletions: not just of scientific relevance.
in Brain : a journal of neurology
Cluett TJ
(2018)
Transcript availability dictates the balance between strand-asynchronous and strand-coupled mitochondrial DNA replication.
in Nucleic acids research
Durigon R
(2018)
LETM 1 couples mitochondrial DNA metabolism and nutrient preference
in EMBO Molecular Medicine
De La Casa-Fages B
(2019)
Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.
in Movement disorders : official journal of the Movement Disorder Society
Related Projects
Project Reference | Relationship | Related To | Start | End | Award Value |
---|---|---|---|---|---|
MC_PC_13029/1 | 23/01/2013 | 30/08/2016 | £184,168 | ||
MC_PC_13029/2 | Transfer | MC_PC_13029/1 | 31/08/2016 | 31/01/2019 | £1,042,186 |
Description | Bologna, Italy |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Impact | PMID: 32898308 |
Description | ENMC, Heemskerk, The Netherlands. |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
Description | Quality control of the Mitochondrial Gene Expression System in health and disease |
Amount | £2,600,000 (GBP) |
Organisation | Marie Sklodowska-Curie Actions |
Sector | Charity/Non Profit |
Country | Global |
Start | 09/2022 |
End | 09/2026 |
Title | New sequencing method |
Description | The new method is able to determine the identity of the embedded ribonucleotides incorporated in DNA. We have used the new method to study the ribonucleotide incorporation in mitochondrial DNA in health and disease state. |
Type Of Material | Technology assay or reagent |
Year Produced | 2017 |
Provided To Others? | Yes |
Impact | The method has allowed the identification of a new mtDNA abnormality, which we predict to be a feature of many disorders in which mitochondrial function is impaired |
Title | Nucleotide measurement |
Description | We have developed a novel non-radioactive method capable of accurately determining the concentration of the building blocks for DNA synthesis (nucleotides) in both cytosol and mitochondria. To validate its reliability, we compared the obtained values with those derived from the standard radioactive-based assay. |
Type Of Material | Technology assay or reagent |
Year Produced | 2023 |
Provided To Others? | No |
Impact | This method has enabled us to measure the levels of nucleotides in tissues of mice subjected to potential therapeutic interventions identified by our group. We are currently preparing a manuscript outlining these findings, which we plan to submit to a high-profile journal. We anticipate that other researchers in the field will adopt this method due to its efficiency and reliability. |
Title | small molecules |
Description | Identification of small molecules that purge the cells of mutant mitochondrial genome and restore mitochondrial function |
Type Of Material | Technology assay or reagent |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | One of the molecules tested in control animal increases mitochondrial functionality. Currently, the team is preparing a clinical trial to test the effect of the compound on a cohort of patients with mitochondrial DNA disorders. |
Description | Elucidating the function of MPV17p |
Organisation | Francis Crick Institute |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | We isolated RNA from Mpv17 WT and KO mouse tissues |
Collaborator Contribution | Transcriptomic analysis of Mpv17 WT and KO mouse tissues |
Impact | Signalling pathways and compensatory mechanisms associated to the tissue-specific Mpv17 dysfunction |
Start Year | 2016 |
Description | Manipulating the selection of mtDNA variants |
Organisation | Newcastle University |
Department | Wellcome Trust Centre for Mitochondrial Research |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Investigating the effects of a small molecule on the level of mutated mtDNA and mitochondrial respiration. |
Collaborator Contribution | Recruitment of patients and their clinical assessment and follow up |
Impact | To determine whether the compound that works in in vitro systems is also effective in vivo. |
Start Year | 2018 |
Description | Manipulating the selection of mtDNA variants |
Organisation | The Lily Foundation |
Country | United Kingdom |
Sector | Charity/Non Profit |
PI Contribution | Investigating the effects of a small molecule on the level of mutated mtDNA and mitochondrial respiration. |
Collaborator Contribution | Recruitment of patients and their clinical assessment and follow up |
Impact | To determine whether the compound that works in in vitro systems is also effective in vivo. |
Start Year | 2018 |
Description | Manipulating the selection of mtDNA variants |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Investigating the effects of a small molecule on the level of mutated mtDNA and mitochondrial respiration. |
Collaborator Contribution | Recruitment of patients and their clinical assessment and follow up |
Impact | To determine whether the compound that works in in vitro systems is also effective in vivo. |
Start Year | 2018 |
Description | Measurement of metabolites |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Tissues samples from WT and Mpv17 KO mice |
Collaborator Contribution | Determination of metabolites in several tissues |
Impact | The effect of mtDNA perturbation on cellular metabolism |
Start Year | 2018 |
Description | Molecular basis of mitochondrial disorders |
Organisation | University College London |
Department | Institute of Neurology |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Characterization of the biochemical and molecular phenotypes in patient-derived cells and tissues |
Collaborator Contribution | The partners have identified new genes likely causative of human disorders. They have provided cell lines and tissues from affected patients |
Impact | Changes in mitochondrial metabolism supportive of the functional role of the causative genes. Papers in high profile journal |
Start Year | 2016 |
Description | Molecular basis of mitochondrial myopathy |
Organisation | Newcastle University |
Department | Mitochondrial Research Group |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | In situ analysis of mtDNA distribution and the cellular response to mitochondrial DNA instability |
Collaborator Contribution | Providing muscle biopsy from subjects with mtDNA disorders and controls |
Impact | Identification of processes and pathways supporting the genesis and propagation of mutant mtDNA. Publication in journal of high profile. |
Start Year | 2019 |
Description | Molecular basis of mitochondrial myopathy |
Organisation | Newcastle University |
Department | Wellcome Trust Centre for Mitochondrial Research |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Muscle samples from WT and KO mice |
Collaborator Contribution | Histology and Immunohistochemistry |
Impact | Time course of muscle pathology in a murine model of a mtDNA related disoder |
Start Year | 2018 |
Description | New causative genes of mitochondrial disorders |
Organisation | Newcastle University |
Department | Wellcome Trust Centre for Mitochondrial Research |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Characterization of the biochemical and molecular phenotypes in patient-derived cells and tissues |
Collaborator Contribution | The partners have identified new genes likely causative of human disorders. They have provided cell lines and tissues from affected patients |
Impact | Changes in mitochondrial metabolism supportive of the functional role of the causative genes. PMID: 31600844 PMID: 36055214 PMID: 33742325 PMID: 31039582 |
Start Year | 2017 |
Description | New causative genes of mitochondrial disorders |
Organisation | Ospedale Pediatrico Bambino Gesu (OPBG) |
Country | Italy |
Sector | Academic/University |
PI Contribution | Characterization of the biochemical and molecular phenotypes in patient-derived cells and tissues |
Collaborator Contribution | The partners have identified new genes likely causative of human disorders. They have provided cell lines and tissues from affected patients |
Impact | Changes in mitochondrial metabolism supportive of the functional role of the causative genes. PMID: 31600844 PMID: 36055214 PMID: 33742325 PMID: 31039582 |
Start Year | 2017 |
Description | New causative genes of mitochondrial disorders |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Characterization of the biochemical and molecular phenotypes in patient-derived cells and tissues |
Collaborator Contribution | The partners have identified new genes likely causative of human disorders. They have provided cell lines and tissues from affected patients |
Impact | Changes in mitochondrial metabolism supportive of the functional role of the causative genes. PMID: 31600844 PMID: 36055214 PMID: 33742325 PMID: 31039582 |
Start Year | 2017 |
Description | Nucleoside-based therapy for mtDNA disorders |
Organisation | Zogenix Inc |
Department | Modis Therapeutics |
Country | United States |
Sector | Private |
PI Contribution | Testing the effect of modified molecules on mtDNA dysfunction in a mouse model of mtDNA depletion |
Collaborator Contribution | Developed modified compounds that increase in vivo bioaviability |
Impact | Ongoing analysis |
Start Year | 2019 |
Description | Pathophysiological consequences of mitochondrial DNA replication defects |
Organisation | Helmholtz Association of German Research Centres |
Department | Helmholtz Zentrum Munchen |
Country | Germany |
Sector | Academic/University |
PI Contribution | Characterization of the consequences of mtDNA dysfunction in vitro and in vivo |
Collaborator Contribution | Study of the calcium metabolism in cells and mouse models of mitochondrial DNA dysfunction |
Impact | Identification of specific perturbation of calcium metabolism |
Start Year | 2022 |
Description | Pharmacological manipulation of mitochondrial DNA selection |
Organisation | Newcastle University |
Department | Newcastle University Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Identification of small molecules that select functional mitochondrial genomes |
Collaborator Contribution | Providing cells from patients with mitochondrial DNA disorders |
Impact | Publication, PMID:34873176 Patent, GB2116499.1. |
Start Year | 2016 |
Description | Pharmacological manipulation of mitochondrial DNA selection |
Organisation | University College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Identification of small molecules that select functional mitochondrial genomes |
Collaborator Contribution | Providing cells from patients with mitochondrial DNA disorders |
Impact | Publication, PMID:34873176 Patent, GB2116499.1. |
Start Year | 2016 |
Description | Physiopathology of mtDNA disorders |
Organisation | Centre for Cooperative Research in Biomaterials (CIC BiomaGUNE) |
Country | Spain |
Sector | Academic/University |
PI Contribution | 1)Pathological characterization of a mouse model of mtDNA disorder 2) Identification of a small molecule ( 2-Deoxy-D-Glucose, 2DG) that promote the propagation of the functional mitochondrial DNA in models of disorders where mutant and wild-type mitochondrial genomes coexist. |
Collaborator Contribution | Imagining in an in vivo model of mtDNA disorders Imaging and tissues analyses of control mice treated with 2DG |
Impact | -Publication, PMID:35478201 -The collaboration involves molecular biology, imaging, omic studies (proteomic) |
Start Year | 2019 |
Description | Ribonucleotide incorporation in mtDNA |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Purified mtDNA from mouse tissues and culture cells for sequencing analysis |
Collaborator Contribution | Sequencing of the mtDNA using a new approach developed by the collaborators (Emboriboseq) and analysis of the data |
Impact | Identification of the identity and distribution of the ribonucleotide incorporated in mtDNA of normal tissues and cells. Identification of a new mtDNA abnormality, aberrant ribonucleotide incorporation, in tissues of the Mpv17 KO mouse. Paper in journal of high profile (PMID:29106596) |
Start Year | 2016 |
Title | Compounds for the treatment of heteroplasmic mitochondrial DNA disorders |
Description | Compounds for the treatment of mitochondrial DNA disorders |
IP Reference | GB2116499.1. |
Protection | Patent application published |
Year Protection Granted | 2021 |
Licensed | No |
Impact | Pharmacompanies are interested in licensing the patent. This could lead to investments on basic research and clinical trials |
Description | ENMC, Heemskerk, The Netherlands. |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Study participants or study members |
Results and Impact | The 232nd ENMC International Workshop held in Heemskerk, The Netherlands in June 2017. Among the participant were expert in the field of mDNA metabolism, relatives of patients and members of biopharmaceutical companies. The aims of the workshop were to identify actions needed to advance the clinical recognition, diagnosis, and treatment of patients suffering from disorders of mtDNA maintenance. Clear guidelines were issued. |
Year(s) Of Engagement Activity | 2017 |
Description | Gdansk, 17th symposium on Purine and Pyrimidine in Man |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | I was invited to give a presentation as leader in the field in mtDNA disorders. The new findings stimulated interest in the research topic. Novel collaborations started after the meeting. |
Year(s) Of Engagement Activity | 2017 |
Description | Invited speaker at an International scientific meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | AS presented her group progress in developing potential treatments for mitochondrial DNA disorders. |
Year(s) Of Engagement Activity | 2022 |
Description | Invited speaker at an International scientific meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | AS presented the progress her group has made in developing potential treatments for mitochondrial DNA disorders. |
Year(s) Of Engagement Activity | 2022 |
Description | MEET final meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | My group organized the final event of the Mitocondrial European Education and Training (MEET) in London ( 12 Dec 2016). The event included a scientific conference with eminent speakers from the mitochondria - and non - community, and a dissemination part. |
Year(s) Of Engagement Activity | 2016 |
Description | Mitochondrial Conferences; Seminar to Universities |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Other audiences |
Results and Impact | Invitation to King's College to give a seminar (2015). Invitation to Newcastle University to give a seminar ( 2014). |
Year(s) Of Engagement Activity | 2014,2015 |
Description | Patient group workshop |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | AS presented, during an online meeting, the group progress in developing potential treatments for mitochondrial DNA disorders. |
Year(s) Of Engagement Activity | 2020 |
Description | Seminar to Neurological Institute Besta |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | AS presented, during an online meeting, the group progress in developing potential treatments for mitochondrial DNA disorders. |
Year(s) Of Engagement Activity | 2022 |
Description | UK Neuromuscular Translational Research Conference 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | AS was invited to give a presentation on her latest research on mtDNA selection and one of her fellow was selected for a poster presentation. Both presentations stimulated increased interest in the research topic. |
Year(s) Of Engagement Activity | 2019 |