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: MRC National Inst for Medical Research

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. Already we have found that nutrient availability has a marked impact on mitochondrial function and so we plan to extend this work and test its applicability to diseases in mice with a view to designing and implementing clinical trials in humans.

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.
 
Description Third scientific review of the safety and efficacy of methods to avoid mitochondrial disease through assisted conception: 2014 update
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact a
URL https://www.hfea.gov.uk/
 
Description Marie Curie
Amount € 310,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2013 
End 01/2017
 
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 
 
Description Elucidating the cellular metabolic alterations in mitochondrial dysfunction 
Organisation Helmholtz Association of German Research Centres
Department Helmholtz Zentrum Munchen
Country Germany 
Sector Academic/University 
PI Contribution Metabolomics and proteomics analysis in model of mitochondrial dysfunction
Collaborator Contribution Tissues from a murine model of mitochondrial dysfunction
Impact To characterize pathways altered in mitochondrial disorders, which will represent attractive targets for drug treatment
Start Year 2015
 
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 Elucidating the function of new proteins involved in mitochondrial biogenesis 
Organisation Catholic University of the Sacred Heart
Country Italy 
Sector Academic/University 
PI Contribution We are currently studying the cell lines with methods and antibodies developed in house
Collaborator Contribution The collaborators have provided patient-derived cell lines.
Impact Mitochondrial deficient phenotype linked to new functional aspects of mitochondrial proteins. Papers in high profile journal
Start Year 2014
 
Description Elucidating the function of new proteins involved in mitochondrial biogenesis 
Organisation Newcastle University
Department Mitochondrial Research Group
Country United Kingdom 
Sector Academic/University 
PI Contribution We are currently studying the cell lines with methods and antibodies developed in house
Collaborator Contribution The collaborators have provided patient-derived cell lines.
Impact Mitochondrial deficient phenotype linked to new functional aspects of mitochondrial proteins. Papers in high profile journal
Start Year 2014
 
Description Elucidating the role of Mpv17 in nucleotide metabolism 
Organisation Vall d'Hebron University Hospital
Country Spain 
Sector Hospitals 
PI Contribution Tissues and mitochondria from Wt and Mpv17 KO mice
Collaborator Contribution Analysis of mitochondrial subfractions
Impact Abstract for meetings. Consortium organization for the study of mitochondrial DNA depletion and deletions Syndromes.
Start Year 2018
 
Description Manipulating mtDNA segregation 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of small compounds that drive the wild-type mtDNA segregation
Collaborator Contribution Characterization of the pathways underpinning the wild-type mtDNA segregation
Impact The knowledge of the pathways necessary for the selection of mtDNA variants The identification of new small molecules that drive mtDNA segregation in patients derived fibroblasts. Paper in high profile journal
Start Year 2013
 
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
Department Institute of Neurology
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 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 Metabolomics 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Characterization of mitochondrial metabolism in cells growing under different nutrient conditions. Characterization of metabolites in in vitro and in vivo model of mitochondrial dysfunction.
Collaborator Contribution Metabolomic analysis in cancer cells. Metabolomic analysis in patients-derived fibroblasts and mouse models of mitochondrial disease.
Impact Changes in metabolite profile in cells growing under amino acid starvation.
Start Year 2013
 
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 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 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.
Start Year 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 Nijmegen 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Marie Curie ITN graduate students, Supervisors, patients and patients' family met for two days to discuss research outcomes and outline future plans. Formal and informal discussions stimulated novel collaborations and created additional bonds among the students. Patients and their families felt supported and heard.
Year(s) Of Engagement Activity 2016
URL http://www.itn-meet.org/