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: National Institute 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.

Publications

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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

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Dalla Rosa I (2014) MPV17L2 is required for ribosome assembly in mitochondria. in Nucleic acids research

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Pearce S (2013) Mitochondrial diseases: translation matters. in Molecular and cellular neurosciences

 
Description Marie Curie
Amount € 310,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2013 
End 01/2017
 
Description Elucidating the cellular metabolic alterations in mitochondrial dysfunction 
Organisation Helmholtz Association of German Research Centres
Department Helmholtz Zentrum Munchen
Country Germany 
Sector Public 
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 Charity/Non Profit 
PI Contribution We isolated RNA from Mpv17 WT and KO mouse tissues
Collaborator Contribution Trascriptomic analysis of Mpv17 WT and KO mouse tissues
Impact To learn the 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.
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.
Start Year 2014
 
Description Manipulating mtDNA segregation 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Characterization of the pathways underpinning the wild-type mtDNA segregation
Collaborator Contribution Identification of small compounds that drive the wild-type mtDNA segregation
Impact The knowledge of the pathways necessary for the function mtDNA segregation. The identification of new small molecules that drive mtDNA segregation in patients derived fibroblasts.
Start Year 2013
 
Description Metabolomics 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Public 
PI Contribution Characterization of mitochondrial metabolism in cells growing under different nutrient conditions. Characterization of metabolite 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 metabolomic 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 journals of high impact
Start Year 2016
 
Description Molecular basis of mitochondrial disorders 
Organisation University of Melbourne
Department Murdoch Children's Research Centre
Country Australia 
Sector Academic/University 
PI Contribution Characterization of the cellular and mitochondrial metabolism in cells derived from patients with mutations in a new causative gene of mitochondrial disease.
Collaborator Contribution Identification of a new genetic cause of mitochondrial disorders. Fibroblasts from mutant patients.
Impact Cholesterol and mtDNA metabolisms are co-regulated. Papers in high impact journals.
Start Year 2016
 
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 high impact journal.
Start Year 2016
 
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 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 a
Year(s) Of Engagement Activity 2016
URL http://www.itn-meet.org/