Mitochondrial biogenesis and human disease

Lead Research Organisation: Medical Research Council

Abstract

Mitochondria have a central role in producing energy in a suitable form for 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 cellular nucleus, and one way that signalling is carried out involves very reactive oxygen molecules that are generated in mitochondrion. When these processes go wrong, they can lead to human diseases including heart disease, diabetes, neurodegenerative disorders, obesity and cancer. If we understand the basic processes, we are more likely to understand what is happening when these processes in the mitochondrion go wrong, and to be able to provide therapies to compensate for or correct the faults. This programme will study how the mitochondria themselves are made and put together, and how they increase their numbers in response to the changing requirements of the cell. It will try and to provide diagnostic tests and therapies for patients when these processes no longer work properly.|

Technical Summary

The biogenesis of mitochondria is a complex process controlled by communication between the nucleus and the organelle. It requires the coordination of the cytoplasmic synthesis and import into the organelle of about 1,500 proteins encoded in the nucleus, with the synthesis in the organelle of 13 proteins encoded by mtDNA, followed by the assembly of multisubunit enzyme complexes containing proteins from both genomes. In addition, it involves the regulation of fission and fusion of mitochondria, and of the turnover of mitochondria by mitophagy in response to various stimuli. Disruption of any of these processes in human can lead to defective mitochondria and pathology. The aim of this programme is to identify the mechanisms involved in biogenesis of mitochondria especially those involving the mitochondrial inner membrane protein, MPV17.

Publications

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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

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Spinazzola A (2011) Mitochondrial DNA mutations and depletion in pediatric medicine. in Seminars in fetal & neonatal medicine

 
Description International fellowship
Amount € 231,427 (EUR)
Funding ID PIEF-GA-2009-255578 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2010 
End 04/2012
 
Description Elucidating the function of MPV17p 
Organisation Tsuyama Central Hospital
Department Department of Pediatrics
Country Japan 
Sector Hospitals 
PI Contribution We are currently studying the patient cell lines using methods and antibodies developed in house
Collaborator Contribution The collaborators has provided MPV17 patients material to validate my results
Impact remodelling mtDNA associated proteins in absence of MPV17
Start Year 2011
 
Description Elucidating the function of MPV17p 
Organisation University of Cambridge
Department Institute of Metabolic Science (IMS)
Country United Kingdom 
Sector Academic/University 
PI Contribution We are currently study Mpv17 KO mouse tissues using methods and antibodies developed in house
Collaborator Contribution 1) The collaborator has helped to isolate tissues for Mpv17 KO mouse. 2) The Mpv17-/- mouse on the original background (CFW) has been back-crossed to C57Bl/J6. The congenity has been confirmed using the Marker-Assisted Accelerated Backcrossing (MAX-BAX®) provided by Charles River
Impact 1)Remodelling of mtDNA associated proteins in absence of Mpv17p 2) A KO models on a homogeneous inbred genetic background available for characterization.
Start Year 2011
 
Description Metabolomics in Mpv17 KO mouse 
Organisation University of Cambridge
Department Department of Biochemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We are providing samples from Mpv17 KO mouse and MPV17 overexpressing cell lines
Collaborator Contribution The collaborator has performed metabolite analysis in the Mpv17 mouse tissues.
Impact Altered metabolic profiles in the Mpv17 mouse tissues
Start Year 2011
 
Description Mitochondrial dNTPs measurement 
Organisation Vall d'Hebron University Hospital
Country Spain 
Sector Hospitals 
PI Contribution We have isolated mitochondria from Mpv17 KO mouse tissues and extract mitochondrial dNTP from the samples
Collaborator Contribution The collaborator has measured mitochondrial dNTP pools from Mpv17 ko mouse
Impact Imbalance of mitochondrial dNTPs pool Paper in high impact journal
Start Year 2012
 
Description elucidating the function of MPV17p 
Organisation Columbia University Medical Center
Country United States 
Sector Academic/University 
PI Contribution We are currently studying the cell lines with methods and antibodies developed in house
Collaborator Contribution The partners have provided cell lines from control subjects and patients with mitochondrial DNA depletion syndromes
Impact 1)Remodelling of mtDNA associated proteins 2)Mitochondrial deficient phenotype linked to new function of the protein Paper in high impact journal
Start Year 2011
 
Description elucidating the function of MPV17p 
Organisation Newcastle University
Department Institute for Ageing and Health
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 partners have provided cell lines from control subjects and patients with mitochondrial DNA depletion syndromes
Impact 1)Remodelling of mtDNA associated proteins 2)Mitochondrial deficient phenotype linked to new function of the protein Paper in high impact journal
Start Year 2011
 
Description elucidating the function of MPV17p 
Organisation University of Melbourne
Department Department of Paediatrics
Country Australia 
Sector Academic/University 
PI Contribution We are currently studying the cell lines with methods and antibodies developed in house
Collaborator Contribution The partners have provided cell lines from control subjects and patients with mitochondrial DNA depletion syndromes
Impact 1)Remodelling of mtDNA associated proteins 2)Mitochondrial deficient phenotype linked to new function of the protein Paper in high impact journal
Start Year 2011
 
Description elucidating the function of MPV17p 
Organisation University of Oxford
Department Nuffield Department of Obstetrics & Gynaecology
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 partners have provided cell lines from control subjects and patients with mitochondrial DNA depletion syndromes
Impact 1)Remodelling of mtDNA associated proteins 2)Mitochondrial deficient phenotype linked to new function of the protein Paper in high impact journal
Start Year 2011