Energy production and mitochondrial DNA function in normal and disease states

Lead Research Organisation: Medical Research Council

Abstract

Food is utilised by the compartment of the cell called mitochondria to generate the bulk of the energy required by the human body. A small piece of DNA located in mitochondria makes an essential contribution to energy production. Mutations in mitochondrial DNA cause a wide range of diseases, including neurodegeneration, diabetes mellitus and cardiac dysfunction, which are important causes of morbidity. We are studying how this essential molecule is copied and inherited in order to design drug or molecular therapies for mitochondrial diseases.

Technical Summary

The aim of the group is to understand all aspects of mitochondrial DNA metabolism, in particular the parameters that determine fixation of pathological mitochondrial DNA variants in humans. Pathological mitochondrial DNA variants are implicated in a wide-range of human diseases and the accumulation of mutations in mitochondrial DNA has been linked to ageing. Our aim includes elucidation of the mechanism and machinery of mitochondrial DNA replication and maintenance, and identification of the factors influencing segregation of different mitochondrial DNA genotypes. DNA replication mechanisms are being studied using two-dimensional agarose gel electrophoresis in conjunction with atomic force microscopy and other techniques. Two schemes are to be employed to dissect the machinery of mitochondrial DNA replication; analytical protein chemistry of purified mitochondria and a combined reverse genetics and bioinformatics approach. Identification of factors that regulate replication and segregation of normal and mutant mitochondrial DNA offers a means to manipulate mutant load, initially in cell culture and subsequently in animal models of mitochondrial disease. Ultimately the aim is to restrict the propagation of mutant mitochondrial DNA in specific tissues of patients with mitochondrial disease, and potentially slow the natural process of ageing in normal individuals.

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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Bowmaker M (2003) Mammalian mitochondrial DNA replicates bidirectionally from an initiation zone. in The Journal of biological chemistry

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

 
Description Mitochondrial DNA Organisation 
Organisation Radboud University Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution Intellectual, practical and financial
Collaborator Contribution Reagents (cell lines, constructs), Intellectual
Impact Three joint publications, to date.
 
Description Mitochondrial DNA Segregation 
Organisation University of Padova
Country Italy 
Sector Academic/University 
PI Contribution Intellectual and minor practical contributions made to Dr Vergani's research programme.
Collaborator Contribution Helped to identify factors underpinning biased segregation of mutant and wild-type mitochondrial DNA
Impact Demonstrated the effect of the mitochondrial fission apparatus on the segregation of mutant and wild-type mitochondrial DNA, with implications for the associated human disease. Paper published in Human Molecular Genetics Journal in 2009
 
Description Mitochondrial DNA replication Mechanisms 
Organisation Autonomous University of Madrid
Department Centre for Molecular Biology Severo Ochoa
Country Spain 
Sector Academic/University 
PI Contribution Intellectual, practical and financial
Collaborator Contribution Intellectual
Impact numerous publications on the topic
 
Description Mitochondrial DNA replication Mechanisms 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution Intellectual, practical and financial
Collaborator Contribution Intellectual
Impact numerous publications on the topic
 
Description Mitochondrial DNA replication Mechanisms 
Organisation Tampere University of Technology
Country Finland 
Sector Academic/University 
PI Contribution Intellectual, practical and financial
Collaborator Contribution Intellectual
Impact numerous publications on the topic
 
Description RNase H1 
Organisation National Institutes of Health (NIH)
Country United States 
Sector Public 
PI Contribution We helped define the sub-cellular compartments to which RNaseH1 is trafficked We are characterizing the effects on mitochondrial DNA replication on the loss of RNase H1, using a cell line developed by Dr Crouch
Collaborator Contribution They define the sub-cellular compartments to which RNaseH1 is trafficked RNase H1 ablated cell line.
Impact PMID: 20823270 PMID: 20184890
Start Year 2008