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Mitochondrial disorders are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes for mitochondrial biogenesis. There are no established treatments for preventing or slowing their progression.

Towards a new type of drug therapy for mitochondrial disease

Mitochondrial disorders are caused by mutations in mitochondrial DNA (mtDNA) or in nuclear genes for mitochondrial biogenesis. There are no established treatments for preventing or slowing their progression.

The Nobel Laurate Yoshinori Ohsumi was recently recognised for his work on autophagy, a fundamental process for degrading damaged cellular components. Mitophagy is a subtype of autophagy that is specific for recycling spent mitochondria. Defects in mitophagy are a well established cause of Parkinson’s disease. We propose that drug modulators of mitophagy may be used to treat mitochondrial disease, particular targetting mitochondria harbouring mutant mitochondrial DNA. Increasing mitophagy might be appropriate treatment for other disorders, including neurodegenerative diseases associated with low levels of somatic mtDNA mutations such as Parkinson’s disease. Furthermore, drugs commonly used in mitochondrial disease have profound effects on mitophagy, which could underlie their beneficial/detrimental effects.

We have recently validated two new high throughput objective ways of quantitating mitophagy and are developing cell lines to facilitate its detection.

AIMS:

1) We will assess whether load of mutant mtDNA can be driven by drug modulators of mitophagy in cell cultures from a range of patients with heteroplasmic mtDNA disease. We will obtain cells from a panel of patients with mtDNA disorders.

2) We will characterise candidate drugs idenified from a drug library for their effect on mitophagy and mutant load on cells from a panel of heteroplasmic patients

3) We will screen other drugs of interest to ourselves and our collaborators on this panel of patient cultures for effects on mitophagy

TECHNIQUES:

Cell culture, PCR, high throughput microscopy, SiRNA, westerns.

OUTCOMES:

1) Improve our understanding and refine our usage of routine supportive drug therapies for mitochondrial patients

2) Identify candidate modulators of mitophagy that may attenuate disease progression

Training opportunities

The research will take place in our laboratories in the Nuffield Department of Obstetrics and Gynaecology at the University of Oxford. We have access to core equipment in the nearby Weatherall Institute of Molecular Medicine and collaborative projects with colleagues in The Oxford Fertility Unit, located within the NDOG in the Institute of Reproductive Sciences.    

There will be the opportunity to learn or develop skills in cell and molecular biology, protein biochemistry, advanced microscopy techniques and bioinformatics, with collaborative opportunities across the university.    

Students will be encouraged to present and publish their work, attend weekly lab meetings and journal clubs together with departmental seminars and training courses.  We hold "MitOX" annually on the JR campus. This is a one day national meeting on mitochondria at which the student would be expected to present.  

Supervisor

Professor Joanna Poulton