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Mitochondrial Medicine: developing treatments of OXPHOS-defects in recombinant mammalian models

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New treatment pathways for mitochondrial disorders

The MitCare project has been exploring new approaches to deal with mitochondrial disease. Its experimental therapies show much promise for patients living with this incurable condition.


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Mitochondrial disease has been a biological conundrum for decades. Ever since 1962, when it was first diagnosed, the condition has remained incurable. Treatments developed so far have only been able to alleviate symptoms, and research is currently hindered by the complexity of the mechanisms controlling mitochondrial genetics and biology. Mitochondria are controlled by two physically distinct genomes which are encoded by the mitochondrial DNA (mtDNA) and nuclear DNA, respectively. We do know that mutations in both genomes can lead to mitochondrial dysfunction and disease. But in spite of intense investigation on the pathogenic mechanisms of mitochondrial diseases, an effective therapy has yet to become available. “There are no models for mtDNA mutations in mice, which makes its controlled manipulation a major problem,” says Prof. Massimo Zeviani, Director of the MRC Mitochondrial Biology Unit at the University of Cambridge and coordinator of the MitCare project. “Diseases due to nuclear genes can in principle be easier to correct because there are tools, such as AAV vectors, that can replace the affected gene. However, the blood-brain barrier (BBB) and the multisystem features of mitochondrial disorders still represent major hurdles for treatment.” To overcome these problems, Prof. Zeviani and his team have tried various approaches. “We have been exploring the controlled manipulation of mtDNA by targeting sequence-specific zinc fingers. This is a radically new approach developed in collaboration with Dr Michal Minczuk, programme leader at the MBU. Furthermore, for diseases due to nuclear genes, we have tried using tools such as AAV vectors to replace the affected gene,” he explains. On the pharmacological front, the team focused on increasing the biogenesis of the mitochondrial respiratory chain. They did so by using the precursors of NAD, the substrate of Sirtuin1 – which activates the master regulator of mitochondrial biogenetic programme PGC1alpha – as well as AICAR, which does the same by activating AMP-activated protein kinase (AMPK). Five years after its launch, the project has been reporting encouraging results related to the use of mitochondriogenic agents, rapamycin, specific AAV vectors, and mtDNA editing strategies. The team is hopeful that convincing evidence will soon be developed to allow for clinical trials. A first attempt is already ongoing, using the NAD precursor nicotinamide riboside. In its efforts, the team has also developed strategies to target critical organs with therapeutic genes. One such organ is the liver. By creating suitable constructs expressing genes impaired in mitochondrial conditions, researchers demonstrated that the liver can act as an effective filter to clear the toxic compounds from the bloodstream. It does so when expressing the corresponding missing enzymes. Such an approach can substantially improve the clinical outcome. “This proof of principle has been exploited to propose the use of liver transplantation in both MNGIE and Ethylmalonic encephalopathy, with very positive and encouraging results in patients,” Prof. Zeviani enthuses. All in all, the project has successfully elucidated new roles for disease-related genes and proteins. It has unravelled new signalling pathways relevant to mitochondrial diseases and, finally, has enabled the development of several experimental therapies – some of which are quite promising. The next step will consist of providing further evidence of the usefulness and benefits of the project’s approaches. The team notably hopes to convince European agencies to approve its new compounds stimulating mitochondrial biogenesis in mild forms of mitochondrial disease.


MitCare, mitochondria, mitochondrial disease, mtDNA, nuclear genes

Project information

Grant agreement ID: 322424


Closed project

  • Start date

    1 July 2013

  • End date

    30 June 2018

Funded under:


  • Overall budget:

    € 2 500 000

  • EU contribution

    € 2 500 000

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