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Rational Treatment Strategies Combating Mitochondrial Oxidative Phosphorylation (OXPHOS) Disorders

Final Report Summary - EUMITOCOMBAT (Rational treatment strategies combating mitochondrial oxidative phosphorylation (OXPHOS) disorders)

The project's main goals were to obtain a detailed understanding of the clinical and pathobiological consequences of OXPHOS-disease in order to develop new treatment strategies. The efforts were focused on diseases of OXPHOS enzyme complexes, as well as on mitochondrial DNA maintenance and protein synthesis disturbances.

The studies of the mitochondrial nucleoid via affinity purification and mass spectrometry, led by MRC, identified many candidate proteins. UTA, using a cell model system, and KI, using purified recombinant proteins, have added substantial new information on Twinkle DNA helicase and DNA polymerase gamma in normal and disease states. KI have also begun to apply this knowledge in order to develop an in vitro replication system. Mouse knockout models made by KI have provided further insights into the role of the mtDNA packaging protein Tfam in mtDNA maintenance and transcription.

A recent major success was the creation of a mouse lacking a gene whose protein product was inferred to function as a negative regulator of mitochondrial transcription. Refinement of EPR methods and the development of improved isolation protocols, combined with a better lipid environment, have enabled MRC's mechanistic studies of OXPHOS complex I to advance. New factors involved in complex I assembly have been identified using bioinformatics and biochemical approaches (UMCN). The new findings define in some detail the assembly pathway for complex I.

Complex IV assembly is also better understood thanks to gene-silencing studies combined with the application of native gel electrophoresis (CU and INN). A combined bioinformatic, genetic and biochemical approach to the study of mitochondrial transporters has enabled UBAR to identify new carrier family members, characterise their role in mitochondrial biogenesis and provide valuable information on defects of nucleotide metabolism that cause mtDNA depletion syndrome. New knowledge of structure-function relationships has given insight into pathological roles of members of the mitochondrial carrier family.

The main outcomes of the EUMITOCOMBAT project have been reported through the standard, peer-reviewed scientific literature, with an emphasis on journals of high impact and good academic standing. In addition, the findings have been presented at a host of national and international colloquia, including the EUROMIT congresses of 2004 and 2008. These are the benchmark scientific meetings of the field worldwide, designed to promote interactions between clinical and basic scientists, and rapidly disseminate new knowledge for the benefit of patients.

EUMITOCOMBAT members have played leading roles in organizing, chairing and presenting their findings at these meetings, in which leading North American and Asian colleagues also participate. As a consequence, the achievements of EUMITOCOMBAT in identifying new disease genes, defining fundamental cellular mechanisms, charting the natural history of disease, establishing and exploiting pathophysiological models, and progressing towards therapy, have been brought to global attention.

Several new and promising avenues for therapy have emerged in the course of the work, and the collaborations established by EUMITOCOMBAT between scientists, industry and physicians will enable these to proceed to eventual clinical trials in the follow-up phase. The decision to share IPR amongst all partners, and the consequent legal and administrative complications has, conversely, acted as an impediment to the rapid exploitation of some findings, and opportunities for commercialisation might have been lost.

Finally, EUMITOCOMBAT scientists have taken leading roles in communicating the importance, for public health, of this previously rather neglected research area. Public awareness of mitochondrial disorders and their many complexities was greatly increased, most notably in the leading countries of the consortium (the Netherlands, United Kingdom, Finland, Italy, France). The project also resulted to policymakers, as well as the general public, becoming much more aware of the vital role that pan-European collaboration has played in enabling pioneering research on a collection of so-called rare diseases that would otherwise be beyond the remit of any individual national research programme.