The aim of my lab is to understand the molecular pathogenesis of mitochondrial diseases in order to develop novel and more effective therapies. Mitochondrial diseases are the most common form of inherited disorders, striking 1:5000 people. Over 300 genes have been identified as mutated in mitochondrial patients world-wide, but about 50% of them remain undiagnosed. A first goal of my lab is to contribute to the catalogue of disease genes, and to investigate the physiological role of their protein products by using cellular models, blue native gel electrophoresis and proteomic approaches.

No effective is currently available for these conditions. In the last 10 years our lab introduced and tested new concepts to tackle the problem of the therapy of mitochondrial diseases. We used both pharmacological and AAV-based gene therapy approaches to treat mouse models of these lethal conditions.

A first approach was based on the stimulation of mitochondrial biogenesis by acting on PGC1alpha, the master regulator of this process, which is modulated by both phosphorylation, operated by AMPK and deacetylation, operated by Sirt1. Thus, either stimulation of AMPK by the AMP analogue AICAR, or Sirt1 by the NAD+ precursor nicotinamide riboside, lead to activation of mitochondrial biogenesis. In addition, inhibition of PARP1, the most important NAD+ consumer in the cells, gave similar results by increasing NAD+ cellular content, in turn boosting Sirt1 activity.

A second pharmacological approach we tested was based on the stimulation of autophagy, a cellular process that removes protein aggregates and dysfunctional organelles. We demonstrated that inhibition of MTORC1, a Ser/Thr kinase regulating a large number of cellular processes, using rapamycin induced both autophagy and lysosomal biogenesis, leading to a marked improvement in the myopathic phenotype of a mouse model characterized by severe mitochondrial muscle disease.

Adeno-associated viral vectors are the most promising tool for gene therapy, and a large number of clinical trials are currently underway by using this approach. Mitochondrial diseases are particularly difficult from this point of view, because the protein product has to cross two membranes to be imported into mitochondria and eventually incorporated into macromolecular complexes. We have focused on this etiological approach, which, in principle, should be the most effective against genetic disorders. Accordingly, we demonstrated the efficacy of different AAV-serotypes in several mitochondrial disease models, including: ethylmalonic encephalopathy, MNGIE, and Leigh disease. Despite these rather successful attempts, there are still limitations such as a reduced lifespan in the Leigh syndrome model, which survives longer than the untreated littermates, but still die well before the wild types.