The first pathogenic mutation in human mitochondrial DNA (mtDNA) was identified in 1988. In the last 20 years research on
mitochondrial diseases has developed rapidly and is continuously evolving. More than 100 pathogenic mutations in mitochondrial
DNA have now been described. Moreover, the completion of the human genome project has been a great contribution in helping
identify mutations in nuclear genes that cause mitochondrial diseases.
Through the past several years, basic and clinical researchers have been working together to form a "task force" to clarify the still many obscure aspects of the biology and pathology of mitochondria.
In Europe there is a network of 51 research laboratories including our own , and covering different branches of research, actively working on the elucidation of the molecular, cellular and physiopathological mechanisms of mitochondrial diseases with the aim of identifying effective treatments.
Our most important programs cover different fields of research:
Thanks to an intense research activity and to National and International collaborations, our Centre has identified the genetic cause of several human pathologies, characterized by quantitative and qualitative alteration of mtDNA Several years ago, our Centre discovered that mutations in Surf1 are responsible for Leigh syndrome, an infantile severe neurodegenerative disease associated with the biochemical defect of cytochrome c oxidase, or complex IV of the respiratory chain. Several projects aimed at identifying new disease genes in mitochondrial disorders are in progress. During the 2009 we identified a new gene named SDHAF1, which codes for the first assembly factor of Complex II. Mutations in this gene are responsible for rapidly progressive severe infantile leukoencephalopathy associated with defective biochemical activity of complex II. In 2004, our Centre discovered that a severe infantile metabolic disorder called Ethylmalonic Encephalopathy, was caused by mutations in the Ethe1 gene. This disease affects the brain, the gastrointestinal tract and the small blood vessels. In 2009 we clarified the pathogenetic mechanism underpinning this disorder, which is due to defective mitochondrial catabolism of inorganic sulfur. The absence or malfunctioning of the ETHE1 protein causes an accumulation of sulfidric acid (H2S) in different tissues, which is toxic for several enzymatic activities including cytochrome c oxidase (COX) and short chain acyl coA dehydrogenase (SCAD). The elucidation of this pathogenic mechanism allowed us to start an experimental therapy in animals, and also in some patients, based on the reduction or buffering of H2S accumulation.
Our Centre is also actively working in the development of rapid and efficient molecular tests, mainly
based on the use of high-throughput platform for mutational screening. This objective is part of a
trans-national collaborative effort to improve and wide the diagnostic offer to patients and families.
A similar technological implementation will concern the use of new instruments able to measure the
biochemical respiratory profile of cells in culture.
Our Centre intends to implement the offer of an integrated diagnostic approach to mitochondrial disorders, which include the most comprehensive molecular and biochemical analysis using innovative technologies. As concerning experimental therapy a consistent part of our research has been re-oriented in the evaluation of therapeutic approaches in diseases affecting the mitochondrial respiratory chain. This is now possible because several animal and cellular models have been developed and can be used as a proof of principle to test the efficacy of treatments. Recent observations indicate that novel therapeutic approaches are now available and exploitable in the field of mitochondrial disorders, including gene therapy, pharmacological treatments, and rehabilitative option.
Sample storage in liquid nitrogen
Cultured fibroblasts and cellular disease models
DHPLC-based mutational screening
Making a DNA bank