Identification and characterization of new mitochondrial disease genes

Mitochondria are the major source of ATP that is synthesized by the respiratory chain through the process of oxidative phosphorylation (OXPHOS), a complex biochemical process carried out through the dual control of physically separated, but functionally interrelated, genomes, nuclear and mitochondrial DNAs. The genetic and biochemical intricacy of mitochondrial bioenergetics explains the extreme heterogeneity of mitochondrial disorders, a group of highly invalidating human conditions, for which no effective treatment is nowadays available. In addition to bioenergetic failure, other mechanisms are probably predominant in the pathogenesis of specific syndromes, such as alterations of cellular redox status, the production of reactive oxygen species, compromised Ca2+ homeostasis, mitochondrial protein and organelle quality control, and mitochondrial pathways of apoptosis. By investigating selected families and patients, we have identified several new disease genes, each responsible of distinct defects of the respiratory chain, mtDNA metabolism, or both. Recently published and still unpublished findings will be presented and discussed. Structural analysis and the creation of ad hoc recombinant lines in yeast, flies, and mice have allowed us to dissect out the molecular consequences of the ablation or defects of some of these proteins, and their physical status in normal and disease conditions. These models have also been exploited to implement experimental therapeutic strategies, based on gene and cell replacement, or pharmacological control of mitochondrial biogenesis.