Therapeutic strategies to combat mitochondrial disorders

Mitochondrial Disorders are a group of genetic maladies characterized by dysfunction of oxidative phosphorylation (OXPHOS), the energy-supplying metabolic pathway carried out by the mitochondrial respiratory chain (MRC) complexes. Thirteen MRC protein subunits are encoded by mtDNA, which adds to the genetic, functional and structural complexity of OXPHOS, and of its disorders as well. The heterogeneity of mitochondrial disorders makes the identification of effective therapy an exceedingly difficult task. However, the elucidation of many of the pathophysiological features of these conditions give us now several clues for the development of therapeutic strategies, with the ultimate goal to cure mitochondrial disease. The most frequent biochemical abnormalities in mitochondrial disorders include isolated defects of complex I (cI) or of complex IV (cIV), and combined defects of both. The MitCare Telethon Consortium will test approved and new chemical compounds, gene and cell replacement, and a combination of these treatments, in different conditions and on systems of increasing complexity, that is, cell lines, animal models, and patients. To implement this program, MitCare will deploy three workpackages (WP). WP1 will exploit an array of patient-derived cell lines with specific biochemical defects, that will be tested using drugs involved in mitobiogenesis, calcium signaling, ROS and toxic buffering, and antiapoptotic agents. WP2, will exploit several mouse models corresponding to specific human mitochondrial disorders to test the effects of the same compounds used in WP1, or of the expression of genes able to by-pass cI or cIV defects. WP3, will test the efficacy of approved compounds targeting the same pathways as in WP1 and WP2 in patients with Leber's hereditary optic neuropathy (LHON), dominant optic atrophy (DOA) and ethylmalonic encephalopathy (EE). Validated therapies will then be extended to patients affected by other mitochondrial disorders.