LEBER’S HEREDITARY OPTIC NEUROPATHY: SYSTEMATIC INVESTIGATION OF ENERGY DEPLETION AND OXIDATIVE STRESS, AND THEIR RELEVANCE TO CELL DEATH, USING CYBRID CELL LINES WITH 11778, 3460,14484 AND 14459 MUTANT MITOCHONDRIA

LHON is a genetic disease passed exclusively through women, due to a defect in the mitochondrial DNA that is maternally inherited. The disease is characterized by a rapid loss of vision that affects prevalently males in young-adult age. In a few months the optic nerve becomes irreversibly atrophic, leaving a profound permanent visual defect. The majority of patients harbor one of a few causative mutations in mitochondrial DNA (at positions 11778, 3460, 14484, 14459). These three mutations affect different parts of the same enzyme, defined as complex I. Complex I is an important component of the mitochondrial respiratory chain, the metabolic process through which most of the cellular ATP is produced, the indispensable source of energy that the cell use for its vital functions. Despite the genetic defect in LHON has been known for years, the mechanism through which the disease affects specifically the optic nerve is still unclear and there is no available therapy for these patients. The two main hypotheses point on one side to an energy depletion, on the other to a possible increased production of toxic byproducts known as oxygen radicals, both possible consequences of complex I dysfunction. This project is aimed to study both these, not necessarily exclusive, hypotheses, investigating directly the patients and using patient-derived cell lines. The study of the respective contribution of these hypotheses to cellular death should open the possibility of setting up proper therapies to correct this metabolic defect. Complex I dysfunction, and more in general dysfunction of the mitochondrial respiratory chain, are not limited to LHON, but are of wider interest, given the increasing number of neurodegenerative diseases that seem to be associated with this metabolic dysfunction, such as Parkinson disease.