MOLECULAR MECHANISMS LEADING TO APOPTOSIS IN MITOCHONDRIAL ENCEPHALOMYOPATHIES AND OTHER NEUROMUSCULAR DISORDERS

Apoptosis is the cell programmed “suicide” and requires the activation of specific genes. This mechanism has a crucial role during the embryogenesis because eliminates cells in excess. Dysfunction of apoptotis is associated with several diseases, including some neurodegenerative disorders. Apoptosis can be induced by several factors that, together or independently, trigger a chain of events. One of the key elements of this mechanism is the mitochondrion, a sub-cellular organelle that supplies the energy for the cell metabolism and operates as a switchboard that receives, amplifies and integrates different signals. Mitochondrial dysfunction is the cause of a group of extremely heterogeneous diseases named mitochondrial encefalomyopathies (ME). Although the underlying gene defects of many of these diseases are known, the mechanisms that determine clinical symptoms remains to be elucidated. Thus, the aim of our study is to understand these mechanisms and the role of apoptosis in ME. In fact, a dysfunctional mitochondrion produces toxic molecules, such as reactive oxygen species (ROS), which damage the cell. ROS are able to activate apoptotis in order to eliminate dysfunctional cells. However, too much apoptosis leads to a higher loss of cells and thus to organ failure. A metabolic impairment is also present in acute quadriplegic myopathy (AQM), a prolonged muscle weakness that occurs in critically ill patients in response to multiple stimuli. We have demonstrated that apoptosis plays a role in the massive atrophy that characterized this disorder. Aim of this proposal is to further elucidate the role of apoptosis in muscle diseases using two approaches a) morphological and molecular studies on muscle biopsies and other tissues from patient with mitochondrial encephalomyopathies and AQM b) functional studies in primary muscle cultures. A better understanding of the chain of events leading to apoptosis may lead to a more rational therapeutic approach of these diseases.