Role of the mitochondrial fusion protein optic atrophy (OPA)-1 in platelet hyperactivity and thrombosis



 DESCRIPTION (provided by applicant): Cardiovascular diseases (CVD) are the leading cause of death in the United States (Center for Disease Control). Thrombosis represents one of the most common underlying pathologies in CVD. Diabetics are more susceptible to CVD, which is the leading cause of death in these individuals; the mechanisms by which platelet dysfunction develops in diabetics are incompletely understood. Preliminary findings revealed enrichment in transcripts encoding the mitochondrial dynamics proteins mitofusin (MFN)-2, optic atrophy (OPA)-1, dynamin-related protein (DRP)-1, and mitochondrial fission 1 protein (FIS1) in diet-induced obese mice; suggesting that platelet dysfunction in the diabetic milieu might be related to abnormal mitochondrial dynamics in platelets. Thus, in an effort to define the relationship between mitochondrial dynamics and platelet dysfunction/thrombosis we performed platelet-specific deletion of proteins that regulate mitochondrial dynamics. This proposal will focus on the role of the mitochondrial fusion protein Optic Atrophy (OPA)-1. Thus, the effects of OPA-1 deletion on the signaling pathways leading to platelet activation by various ligands will be evaluated. Our central hypothesis is that changes in mitochondrial dynamics and mitochondrial dysfunction will accelerate the development of thrombosis by increasing oxidative stress and subsequent platelet hyperactivity, in part, by promoting MPTP opening. We expect that the mitochondrial changes in OPA-1 deficient platelets will mirror the changes in the diabetic milieu of high fat fed insulin resistant mice. Mitochondrial dynamics is critical for mitochondrial health and may be one underlying mechanism for increased thrombosis in diabetics. Validation of this mechanism would provide critical insight into the pathophysiology of thrombosis, particularly in diabetics which represent an at risk population for cardiovascular complications such as myocardial and critical limb ischemia and cerebral strokes