Abstract 16277: Gender-dimorphic Effect of Optic Atrophy Protein (OPA)-1 on Platelet Activation and Thrombosis

Abstract

Mitochondrial dysfunction is strongly associated with many disorders including metabolic and cardiovascular diseases and their complications. Preliminary studies of platelets from the Framingham offspring cohort, revealed enrichment in transcripts encoding for the mitochondrial dynamics proteins: optic atrophy-I in females, and mitofusin II in both genders that correlated with cardiovascular risk. These transcripts encode established regulators of mitochondrial fusion, electron transport complex (ETC) assembly and apoptosis, thereby suggesting that altered mitochondrial dynamics may contribute to platelet dysfunction. Thus, to determine whether the enrichment in OPA1 transcripts in females that correlates with increased CVD risk represents an adaptive or pathophysiological response, mice with platelet-specific deletion of OPA1 (pOPA-1 KO) were generated. Male pOPA-1 KO mice exhibited compromised cristae morphology and a 50% reduction in mitochondrial DNA. Additionally, mitochondrial function assessed by an extracellular flux analyzer (XF24 Seahorse biosciences) was reduced by 50%. Mitochondrial dysfunction in male pOPA-1 KO mice was associated with heightened agonist response (a hyperactive phenotype). Male pOPA-1 KO mice had a shortened time to stable occlusion of the carotid artery as assessed in vivo by rose Bengal photochemical injury, and were more prone to develop a thrombus (14/15 knockouts vs. 4/8 controls) following permanent ligation of the inferior vena cava. In contrast, cristae morphology was normal and mitochondrial DNA unchanged in females. Additionally, the females revealed no evidence of heightened agonist response or increased incidence of thrombus formation. Thus OPA1 plays an essential role in regulating platelet mitochondrial function, platelet activation and thrombosis in males but not in females. These findings suggest that whereas maintaining OPA1 expression might be a protective adaptation in males, OPA1 induction in platelets of females with diabetes might not protect against platelet hyperactivation.