Mitochondrial oxidants promote platelet activation and thrombotic susceptibility in prediabetes

Recent studies suggest prediabetes is an independent risk factor for cardiovascular thrombotic events. However, the mechanisms that may promote platelet activation and thrombosis in prediabetes remain elusive. To determine mechanisms linking prediabetes and thrombosis as a function of age, we recruited military veterans with prediabetes and veterans who were normoglycemic, in young and middle-age groups. Compared with normoglycemic participants, platelets from those with prediabetes exhibited increased activation, mitochondrial oxidant load, mitochondrial membrane hyperpolarization, and greater thrombus formation ex vivo regardless of age. Preincubation of platelets with mitochondria-targeted antioxidants, such as SOD mimetic or mitoquinol (MitoQ), rescued this prothrombotic phenotype. These phenotypes were recapitulated in C57BL6/J mice exhibiting early onset of glucose intolerance when fed a high-fat (HF) diet for 2 weeks. Treatment of HF-fed mice with a SOD mimetic or MitoQ, or genetic overexpression of catalase within mitochondria, not only lowered mitochondrial oxidants, hyperpolarization, Ca2+ levels, and platelet activation but also protected against increased potential for carotid and pulmonary thrombosis. We also observed a bidirectional regulation of platelet activation by Ca2+ and mitochondrial oxidants. These findings support the idea that mitochondrial oxidant-dependent platelet activation induces a prothrombotic state in clinical prediabetes and preclinical models of short-term glucose intolerance and can be reversed by mitochondria-targeted antioxidants.