Beyond energy: Mitochondrial control of platelet lifecycle through redox, calcium, and dynamics.

Platelet disorders, caused by quantitative deficiencies or functional impairments, significantly contribute to cardiovascular, neurological, and iatrogenic pathologies. Although platelets are indispensable for hemostasis, thrombosis, and immune responses, the molecular mechanisms governing their biogenesis from megakaryocytes (MKs) and subsequent functional regulation remain incompletely understood. Mitochondria, inherited from MK progenitors, are now recognized as central regulators of platelet physiology and pathology. Emerging evidence demonstrates that mitochondrial processes critically regulate MK differentiation and thrombopoiesis, unveiling novel pathways in platelet formation. Mitochondria regulate metabolism, calcium (Ca2+) regulation, reactive oxygen species (ROS) signaling, autophagy, and dynamics, directly modulate essential platelet activities, such as activation dynamics, lifespan, and coagulation efficiency, in physiological and pathological contexts. This review synthesizes emerging evidence on the multi-layered mitochondrial control of thrombopoiesis and platelet functionality. We critically assess the translational potential of targeting mitochondria for treating platelet-related disorders, delineating specific molecular targets within MKs and platelets. Furthermore, we propose a framework for developing mitochondrial-based therapeutic strategies to prevent and manage platelet-associated diseases, thereby advancing clinical translation in this field.