Mitochondrial metabolism as a determinant of heterogeneous platelet functional phenotypes: Implications for antiplatelet resistance.

Platelets are increasingly recognized as a heterogeneous circulating cell population whose functional behavior cannot be fully explained by receptor-agonist signaling alone; instead, their bioenergetic state emerges as a molecular determinant that shapes both physiological hemostasis and disease-associated hyperreactivity. This review synthesizes evidence supporting energetic specialization in platelets, where glycolytic ATP predominantly supports rapid responses such as shape changes and aggregation; mitochondrial oxidative phosphorylation (OXPHOS) instead is critical for high-demand functions, particularly sustained granule secretion and thrombus amplification. Building on this framework, we propose that mitochondria act as a molecular "switch" that sets the threshold between an aggregatory phenotype and procoagulant fate, for which mitochondrial membrane potential (ΔΨm) instability and sustained opening of the mitochondrial permeability transition pore (mPTP) drive commitment to a procoagulant crisis. Mitochondrial quality-control pathways, including fission/fusion dynamics and mitophagy, emerge as a key regulator that preserve this threshold; their impairment increases susceptibility to stress and predisposes platelets to pathological activation. In cardiometabolic disorders (e.g., type 2 diabetes and obesity), mitochondrial remodeling, oxidative stress, and a shift toward a more glycolytic profile are associated with intrinsically heightened reactivity and pharmacodynamic failure manifesting as high on-treatment platelet reactivity (HTPR), underscoring the need for functional stratification. Collectively, these findings support a bioenergetically informed framework in which mitochondrial function defines platelet functional heterogeneity and contributes to thrombotic risk. Integrating platelet mitochondrial biology into translational research may enable improved risk stratification and the development of precision antithrombotic strategies that preserve essential hemostatic function.