Platelet mitochondria dysfunction in diabetes mellitus: mechanisms and therapeutic implications

FIGURE 1. DM-induced ROS signaling in platelets. Hyperglycemia increases platelet glucose uptake via GLUT1/3, enhancing glycolytic flux and mitochondrial electron transport chain activity, leading to elevated mtROS production. Activation of the polyol pathway depletes NADPH and weakens antioxidant defenses, further amplifying oxidative stress. In parallel, hyperglycemia stimulates NOX2 activation and enhances receptor-mediated signaling, promoting PLC-PKC-dependent ROS generation. Accumulated ROS oxidatively modify key signaling proteins, suppress NO-sGC-cGMP inhibitory pathways, impair SERCA-mediated Ca2+ reuptake, and elevate cytosolic Ca2+. These redox-dependent changes lower the platelet activation threshold, enhance receptor and integrin activation, increase granule secretion, and drive a procoagulant, hyperreactive platelet phenotype under hyperglycemic conditions.

FIGURE 2. Hyperglycemia-induced Ca2+ dysregulation in platelets. Mitochondrial Ca2+ buffering is compromised under metabolic stress, contributing to sustained cytosolic Ca2+ elevation. Store-operated Ca2+ entry via STIM1-ORAI-1, along with TRPC6 and reverse-mode NCX1, further augments Ca2+ influx. Simultaneously, impaired SERCA-mediated reuptake and reduced PMCA-dependent efflux limit Ca2+ clearance. Hyperglycemia enhances platelet receptor signaling, activating PLC pathways and increasing IP3-mediated Ca2+ release from the DTS. The resulting Ca2+ overload drives granule secretion, thromboxane production, platelet hyperreactivity, and aggregation in hyperglycemic conditions.

FIGURE 3. Hyperglycemia increases platelet glucose uptake through GLUT1 and GLUT3, enhancing glycolysis and mitochondrial substrate supply. Elevated NADH and FADH2, overloading the electron transport chain and increasing mtROS production. mtROS disrupts ΔΨm, promotes Ca2+ overload, and facilitate mPTP opening. These changes impair redox balance and mitochondrial function, leading to the release of mtROS and damaged mitochondrial components. Collectively, these alterations enhance platelet activation, hyperreactivity, and aggregation under hyperglycemic conditions.

FIGURE 4. Interplay between mitochondrial dysfunction, oxidative stress, and Ca2+ dysregulation in hyperglycemia-induced platelet hyperreactivity. Chronic hyperglycemia induces excessive metabolic flux through platelet mitochondria, leading to ETC, overload, elevated mtROS generation, dysregulated ATP production, loss of ΔΨm leading to sustained mPTP-VDAC mediated release of mtROS and Ca2+. This released mtROS amplifies oxidative stress through NOX2 activation, impairs antioxidant defenses, further enhancing redox-sensitive signaling pathways, while mitigating the inhibitory NO-sGC-cGMP pathways. Oxidative modifications of Ca2+-handling proteins promote increased Ca2+ influx (via ORAI1/TRPC6), elevated PLC activity induces IP3 receptor-mediated Ca2+ release, reduced SERCA-dependent reuptake, and diminished PMCA-mediated efflux, resulting in sustained cytosolic Ca2+ elevation. Elevated cytosolic Ca2+ further increases mitochondrial Ca2+ uptake, exacerbating mitochondrial dysfunction and ROS production. These three interconnected processes form a self-reinforcing pathological cycle that lowers the activation threshold of platelets, promotes granule secretion and integrin activation, and…