Platelet mitochondria: the mighty few

Abstract

Purpose of review: Platelet mitochondrial dysfunction is both caused by, as well as a source of oxidative stress. Oxidative stress is a key hallmark of metabolic disorders such as dyslipidemia and diabetes, which are known to have higher risks for thrombotic complications.

Recent findings: Increasing evidence supports a critical role for platelet mitochondria beyond energy production and apoptosis. Mitochondria are key regulators of reactive oxygen species and procoagulant platelets, which both contribute to pathological thrombosis. Studies targeting platelet mitochondrial pathways have reported promising results suggesting antithrombotic effects with limited impact on hemostasis in animal models.

Summary: Targeting platelet mitochondria holds promise for the reduction of thrombotic complications in patients with metabolic disorders. Future studies should aim at validating these preclinical findings and translate them to the clinic.

Figure 1.. Fueling platelets with glucose is mediated by GLUT1 and GLUT3.

(1) Under basal conditions, GLUT1 (Glucose transporter 1) is the primary glucose transporter on platelets. (2) Upon platelet activation, GLUT3 translocates to the plasma membrane and mediates increased glucose uptake. (3) Additionally, GLUT3 drives glucose uptake in α-granules which allows for proper degranulation. (4) Platelets generate energy by combining glycolysis and mitochondrial OXPHOS (oxidative phosphorylation), with aerobic glycolysis being the predominant provider of cellular ATP. (5) Platelets achieve this by inhibiting the oxidation of pyruvate, which is mediated by PDK (pyruvate dehydrogenase kinase) blocking PDH (pyruvate dehydrogenase)-mediated catabolization of pyruvate. This blocks pyruvate from entering the TCA (tricarboxylic acid cycle) cycle preventing a decline in mitochondrial respiration and increases production of lactate.

Figure 2.. Platelet activation induces the formation of mitochondrial ROS and the formation of procoagulant platelets.

(1) Platelet activation triggers the opening of intracellular Ca²⁺ stores. (2) This results in mitochondrial Ca²⁺ uptake through the MCU (mitochondrial calcium uniporter) complex. Platelet activation requires ATP generation. In the process of producing ATP mitochondrial ROS is generated as a byproduct, which can potentiate platelet activation. (3) When mitochondrial Ca²⁺ levels reach a critical threshold, mitochondria will form the mitochondrial permeability transition pore (mPTP) resulting in procoagulant platelet formation.