Platelet mitochondria drive platelet activation and thrombosis by fueling energy demands via metabolic reprogramming, regulating calcium-mediated procoagulant signaling, and maintaining functional integrity through quality control mechanisms. Current antiplatelet agents, including P2Y12 antagonists, cyclooxygenase-1 inhibitors, glycoprotein IIb/IIIa blockers, and protease-activated receptor-1 antagonists, effectively prevent thrombosis but increase bleeding risk, underscoring the need for metabolism-targeting strategies.
Recent Advances:
Here, we summarize key platelet mitochondrial mechanisms driving platelet activation: metabolic reprogramming through oxidative phosphorylation (OXPHOS)-to-glycolysis shifts, calcium flux mediated by the mitochondrial calcium uniporter controlling coagulation, quality control through dynamics and mitophagy, and mitochondrial genome (mtDNA) regulation linked to relevant diseases.
Critical Issues:
The variable role of OXPHOS in thrombosis remains incompletely understood. Metabolic flexibility complicates therapeutic intervention, while the cytotoxic effects of mitochondrial modulators and technical limitations in the quantification of circulating mtDNA present significant translational challenges.
Future Directions:
Development of therapies based on mitochondria-targeted antioxidants and metabolic enzyme modulators is proposed as a promising antiplatelet strategy. Transplantation of platelet-derived mitochondria and standardized detection of mtDNA warrant further exploration for thrombotic diseases. Antioxid. Redox Signal. 00, 000–000.
AkkermanJW, HolmsenH. Interrelationships among platelet responses: Studies on the burst in proton liberation, lactate production, and oxygen uptake during platelet aggregation and Ca2+ secretion. Blood1981;57(5):956–966.
4.
AlfatniA, RiouM, CharlesAL, et al.Peripheral blood mononuclear cells and platelets mitochondrial dysfunction, oxidative stress, and circulating mtDNA in cardiovascular diseases. J Clin Med2020;9(2):311.
5.
AnnarapuGK, Nolfi-DoneganD, ReynoldsM, et al.Mitochondrial reactive oxygen species scavenging attenuates thrombus formation in a murine model of sickle cell disease. J Thromb Haemost2021;19(9):2256–2262.
6.
ArcherSL. Mitochondrial dynamics–mitochondrial fission and fusion in human diseases. N Engl J Med2013;369:2236–2251.
7.
AugustinHG, KohGY. A systems view of the vascular endothelium in health and disease. Cell2024;187(18):4833–4858.
8.
AvilaC, HuangRJ, StevensMV, et al.Platelet mitochondrial dysfunction is evident in type 2 diabetes in association with modifications of mitochondrial anti-oxidant stress proteins. Exp Clin Endocrinol Diabetes2012;120(4):248–251.
9.
BaccarelliAA, ByunHM. Platelet mitochondrial DNA methylation: A potential new marker of cardiovascular disease. Clin Epigenetics2015;7(1):44.
10.
BaharvandF, Habibi RoudkenarM, Pourmohammadi-BejarpasiZ, et al.Safety and efficacy of platelet-derived mitochondrial transplantation in ischaemic heart disease. Int J Cardiol2024;410:132227.
11.
BarileCJ, HerrmannPC, TyvollDA, et al.Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration. Proc Natl Acad Sci U S A2012;109(7):2539–2543.
12.
BegMA, HuangM, VickL, et al.Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases. Trends Pharmacol Sci2024;45(4):290–303.
13.
BenderM, PalankarR. Platelet shape changes during thrombus formation: Role of actin-based protrusions. Hamostaseologie2021;41(1):14–21.
14.
BennettJA, MastrangeloMA, TureSK, et al.The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function. Nat Commun2020;11(1):3479.
15.
BerridgeMV, CrassoC, NeuzilJ. Mitochondrial genome transfer to tumor cells breaks the rules and establishes a new precedent in cancer biology. Mol Cell Oncol2018;5(5):e1023929.
BoilardE. Extracellular vesicles and their content in bioactive lipid mediators: More than a sack of microRNA. J Lipid Res2018;59(11):2037–2046.
18.
BonoraM, PatergnaniS, RimessiA, et al.ATP synthesis and storage. Purinergic Signal2012;8(3):343–357.
19.
BorcherdingN, BrestoffJR. The power and potential of mitochondria transfer. Nature2023;623(7986):283–291.
20.
BoudreauLH, DuchezAC, CloutierN, et al.Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A2 to promote inflammation. Blood2014;124(14):2173–2183.
21.
BrestoffJR, WilenCB, MoleyJR, et al.Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity. Cell Metab2021;33(2):270–282.e8.
22.
BuckMD, O’sullivanD, Klein GeltinkRI, et al.Mitochondrial dynamics controls T cell fate through metabolic programming. Cell2016;166(1):63–76.
23.
BudnikI, KumskovaM, ChauhanAK. Metabolic pathways in deep vein thrombosis: A new frontier for therapeutic intervention. Blood2025;146(1):29–40.
24.
ByrneRA, RosselloX, CoughlanJJ, ESC Scientific Document Group. et al.; 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J2023;44(38):3720–3826.
25.
CairnsRA, HarrisIS, MakTW. Regulation of cancer cell metabolism. Nat Rev Cancer2011;11(2):85–95.
26.
ChackoBK, KramerPA, RaviS, et al.Methods for defining distinct bioenergetic profiles in platelets, lymphocytes, monocytes, and neutrophils, and the oxidative burst from human blood. Lab Invest2013;93(6):690–700.
27.
ChanDC. Mitochondrial dynamics and its involvement in disease. Annu Rev Pathol2020;15:235–259.
28.
ChaudhryAA, SagoneALJR, MetzEN, et al.Relationship of glucose oxidation to aggregation of human platelets. Blood1973;41(2):249–258.
29.
ChenLL. The expanding regulatory mechanisms and cellular functions of circular RNAs. Nat Rev Mol Cell Biol2020;21(8):475–490.
30.
ChenT, XuPC, GaoS, et al.Monomeric C-reactive protein promotes platelets to release mitochondrial DNA in anti-neutrophil cytoplasmic antibody-associated vasculitis. Mol Immunol2021;137:228–237.
31.
ChenX, WuH, LiuY, et al.Metabolic Reprogramming: A Byproduct or a Driver of Cardiomyocyte Proliferation? Circulation2024a;149(20):1598–1610.
ChenY, PalS, LiW, et al.Engineered platelets as targeted protein degraders and application to breast cancer models. Nat Biotechnol2024b;43(11):1800–1812.
34.
ChenZ, XuL, YuanY, et al.Metabolic crosstalk between platelets and cancer: Mechanisms, functions, and therapeutic potential. Semin Cancer Biol2025;110:65–82.
35.
ChengG, ZielonkaJ, OuariO, et al.Mitochondria-targeted analogues of metformin exhibit enhanced antiproliferative and radiosensitizing effects in pancreatic cancer cells. Cancer Res2016;76(13):3904–3915.
36.
ChungJ, JeongD, KimGH, et al.Super-resolution imaging of platelet-activation process and its quantitative analysis. Sci Rep2021;11(1):10511.
37.
CitrinKM, ChaubeB, Fernández-HernandoC, et al.Intracellular endothelial cell metabolism in vascular function and dysfunction. Trends Endocrinol Metab2025;36(8):744–755.
38.
CohenP, DerksenA, Van den BoschH. Pathways of fatty acid metabolism in human platelets. J Clin Invest1970;49(1):128–139.
39.
Colon HidalgoD, ElajailiH, SulimanH, et al.Metabolism, mitochondrial dysfunction, and redox homeostasis in pulmonary hypertension. Antioxidants (Basel)2022;11(2):428.
40.
CorsiS, IodiceS, VignaL, et al.Platelet mitochondrial DNA methylation predicts future cardiovascular outcome in adults with overweight and obesity. Clin Epigenetics2020;12(1):29.
41.
CostaFR, PuritaJ, MartinsR, et al.Not all platelets are created equal: A review on platelet aging and functional quality in regenerative medicine. Cells2025;14(15):1206.
42.
DAVìG, PatronoC. Platelet activation and atherothrombosis. N Engl J Med2007;357(24):2482–2494.
43.
DayalS, WilsonKM, MottoDG, et al.Hydrogen peroxide promotes aging-related platelet hyperactivation and thrombosis. Circulation2013;127(12):1308–1316.
44.
DE MeloJML, BlondMB, JensenVH, et al.Time-restricted eating in people at high diabetes risk does not affect mitochondrial bioenergetics in peripheral blood mononuclear cells and platelets. Sci Rep2025;15(1):10175.
45.
DelaneyMK, KimK, EstevezB, et al.Differential roles of the NADPH-Oxidase 1 and 2 in platelet activation and thrombosis. Arterioscler Thromb Vasc Biol2016;36(5):846–854.
46.
DenormeF, CampbellRA. Procoagulant platelets: Novel players in thromboinflammation. Am J Physiol Cell Physiol2022;323(4):C951–Cc958.
47.
DhaneshaN, PatelRB, DoddapattarP, et al.PKM2 promotes neutrophil activation and cerebral thromboinflammation: Therapeutic implications for ischemic stroke. Blood2022;139(8):1234–1245.
48.
DiazF, MoraesCT. Mitochondrial biogenesis and turnover. Cell Calcium2008;44(1):24–35.
49.
DingY, GuiX, ChuX, et al.MTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis. Nat Commun2023;14(1):4829.
50.
DionisioLM, ZhengY, CancelasJA. Redox control in platelet activity and therapy. Antioxidants (Basel)2025;14(11):1286.
51.
DobleB, PufuleteM, HarrisJM, et al.Health-related quality of life impact of minor and major bleeding events during dual antiplatelet therapy: A systematic literature review and patient preference elicitation study. Health Qual Life Outcomes2018;16(1):191.
52.
DoeryJC, HirshJ, CooperI. Energy metabolism in human platelets: Interrelationship between glycolysis and oxidative metabolism. Blood1970;36(2):159–168.
53.
DuZ, WanP, DuM, et al.MAT2A promotes atherosclerotic plaque vulnerability by mediating epigenetic reprogramming of macrophages. Nat Commun2025;16(1):11168.
54.
EcklyA, RinckelJY, ProamerF, et al.Respective contributions of single and compound granule fusion to secretion by activated platelets. Blood2016;128(21):2538–2549.
55.
EicherJD, LettreG, JohnsonAD. The genetics of platelet count and volume in humans. Platelets2018;29(2):125–130.
FangF, WangE, YangH, et al.Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy. Nat Commun2025a;16(1):9117.
58.
FangY, WangJ, LiuC, et al.Targeting P2Y14R alleviates platelet-induced NET formation and venous thrombosis through PKA/AKAP13/RhoA axis. Eur Heart J2025b.
59.
FengY, LiX, WangJ, et al.Pyruvate kinase M2 (PKM2) improve symptoms of post-ischemic stroke depression by activating VEGF to mediate the MAPK/ERK pathway. Brain Behav2022;12(1):e2450.
60.
FinstererJ. Genetic, pathogenetic, and phenotypic implications of the mitochondrial A3243G tRNALeu(UUR) mutation. Acta Neurol Scand2007;116(1):1–14.
61.
FioreM, GuyA, JamesC. Procoagulant platelet characterization by measuring phosphatidylserine exposure and microvesicle release from human purified platelets. J Vis Exp2024(213).
62.
FloraGD, GhatgeM, NayakMK, et al.Deletion of pyruvate dehydrogenase kinases reduces susceptibility to deep vein thrombosis in mice. Blood Adv2024;8(15):3906–3913.
63.
FloraGD, NayakMK, GhatgeM, et al.Metabolic targeting of platelets to combat thrombosis: Dawn of a new paradigm? Cardiovasc Res2023a;119(15):2497–2507.
64.
FloraGD, NayakMK, GhatgeM, et al.Mitochondrial pyruvate dehydrogenase kinases contribute to platelet function and thrombosis in mice by regulating aerobic glycolysis. Blood Adv2023b;7(11):2347–2359.
65.
FreedmanJE. Oxidative stress and platelets. Arterioscler Thromb Vasc Biol2008;28(3):s11–s6.
66.
FuentesE, AraunaD, Araya-MaturanaR. Regulation of mitochondrial function by hydroquinone derivatives as prevention of platelet activation. Thromb Res2023;230:55–63.
67.
FuentesE, Araya-MaturanaR, UrraFA. Regulation of mitochondrial function as a promising target in platelet activation-related diseases. Free Radic Biol Med2019;136:172–182.
68.
FuentesM, Araya-MaturanaR, PalomoI, et al.Platelet mitochondrial dysfunction and mitochondria-targeted quinone-and hydroquinone-derivatives: Review on new strategy of antiplatelet activity. Biochem Pharmacol2018;156:215–222.
69.
FullertonMD, GalicS, MarcinkoK, et al.Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med2013;19(12):1649–1654.
70.
GaoC, DaiY, SpezzaPA, et al.Megakaryocytes transfer mitochondria to bone marrow mesenchymal stromal cells to lower platelet activation. J Clin Invest, 2025a;135(8):e189801.
71.
GaoC, LouC, LieH, et al.Research progress on energy metabolism regulation in stored platelets. Chin J Blood Transfusion2025b:130–135.
72.
Garcia-SouzaLF, OliveiraMF. Mitochondria: Biological roles in platelet physiology and pathology. Int J Biochem Cell Biol2014;50:156–160.
73.
GawazM, GeislerT, BorstO. Current concepts and novel targets for antiplatelet therapy. Nat Rev Cardiol2023;20(9):583–599.
74.
GhatgeM, NayakMK, FloraGD, et al.Mitochondrial calcium uniporter b deletion inhibits platelet function and reduces susceptibility to arterial thrombosis. J Thromb Haemost2023;21(8):2163–2174.
75.
Gioscia-RyanRA, BattsonML, CuevasLM, et al.Mitochondria-targeted antioxidant therapy with MitoQ ameliorates aortic stiffening in old mice. J Appl Physiol (1985)2018;124(5):1194–1202.
76.
GornikHL, AronowHD, GoodneyPP, et al.2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS guideline for the management of lower extremity peripheral artery disease: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation2024;149(24):e1313–e1410.
77.
GremmelT, MichelsonAD, FrelingerALIII,et al.Novel aspects of antiplatelet therapy in cardiovascular disease. Res Pract Thromb Haemost2018;2(3):439–449.
78.
GreseleP, FalcinelliE, MomiS. Potentiation and priming of platelet activation: A potential target for antiplatelet therapy. Trends Pharmacol Sci2008;29(7):352–360.
79.
GrichineA, JacobS, EcklyA, et al.The fate of mitochondria during platelet activation. Blood Adv2023;7(20):6290–6302.
80.
HaeriK, SamieeS, BeigiP, et al.A tight interplay between platelet activation and mitochondrial DNA release promotes platelet storage lesion in platelet concentrates. Vox Sang2024;119(5):439–446.
81.
HalesKG, FullerMT. Developmentally regulated mitochondrial fusion mediated by a conserved, novel, predicted GTPase. Cell1997;90(1):121–129.
82.
HayashiT, TanakaS, HoriY, et al.Role of mitochondria in the maintenance of platelet function during in vitro storage. Transfus Med2011;21(3):166–174.
83.
HayashidaK, TakegawaR, ShoaibM, et al.Mitochondrial transplantation therapy for ischemia reperfusion injury: A systematic review of animal and human studies. J Transl Med2021;19(1):214.
84.
HolmsenH, KaplanKL, DangelmaierCA. Differential energy requirements for platelet responses. A simultaneous study of aggregation, three secretory processes, arachidonate liberation, phosphatidylinositol breakdown and phosphatidate production. Biochem J1982;208(1):9–18.
85.
HolmsenH, SetkowskyCA, DayHJ. Effects of antimycin and 2-deoxyglucose on adenine nucleotides in human platelets. Role of metabolic adenosine triphosphate in primary aggregation, secondary aggregation and shape change of platetets. Biochem J1974;144(2):385–396.
86.
HuY, ZhaLL, DaiKS. [Regulation of Mitochondria on Platelet Apoptosis and Activation]. Zhongguo Shi Yan Xue Ye Xue Za Zhi2023;31(3):816–822.
87.
HuangS, ShiJ, ShenJ, et al.Metabolic reprogramming of neutrophils in the tumor microenvironment: Emerging therapeutic targets. Cancer Lett2025;612:217466.
88.
IbaT, HelmsJ, LeviM, et al.Thromboinflammation in acute injury: Infections, heatstroke, and trauma. J Thromb Haemost, 2024;22(1):7–22.
89.
IulianoL, ColavitaAR, LeoR, et al.Oxygen free radicals and platelet activation. Free Radic Biol Med1997;22(6):999–1006.
90.
JacobS, KosakaY, BhatlekarS, et al.Mitofusin-2 regulates platelet mitochondria and function. Circ Res2024;134(2):143–161.
91.
JiangH, NechipurenkoDY, PanteleevMA, et al.Redox regulation of platelet function and thrombosis. J Thromb Haemost2024;22(6):1550–1557.
92.
JiaoQ, XiangL, ChenY. Mitochondrial transplantation: A promising therapy for mitochondrial disorders. Int J Pharm2024;658:124194.
93.
JohanssonPI, NakahiraK, RogersAJ, et al.Plasma mitochondrial DNA and metabolomic alterations in severe critical illness. Crit Care2018;22(1):360.
94.
KaczaraP, SitekB, PrzyborowskiK, et al.Antiplatelet effect of carbon monoxide is mediated by NAD(+) and ATP depletion. Arterioscler Thromb Vasc Biol2020;40(10):2376–2390.
95.
KeramatiAR, ChenMH, RodriguezBAT, NHLBI Trans-OMICS for Precision (TOPMed) Consortium. et al.; Genome sequencing unveils a regulatory landscape of platelet reactivity. Nat Commun2021;12(1):3626.
96.
KhattakS, TownendJN, ThomasMR. Impact of antiplatelet therapy on microvascular thrombosis during ST-elevation myocardial infarction. Front Mol Biosci2024;11:1287553.
KimSH, LimKM, NohJY, et al.Doxorubicin-induced platelet procoagulant activities: An important clue for chemotherapy-associated thrombosis. Toxicol Sci2011;124(1):215–224.
100.
KiyunaLA, AlbuquerqueRPE, ChenCH, et al.Targeting mitochondrial dysfunction and oxidative stress in heart failure: Challenges and opportunities. Free Radic Biol Med2018;129:155–168.
101.
KnezJ, CauwenberghsN, ThijsL, et al.Association of left ventricular structure and function with peripheral blood mitochondrial DNA content in a general population. Int J Cardiol2016;214:180–188.
102.
KoupenovaM, KehrelBE, CorkreyHA, et al.Thrombosis and platelets: An update. Eur Heart J2017;38(11):785–791.
103.
KramerPA, RaviS, ChackoB, et al.A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: Implications for their use as bioenergetic biomarkers. Redox Biol2014;2:206–210.
104.
KrausF, RoyK, PucadyilTJ, et al.Function and regulation of the divisome for mitochondrial fission. Nature2021;590(7844):57–66.
105.
KulkarniPP, EkhlakM, DashD. Energy metabolism in platelets fuels thrombus formation: Halting the thrombosis engine with small-molecule modulators of platelet metabolism. Metabolism2023a;145:155596.
106.
KulkarniPP, EkhlakM, SinghV, et al.Fatty acid oxidation fuels agonist-induced platelet activation and thrombus formation: Targeting β-oxidation of fatty acids as an effective anti-platelet strategy. Faseb J2023b;37(2):e22768.
107.
KulkarniPP, EkhlakM, SonkarVK, et al.Mitochondrial ATP generation in stimulated platelets is essential for granule secretion but dispensable for aggregation and procoagulant activity. Haematologica2022;107(5):1209–1213.
108.
KulkarniPP, TiwariA, SinghN, et al.Aerobic glycolysis fuels platelet activation: Small-molecule modulators of platelet metabolism as anti-thrombotic agents. Haematologica2019;104(4):806–818.
109.
LazarS, GoldfingerLE. Platelets and extracellular vesicles and their cross talk with cancer. Blood2021;137(23):3192–3200.
110.
LepropreS, KautballyS, OctaveM, et al.AMPK-ACC signaling modulates platelet phospholipids and potentiates thrombus formation. Blood2018;132(11):1180–1192.
111.
LevouxJ, ProlaA, LafusteP, et al.Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming. Cell Metab2021;33(2):283–299.e9.
112.
LiM, LuW, MengY, et al.Tetrahydroxy stilbene glucoside alleviates ischemic stroke by regulating conformation-dependent intracellular distribution of PKM2 for M2 macrophage polarization. J Agric Food Chem2022;70(49):15449–15463.
113.
LiaoR, WangL, ZengJ, et al.Reactive oxygen species: Orchestrating the delicate dance of platelet life and death. Redox Biol2025;80:103489. &
114.
LiesaM, PalacínM, ZorzanoA. Mitochondrial dynamics in mammalian health and disease. Physiol Rev2009;89(3):799–845.
115.
LinRZ, ImGB, LuoAC, et al.Mitochondrial transfer mediates endothelial cell engraftment through mitophagy. Nature2024;629(8012):660–668.
116.
LinX, GaoH, XinM, et al.α-Actinin-1 deficiency in megakaryocytes causes low platelet count, platelet dysfunction, and mitochondrial impairment. Blood Adv2025;9(5):1185–1201.
117.
LiuLP, ChengK, NingMA, et al.Association between peripheral blood cells mitochondrial DNA content and severity of coronary heart disease. Atherosclerosis2017;261:105–110.
118.
LiuL, SakakibaraK, ChenQ, et al.Receptor-mediated mitophagy in yeast and mammalian systems. Cell Res2014;24(7):787–795.
119.
LiuZ, SunY, QiZ, et al.Mitochondrial transfer/transplantation: An emerging therapeutic approach for multiple diseases. Cell Biosci2022;12(1):66.
120.
LongchampsRJ, YangSY, CastellaniCA, et al.Genome-wide analysis of mitochondrial DNA copy number reveals loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation. Hum Genet2022;141(1):127–146.
121.
LonobileC, DI NubilaA, SimoneR, et al.The mitochondrial permeability transition pore in platelets: Mechanisms, physiological roles, and therapeutic perspectives. Antioxidants (Basel)2025;14(8):923.
122.
LuntSY, Vander HeidenMG. Aerobic glycolysis: Meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol2011;27:441–464.
123.
LuoXL, JiangJY, HuangZ, et al.Autophagic regulation of platelet biology. J Cell Physiol2019;234(9):14483–14488.
MackA, Vanden HoekT, DuX. Thromboinflammation and the role of platelets. Arterioscler Thromb Vasc Biol2024;44(6):1175–1180.
126.
MasonKD, CarpinelliMR, FletcherJI, et al.Programmed anuclear cell death delimits platelet life span. Cell2007;128(6):1173–1186.
127.
MasselliE, PozziG, VaccarezzaM, et al.ROS in platelet biology: Functional aspects and methodological insights. Int J Mol Sci2020;21(14):4866.
128.
MatiutoN, ApplewhiteB, HabashN, et al.Harnessing mitochondrial transplantation to target vascular inflammation in cardiovascular health. JACC Basic Transl Sci2025;10(8):101331.
129.
MccallKA, HuangC, FierkeCA. Function and mechanism of zinc metalloenzymes. J Nutr2000;130(5S Suppl):1437s–1446s.
130.
McfadyenJD, SchaffM, PeterK. Current and future antiplatelet therapies: Emphasis on preserving haemostasis. Nat Rev Cardiol2018;15(3):181–191.
131.
MelchingerH, JainK, TyagiT, et al.Role of platelet mitochondria: Life in a nucleus-free zone. Front Cardiovasc Med2019;6:153.
132.
MéndezD, AraunaD, FuentesF, et al.Mitoquinone (MitoQ) inhibits platelet activation steps by reducing ROS levels. Int J Mol Sci2020a;21(17):6192.
133.
MéndezD, Donoso-BustamanteV, Pablo Millas-VargasJ, et al.Synthesis and pharmacological evaluation of acylhydroquinone derivatives as potent antiplatelet agents. Biochem Pharmacol2021;183:114341.
134.
MéndezD, TelleríaF, AlarcónM, et al.Mitocdnb Decreases Platelet Activation Through its Selective Action on Mitochondrial Thioredoxin Reductase. Biomed Pharmacother2025;183:117840.
135.
MéndezD, TelleríaF, Monroy-CárdenasM, et al.Linking triphenylphosphonium cation to a bicyclic hydroquinone improves their antiplatelet effect via the regulation of mitochondrial function. Redox Biol2024;72:103142.
136.
MéndezD, UrraFA, Millas-VargasJP, et al.Synthesis of antiplatelet ortho-carbonyl hydroquinones with differential action on platelet aggregation stimulated by collagen or TRAP-6. Eur J Med Chem2020b;192:112187.
137.
MiddletonEA, RowleyJW, CampbellRA, et al.Sepsis alters the transcriptional and translational landscape of human and murine platelets. Blood2019;134(12):911–923.
138.
MinBK, ParkS, KangHJ, et al.Pyruvate dehydrogenase kinase is a metabolic checkpoint for polarization of macrophages to the M1 phenotype. Front Immunol2019;10:944.
139.
Mosso-PaniMA, BarredaD, SalazarMI. Dynamic regulation of neutrophil immunometabolism by platelet-derived metabolites. Front Immunol2025;16:1542438.
140.
MouraLA, DE AlmeidaAC, DA SilvaAV, et al.Synthesis, anticlotting and antiplatelet effects of 1,2,3-triazoles derivatives. Med Chem2016;12(8):733–741.
141.
MunteanDM, SturzaA, DănilăMD, et al.The role of mitochondrial reactive oxygen species in cardiovascular injury and protective strategies. Oxid Med Cell Longev2016;2016:8254942.
142.
MurrayKO, Berryman-MacielM, DarvishS, et al.Mitochondrial-targeted antioxidant supplementation for improving age-related vascular dysfunction in humans: A study protocol. Front Physiol2022;13:980783.
143.
NayakMK, DhaneshaN, DoddapattarP, et al.Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, inhibits platelet aggregation and arterial thrombosis. Blood Adv, 2018;2(15):2029–2038.
144.
NayakMK, GhatgeM, FloraGD, et al.The metabolic enzyme pyruvate kinase M2 regulates platelet function and arterial thrombosis. Blood2021;137(12):1658–1668.
145.
OlasB, WachowiczB. Resveratrol and vitamin C as antioxidants in blood platelets. Thromb Res2002;106(2):143–148.
146.
PastoriD, PignatelliP, FarcomeniA, et al.Aging-related decline of glutathione peroxidase 3 and risk of cardiovascular events in patients with atrial fibrillation. J Am Heart Assoc2016;5(9):e003682.
147.
PengN, GuoL, WeiZ, et al.Platelet mitochondrial DNA methylation: A novel biomarker for myocardial infarction—A preliminary study. Int J Cardiol2024;398:131606.
148.
PfeifferT, SchusterS, BonhoefferS. Cooperation and competition in the evolution of ATP-producing pathways. Science2001;292(5516):504–507.
149.
PiccaA, MankowskiRT, BurmanJL, et al.Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol2018;15(9):543–554.
150.
PokrovskayaID, YadavS, RaoA, et al.3D ultrastructural analysis of α-granule, dense granule, mitochondria, and canalicular system arrangement in resting human platelets. Res Pract Thromb Haemost2020;4(1):72–85.
151.
PoznyakAV, IvanovaEA, SobeninIA, et al.The role of mitochondria in cardiovascular diseases. Biology (Basel)2020;9(6):137.
152.
PuckettDL, AlquraishiM, ChowanadisaiW, et al.The role of PKM2 in metabolic reprogramming: Insights into the regulatory roles of non-coding RNAs. Int J Mol Sci2021;22(3):1171.
QiaoJ, ArthurJF, GardinerEE, et al.Regulation of platelet activation and thrombus formation by reactive oxygen species. Redox Biol2018;14:126–130.
155.
RackhamO, FilipovskaA. Organization and expression of the mammalian mitochondrial genome. Nat Rev Genet2022;23(10):606–623.
156.
RaveraS, SignorelloMG, PanfoliI. Platelet metabolic flexibility: A matter of substrate and location. Cells2023;12(13):1802.
157.
RaviS, ChackoB, KramerPA, et al.Defining the effects of storage on platelet bioenergetics: The role of increased proton leak. Biochim Biophys Acta2015a;1852(11):2525–2534.
158.
RaviS, ChackoB, SawadaH, et al.Metabolic plasticity in resting and thrombin activated platelets. PLoS One2015b;10(4):e0123597.
159.
RichmanTR, ErmerJA, BakerJ, et al.Mitochondrial gene expression is required for platelet function and blood clotting. Cell Rep2023;42(11):113312.
160.
RochB, PisarevaE, MirandolaA, et al.Impact of platelet activation on the release of cell-free mitochondria and circulating mitochondrial DNA. Clin Chim Acta2024;553:117711.
161.
Rojas-SanchezG, Calzada-MartinezJ, McmahonB, et al.TNF-α impairs platelet function by inhibiting autophagy and disrupting metabolism via syntaxin 17 downregulation. J Clin Invest2025;135(15):e186065.
162.
RossmannMP, DuboisSM, AgarwalS, et al.Mitochondrial function in development and disease. Dis Model Mech2021;14(6):dmm048912.
163.
RowleyJW, OlerAJ, TolleyND, et al.Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes. Blood2011;118(14):e101-11–e111.
164.
RusakT, TomasiakM, CiborowskiM. Peroxynitrite can affect platelet responses by inhibiting energy production. Acta Biochim Pol2006;53(4):769–776.
165.
SchoenwaelderSM, YuanY, JosefssonEC, et al.Two distinct pathways regulate platelet phosphatidylserine exposure and procoagulant function. Blood2009;114(3):663–666.
166.
SerasingheMN, ChipukJE. Mitochondrial fission in human diseases. Handb Exp Pharmacol2017;240:159–188.
167.
ShuangZ, JiawanL, LiZ, et al.Research status of the effects of Ca2+ and mitochondria on platelet function. Chinese Journal of Clinical Pharmacology2023:2418–2422.
168.
SiewieraK, KassassirH, TalarM, et al.Higher mitochondrial potential and elevated mitochondrial respiration are associated with excessive activation of blood platelets in diabetic rats. Life Sci2016;148:293–304.
169.
SmithRA, MurphyMP. Animal and human studies with the mitochondria-targeted antioxidant MitoQ. Ann N Y Acad Sci2010;1201:96–103.
170.
SowtonAP, Millington-BurgessSL, MurrayAJ, et al.Rapid kinetics of changes in oxygen consumption rate in thrombin-stimulated platelets measured by high-resolution respirometry. Biochem Biophys Res Commun2018;503(4):2721–2727.
171.
StalkerTJ, NewmanDK, MaP, et al.Platelet signaling. Handb Exp Pharmacol2012(210):59–85.
172.
StalkerTJ, TraxlerEA, WuJ, et al.Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood2013;121(10):1875–1885.
TamuraN, GotoS, YokotaH, et al.Contributing role of mitochondrial energy metabolism on platelet adhesion, activation and thrombus formation under blood flow conditions. Platelets2022;33(7):1083–1089.
175.
TanAS, BatyJW, DongLF, et al.Mitochondrial genome acquisition restores respiratory function and tumorigenic potential of cancer cells without mitochondrial DNA. Cell Metab2015;21(1):81–94.
176.
TangWH, StithamJ, JinY, et al.Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. Circulation2014;129(15):1598–1609.
177.
TelleríaF, MansillaS, MéndezD, et al.The use of triphenyl phosphonium cation enhances the mitochondrial antiplatelet effect of the compound magnolol. Pharmaceuticals (Basel)2023;16(2):210.
178.
TeslaaT, RalserM, FanJ, et al.The pentose phosphate pathway in health and disease. Nat Metab2023;5(8):1275–1289.
179.
TinA, GramsME, AsharFN, et al.Association between mitochondrial DNA copy number in peripheral blood and incident CKD in the atherosclerosis risk in communities study. J Am Soc Nephrol2016;27(8):2467–2473.
180.
Toller-KawahisaJE, HirokiCH, SilvaCMS, et al.The metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils. Nat Commun2023;14(1):4280.
181.
TrnkaJ, ElkalafM, AndělM. Lipophilic triphenylphosphonium cations inhibit mitochondrial electron transport chain and induce mitochondrial proton leak. PLoS One2015;10(4):e0121837.
182.
TyagiT, JainK, GuSX, et al.A guide to molecular and functional investigations of platelets to bridge basic and clinical sciences. Nat Cardiovasc Res2022;1(3):223–237.
183.
TyagiT, YarovinskyTO, FaustinoEVS, et al.Platelet mitochondrial fusion and function in vascular integrity. Circ Res2024;134(2):162–164.
184.
VaraD, MailerRK, TarafdarA, et al.NADPH oxidases are required for full platelet activation in vitro and thrombosis in vivo but dispensable for plasma coagulation and hemostasis. Arterioscler Thromb Vasc Biol2021;41(2):683–697.
185.
VendrovAE, LozhkinA, HayamiT, et al.Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging. Front Immunol2024;15:1410832.
186.
VioliF, PignatelliP. Platelet NOX, a novel target for anti-thrombotic treatment. Thromb Haemost2014;111(5):817–823.
187.
WallaceDC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: A dawn for evolutionary medicine. Annu Rev Genet2005;39:359–407.
188.
WangL, WuQ, FanZ, et al.Platelet mitochondrial dysfunction and the correlation with human diseases. Biochem Soc Trans2017;45(6):1213–1223.
189.
WangL, ZhouX, LuT. Role of mitochondria in physiological activities, diseases, and therapy. Mol Biomed2025a;6(1):42.
190.
WangS, TanJ, MiaoY, et al.Mitochondrial dynamics, mitophagy, and mitochondria-endoplasmic reticulum contact sites crosstalk under hypoxia. Front Cell Dev Biol2022;10:848214.
191.
WangXB, CuiNH, FangZQ, et al.Platelet bioenergetic profiling uncovers a metabolic pattern of high dependency on mitochondrial fatty acid oxidation in type 2 diabetic patients who developed in-stent restenosis. Redox Biol2024;72:103146.
192.
WangX, LiaoR, HuangQ, et al.Beyond energy: Mitochondrial control of platelet lifecycle through redox, calcium, and dynamics. Redox Biol2025b;87:103892.
193.
WangZ, WangJ, XieR, et al.Mitochondria-derived reactive oxygen species play an important role in Doxorubicin-induced platelet apoptosis. Int J Mol Sci2015;16(5):11087–11100.
194.
WeitzJI. Arterial thrombosis: Present and future. Circulation2024;150(12):905–907.
195.
WeyrichAS, SchwertzH, KraissLW, et al.Protein synthesis by platelets: Historical and new perspectives. J Thromb Haemost2009;7(2):241–246.
YamagishiSI, EdelsteinD, DuXL, et al.Hyperglycemia potentiates collagen-induced platelet activation through mitochondrial superoxide overproduction. Diabetes2001;50(6):1491–1494.
198.
YamaguchiO, MurakawaT, NishidaK, et al.Receptor-mediated mitophagy. J Mol Cell Cardiol2016;95:50–56.
199.
YanC, DuanmuX, ZengL, et al.Mitochondrial DNA: Distribution, mutations, and elimination. Cells2019;8(4):379.
200.
YooHC, YuYC, SungY, et al.Glutamine reliance in cell metabolism. Exp Mol Med2020;52(9):1496–1516.
201.
YueP, JingS, LiuL, et al.Association between mitochondrial DNA copy number and cardiovascular disease: Current evidence based on a systematic review and meta-analysis. PLoS One2018;13(11):e0206003.
202.
ZamanM, ShuttTE. The role of impaired mitochondrial dynamics in MFN2-mediated pathology. Front Cell Dev Biol2022;10:858286.
203.
ZengT, LeiGL, YuML, et al.The role and mechanism of various trace elements in atherosclerosis. Int Immunopharmacol2024;142(Pt B):113188.
204.
ZhangS, HulverMW, McmillanRP, et al.The pivotal role of pyruvate dehydrogenase kinases in metabolic flexibility. Nutr Metab (Lond)2014;11(1):10.
205.
ZhangW, MaQ, SirajS, et al.Nix-mediated mitophagy regulates platelet activation and life span. Blood Adv2019;3(15):2342–2354.
206.
ZhangW, RenH, XuC, et al.Hypoxic mitophagy regulates mitochondrial quality and platelet activation and determines severity of I/R heart injury. Elife2016;5:e21407.
207.
ZhangW, ZhouH, LiH, et al.Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria. Cell Rep2023a;42(9):113147.
208.
ZhangY, SunM, ZhaoH, et al.Neuroprotective effects and therapeutic potential of dichloroacetate: Targeting metabolic disorders in nervous system diseases. Int J Nanomedicine2023b;18:7559–7581.
209.
ZhaoZ, ZhouY, HiltonT, et al.Extracellular mitochondria released from traumatized brains induced platelet procoagulant activity. Haematologica2020;105(1):209–217.
210.
ZharikovS, ShivaS. Platelet mitochondrial function: From regulation of thrombosis to biomarker of disease. Biochem Soc Trans2013;41(1):118–123.
211.
ZhuY, WanM, FuY, et al.Platelet methyltransferase-like protein 4-mediated mitochondrial DNA metabolic disorder exacerbates oral mucosal immunopathology in hypoxia. Int J Oral Sci2025;17(1):49.
212.
ZielonkaJ, JosephJ, SikoraA, et al.Mitochondria-targeted triphenylphosphonium-based compounds: Syntheses, mechanisms of action, and therapeutic and diagnostic applications. Chem Rev2017;117(15):10043–10120.
