Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.

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Published in final edited form as: Circ Res. 2026 Apr 9;138(8):e326987. doi: 10.1161/CIRCRESAHA.125.326987 Search in PMC Search in PubMed View in NLM Catalog Add to search Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer Florian Tupin Florian Tupin 1 Faculté de Médecine de l’Université Laval, Université Laval, Québec, QC, Canada 2 Centre de Recherche ARThrite - Arthrite, Recherche, Traitements, Université Laval, Québec, QC, Canada 3 Axe maladies infectieuses et immunitaires du Centre de recherche du Centre hospitalier universitaire de Québec-Université Laval, Québec, QC, Canada Find articles by Florian Tupin 1, 2, 3, * , Jorge A Gonzalez-Chapa Jorge A Gonzalez-Chapa 4 Division of Rheumatology, University of Washington, Seattle, WA, USA Find articles by Jorge A Gonzalez-Chapa 4, * , Jay Chung Jay Chung 5 Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892. Find articles by Jay Chung 5 , Christian Lood Christian Lood 4 Division of Rheumatology, University of Washington, Seattle, WA, USA Find articles by Christian Lood 4 , Eric Boilard Eric Boilard 1 Faculté de Médecine de l’Université Laval, Université Laval, Québec, QC, Canada 2 Centre de Recherche ARThrite - Arthrite, Recherche, Traitements, Université Laval, Québec, QC, Canada 3 Axe maladies infectieuses et immunitaires du Centre de recherche du Centre hospitalier universitaire de Québec-Université Laval, Québec, QC, Canada Find articles by Eric Boilard 1, 2, 3 Author information Article notes Copyright and License information 1 Faculté de Médecine de l’Université Laval, Université Laval, Québec, QC, Canada 2 Centre de Recherche ARThrite - Arthrite, Recherche, Traitements, Université Laval, Québec, QC, Canada 3 Axe maladies infectieuses et immunitaires du Centre de recherche du Centre hospitalier universitaire de Québec-Université Laval, Québec, QC, Canada 4 Division of Rheumatology, University of Washington, Seattle, WA, USA 5 Laboratory of Obesity and Aging Research, Cardiovascular Branch, National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892. * These authors contributed equally. ✉ Correspondence should be sent to: Eric Boilard, PhD., Faculté de Médecine de l’Université Laval, 2705 Laurier Blvd, room T1-49, Québec, QC, Canada G1V 4G2, [email protected] , Fax: +1 418-654-2765 Issue date 2026 Apr 10. PMC Copyright notice PMCID: PMC13078699  NIHMSID: NIHMS2150482  PMID: 41955328 The publisher's version of this article is available at Circ Res Abstract Mitochondria are organelles that orchestrate numerous cell functions in addition to providing energy. During viral infection or in case of defects in mitochondrial replication, an intricate mechanism of self-destruction is engaged through the formation of mitochondrial pores. This leads to the release of mitochondrial DNA into the cytoplasm, where it triggers innate immune responses. Platelets constitute the principal source of circulating mitochondria, and increasing evidence demonstrates that they actively release mitochondria, some of which are enclosed within extracellular vesicles. This process is enhanced in autoimmune conditions, occurs in platelet storage, and has been linked to adverse reactions following platelet transfusion. Extracellular mitochondria act as carriers of damage-associated molecular patterns and are targets of antibodies in various pathologies, including antiphospholipid syndrome and cardiomyopathies. Moreover, elevated levels of anti-mitochondria antibodies have also been associated with increased mortality and cardiovascular risk in systemic lupus erythematosus. Mitochondrial transplantation, a process by which defective mitochondria in a tissue or organ may be replaced by healthy mitochondria, is receiving growing therapeutic interest. Thus, understanding how extracellular mitochondria interact with the immune system is increasingly important. This review summarizes current knowledge on the multifaceted roles of mitochondria in immunity, with a particular focus on platelets and platelet-derived mitochondria as a key biological context. Subject Terms: Basic Science Research, Cell Biology/Structural Biology, Risk Factors INTRODUCTION Mitochondria are organelles that regulate numerous cellular functions, ranging from energy production to control of cell death. They can form networks, and have an elongated shape, which inspired their name from the Greek words mitos (thread) and khondrion (granule). This organelle has its own genome composed of mitochondrial DNA (mtDNA) and can multiply inside the cell independently of cellular division, depending on cell energy needs and/or nutrient availability. Given their circular genome and the presence of molecules resembling those of bacteria, mitochondria are thought to have descended from an ancestral bacterium that entered into endosymbiosis with eukaryotic cells billions of years ago. 1 Perhaps due to their content of bacteria-like molecules, mitochondria are efficient effectors of the immune system. Release of mtDNA into the cytoplasm is detected by cytosolic DNA sensors that activate the cell, similar to the process described when microbial DNA is found in the cytosol. 2 Furthermore, mitochondria can be released from cells, which can also activate the immune system. While it has been suggested that mitochondria convey damage-associated molecular patterns (DAMPs) that promote innate immune system activation, 3 , 4 they also represent a source of antigens that are targeted by antibodies in course of an adaptive immune response, which may be predictive of cardiovascular diseases or mortality. 5 Conversely, the exchange of mitochondria between cells is also reported under homeostatic conditions. 6 Accumulating evidence suggests that mitochondrial transplantation, leveraged from the naturally occurring intercellular communication of mitochondria, may be utilized to rescue target cells from genetic disorders affecting mitochondrial functions or to replenish damaged organs. 6 , 7 Platelets have a role in both hemostasis and immunity. 8 Different signaling pathways promote platelet activation and production of extracellular vesicles. Upon activation, platelets can release their mitochondria, which are then transferred to other cells. Platelets are the main carrier of mitochondria in blood, and may represent a readily available source of mitochondria for mitochondrial transplantation. This review integrates current understanding of mitochondrial crosstalk with innate and adaptive immunity, positioning extracellular mitochondria as a double-edged signal in immune activation and tissue repair such as in mitochondrial transplantation. The following sections will progressively narrow from global mitochondrial immunology to platelet-derived mitochondria. By adopting a platelet-centered perspective, the review exposes this conceptual gap in mitochondrial immunobiology and challenges dominant cell-centric views by uncovering the hemostatic and pathogenic roles of platelet-derived mitochondria. Section I. FUNDAMENTALS OF MITOCHONDRIA 1.1. Mitochondrial architecture and core functions Mitochondria are double-membraned organelles with an outer mitochondrial membrane (OMM) and an inner mitochondrial membrane (IMM) enclosing the mitochondrial matrix. 9 The OMM contains porins, most notably voltage-dependent anion channels (VDACs), which mediate the exchange of metabolites, ions, and calcium between the cytosol and the intermembrane space. They exist in three isoforms, VDAC1, VDAC2, and VDAC3, of which VDAC1 are the most abundant. 10 By its gating action, VDACs controls oxidative phosphorylation (OXPHOS) while in its open conformation. VDACs also serve as interaction hubs for apoptotic and immune proteins, linking metabolic status to cell-fate decisions. Through voltage-gating, VDACs provide the primary regulated conduit for the exchange of adenine nucleotides, allowing cytosolic ADP to enter mitochondria and newly synthesized ATP to exit, thereby directly coupling mitochondrial ATP generation to cellular energy demand. In addition, VDAC-mediated transport of respiratory substrates and inorganic phosphate supports sustained electron flow through the electron transport chain and ATP synthase activity. VDACs also participate in Ca 2+ transfer into mitochondria, indirectly stimulating matrix dehydrogenases (e.g. tricarboxylic acid (TCA) cycle) and enhancing reducing equivalent production to match energetic workload. Through interactions with metabolic enzymes, including hexokinase and creatine kinase, VDACs organize metabolite channeling at the mitochondrial surface, further optimizing ATP production efficiency. Collectively, VDACs function as gatekeepers of mitochondrial metabolism, integrating substrate availability, ion signaling, and enzymatic coupling to maintain efficient OXPHOS and cellular energy homeostasis. 10 The IMM contains the electron transport chain (ETC) and ATP synthase, which drive OXPHOS. 9 Maintaining IMM integrity and cristae architecture is essential for efficient electron transfer, ATP production, and regulation of reactive oxygen species (ROS). The mitochondrial matrix contains enzymes of the TCA cycle, which generate NADH and FADH2, as well as antioxidants such as manganese superoxide dismutase to mitigate ROS. 11 , 12 Collectively, these compartments orchestrate nutrient oxidation, energy production, and redox homeostasis, making mitochondria hubs of bioenergetic production and signaling in cells. 9 1.2. Cytosolic sensors of mitochondrial integrity Mitochondrial damage, such as by mitochondrial ROS (mtROS), causes mitochondria to release DAMPs (mtDAMPs) into the cytosol, feeding into two dominant innate immune pathways: cGAS–STING 13 and the NLRP3 inflammasome 14 ( Figure 1 ). Generation of mtROS, which promote VDAC1 oligomerization, facilitate cytosolic release of oxidized mtDNA, and induce the opening of mitochondrial permeability transition pores (mPTP), can activate NLRP3. 15 , 16 Oligomerized VDACs can also recruit NLRP3 to mitochondria, localizing the inflammasome at sites of distress. 15 In addition, oxidized cardiolipin translocates from IMM to OMM, where it can also recruit and activate NLRP3. 17 Moreover, although VDAC1 oligomerization and calcium-induced mPTP opening are incompletely understood, they likely reinforce one another to permeabilize the OMM and IMM, respectively, 2 , 15 releasing mitochondrial contents that function in the cytosol as DAMPs to promote inflammatory diseases such as lupus 18 and inflammatory bowel disease, 19 as well as metabolic disorders like type 2 diabetes. 20 In the cytosol, the cGAS–STING pathway is activated by cytosolic double-stranded DNA, whether derived from mitochondria or DNA viruses. 13 Cyclic GMP–AMP synthase (cGAS), catalyzes therefore the synthesis of 2′3′-cGAMP upon DNA binding. 13 cGAMP activates the ER-resident adaptor stimulator of interferon genes (STING), which translocates to the Golgi and recruits TBK1 to activate IRF3. 21 – 23 Beyond antiviral defense, STING regulates autophagy, cell death, and metabolic stress responses. Mechanistically, cGAS activation is initiated by sequence-independent binding to cytosolic dsDNA, which induces cGAS dimerization and conformational rearrangement that enables catalytic conversion of ATP and GTP into 2′3′-cGAMP. 21 – 23 Newly synthesized cGAMP functions as a second messenger that binds STING, triggering its oligomerization and exit from the ER via COPII-dependent trafficking to the ER–Golgi intermediate compartment and Golgi. At the Golgi, STING serves as a signaling scaffold for TBK1 recruitment and trans-autophosphorylation, followed by phosphorylation of STING and IRF3, enabling IRF3 dimerization and downstream transcriptional or nontranscriptional signaling outputs. Signal amplitude and duration are subsequently constrained by STING ubiquitination, palmitoylation, and lysosomal degradation, providing tight regulation of cGAS–STING signaling in response to mitochondrial or pathogen-derived DNA. 21 , 23 , 24 Canonically, cGAS–STING contribute to antiviral defense with induction of type I interferon programs via IRF3 21, 25 but also regulates autophagy, cell death, and metabolic stress responses. 21 Mitophagy, which eliminates damaged mitochondria, limits the release of mtDNA, thereby attenuating activation of the cGAS–STING pathway 18 and the NLRP3 inflammasome. 26 Figure 1. Mitochondria as the inflammatory hub in platelets. Open in a new tab A. Elevated reactive oxygen species (ROS) induce VDAC1 oligomerization and opening of the mitochondrial permeability transition pores (mPTP), leading to rupture of both the inner and outer mitochondrial membranes. Consequently, mitochondrial DNA (mtDNA) fragments from the matrix are released into the cytosol. B. In the cytosol, mtDNA fragments are recognized by the double-stranded DNA sensor cGAS, which catalyzes the production of the dinucleotide cGAMP from ATP and GTP. cGAMP subsequently binds and activates STING, triggering its translocation from the endoplasmic reticulum (ER) to the Golgi. In the Golgi, STING recruits STXBP2, an adaptor for the SNARE machinery, facilitating the fusion of platelet granules with the plasma membrane and promoting the release of granule contents that enhance thrombo-inflammation. Additionally, P-selectin is translocated to the plasma membrane, where it mediates recruitment of immune cells, including neutrophils. C. Released mtDNA also promotes NLRP3 inflammasome assembly, leading to cleavage of pro-caspase-1 into active caspase-1. Caspase-1 subsequently processes pro-IL-1β, pro-IL-18, and pro-GSDMD into their mature forms. The N-terminal fragment of GSDMD forms pores in the plasma membrane, facilitating the release of IL-1β and IL-18 and driving a lytic inflammatory process known as pyroptosis. The figure represents a generalizable concept of how mitochondria contribute to inflammation through an intracellular mechanism in cells. However, the final part involving exposure to P-selectin and the afferent mechanism is specific to platelets. Section II. EXTRACELLULAR MITOCHONDRIA Recent evidence challenges the long-held view that mitochondria are present solely within cells. The mechanisms of mitochondrial release fall into broad two categories, passive release and active secretion. Externalization of mitochondria may take place for several distinct reasons, such as: (i) to maintain intracellular homeostasis, (ii) to restore systemic balance and facilitate cellular cooperation, and (iii) as an alarm signal. 27 2.1. Passive release: the consequence of cellular breakdown When cellular integrity fails, mitochondria are passively liberated into the extracellular space. This occurs during necrosis, pyroptosis, or neutrophil extracellular trap (NET) formation, when membranes rupture and cytoplasmic contents escape. 27 , 28 Passive mitochondrial release is therefore most prominent in settings of acute tissue injury and inflammatory collapse, including trauma and sterile injury with systemic inflammatory response, severe infection and sepsis, ischemic tissue necrosis, and ischemia-reperfusion injury. In cardiovascular and critical care contexts, acute myocardial infarction and ischemia-reperfusion injury are associated with increased extracellular and circulating mtDNA, reflecting extensive cellular damage and metabolic collapse. 29 Similarly, following resuscitation from cardiac arrest, whole-body ischemia-reperfusion induces a marked rise in circulating mtDNA, much of which is associated with extracellular vesicles and capable of activating innate immune responses, thereby contributing to post-resuscitation systemic inflammation. 30 Passive mitochondrial release also occurs during NET formation, in which neutrophils externalize mitochondrial components as part of antimicrobial defense programs. While this process may support host defense, excessive or dysregulated release of mitochondrial material can promote endothelial activation and thrombo-inflammatory signaling. 31 Passive release represents the most primitive form of mitochondrial extrusion, an unplanned consequence of cell death that nonetheless conveys biological meaning ( Figure 2 ). Mitochondria released in this manner are often structurally compromised and metabolically inactive, yet their presence in the extracellular environment reflects the intensity and localization of cellular stress. In tissue injury and metabolic collapse, the abundance of these extracellular mitochondria signals the magnitude of damage. But even in this terminal form, release may serve an adaptive purpose by helping to clear damaged material, activating local repair pathways, and contributing to the reorganization of the tissue microenvironment. 32 Thus, passive mitochondrial release is a biological event of terminal stress-response and cell-death programs, conveying microenvironmental information about the magnitude and location of injury. Figure 2. Mechanisms of intercellular mitochondrial release and transfer. Open in a new tab Mitochondrial release occurs through passive release, active secretion, or tunneling nanotube (TNT)-mediated transfer. Passive release during stress or cell death liberates damaged mitochondria that act as mitochondrial damage-associated molecular patterns (mtDAMPs), fueling inflammation if not cleared. Active secretion involves the regulated export of intact mitochondria or mitochondria-derived extracellular vesicles (MEVs) that enhance repair and metabolic recovery. TNT-mediated transfer enables directed, contact-dependent delivery of functional mitochondria, restoring ATP production and limiting oxidative stress. Together, these mechanisms form a continuum from unregulated mitochondrial leakage to highly coordinated intercellular organelle exchange governing inflammation and regeneration. For platelets, mitochondrial release is mainly described under the active pathway. In stored platelet concentrates, extracellular mitochondrial components may increase over time through both active vesiculation and passive release associated with storage-related damage. TNT-mediated mitochondrial transfer has not been reported for platelets. 2.2. Active secretion: the selective export of mitochondrial cargo Active secretion, distinct from passive release, is the regulated export of mitochondria or their components from living cells. It operates via coordinated routes that preserve cellular homeostasis and mediate intercellular communication by selectively disseminating mitochondrial cargo. 2.2.1. Vesicle-mediated mitochondrial export Living cells can eliminate or share mitochondrial material via regulated energy-dependent vesicular routes. When mitophagy or lysosomal degradation are insufficient, vesicular export removes dysfunctional components while maintaining cytoplasmic homeostasis. Through the coordinated action of Rab GTPases, the ESCRT complex, Miro1, and VDACs, mitochondrial membranes, proteins, and nucleic acids are selectively packaged into extracellular vesicles, often referred to as mitochondria-derived extracellular vesicles (MEVs). 33 MEVs serve two complementary functions. First, they preserve intracellular integrity by preventing accumulation of pro-oxidant or depolarized mitochondrial remnants that threaten cellular stability. 34 Second, they participate in intercellular communication, as exported mitochondrial cargo containing mtDNA, enzymes and small mitochondrial fragments, can modulate the metabolic/redox state of recipient cells, promoting survival, adaptation, or metabolic coordination within tissues. 33 , 35 2.2.2. Whole-mitochondrion release As well as releasing fragmented cargo, some cells can actively release whole mitochondria into the extracellular milieu, especially under stress such as after myocardial ischemia. 36 These whole mitochondria can be released by cells in exceptionally large (up to 20 μm) membrane-enclosed vesicles, recently termed blebbisomes. Exported mitochondria typically retain membrane potential and respiratory activity, indicating that this is a regulated process rather than a result of damage. Electron and fluorescence microscopy show the vesicles’ emergence from transient protrusions or bleb-like structures and their subsequent uptake by neighboring cells or phagocytes. Through this transfer, intact mitochondria support metabolic recovery, tissue regeneration, and broader homeostatic communication among cells. 37 , 38 Although most functional mitochondria appear to be released within vesicular compartments, unencapsulated (“naked”) mitochondria have also been detected in plasma. 39 However, these naked mitochondria are exposed to extracellular enzymes and immune recognition, making their long-term survival unlikely. Only a fraction may remain briefly viable, retaining membrane potential and even respiration before clearance. Though transient, such free mitochondria can act as metabolic cues or mtDAMPs, linking regulated secretion and immune surveillance. 2.2.3. Tunneling nanotube-mediated transfer A distinct form of active mitochondrial exchange occurs through tunneling nanotubes (TNTs), actin-rich cytoplasmic bridges that establish direct continuity between neighboring cells. Mitochondria undergo active Miro1-dependent transport along TNTs to injured or energy-deprived cells. In this way, cells can restore ATP production and alleviate oxidative stress in their neighbors. In contrast to vesicular or extracellular routes, TNTs provide a direct, contact-dependent conduit for organelle exchange, perhaps the most refined form of mitochondrial dialogue between living cells. This mechanism also facilitates the transfer of other mitochondrial components, including proteins and nucleic acids. 40 , 41 Thus, mitochondrial secretion occurs along a continuum, from vesicular release of damaged fragments that fine-tunes intracellular quality control, to intercellular transfer of intact organelles that supports metabolic rescue and tissue adaptation. 2.3. Mechanisms of mitochondrial uptake Once released, mitochondria do not drift passively as inert debris; they act as interpretable bioenergetic and immunological signals within their surroundings. A wide range of recipient cells, immune and non-immune, can internalize extracellular mitochondria via macropinocytosis and receptor-mediated endocytosis, or through TNT-mediated transfer. 42 – 44 Notably, uptake by macrophages depends on cell-surface heparan sulfates, which mediate mitochondrial recognition and endocytosis and thus link organelle communication to the composition of the extracellular matrix. While TNTs have been established as a route for mitochondrial transfer between stromal and immune cells, 45 and macropinocytosis has been functionally confirmed using pharmacological inhibition in endothelial models, 46 the molecular routes by which most other recipient cells internalize exogenous mitochondria remain undefined. This represents an opportunity for new discoveries with potential future therapeutic implications. 2.4. Dual fates of extracellular mitochondria Extracellular mitochondria fate may depend on their structural integrity, membrane potential, and the immune context of the recipient cell. Intact mitochondria can be incorporated into host networks to restore metabolism, whereas damaged or oxidized mitochondria are perceived as a danger, igniting inflammatory cascades. 2.4.1. Metabolic rescue In regenerative or homeostatic settings, uptake of functional mitochondria reestablishes bioenergetic and redox balance in injured or metabolically stressed cells. 47 For example, astrocytes transfer mitochondria to neurons after stroke, improving neuronal survival and recovery, 43 and mesenchymal stromal cells donate mitochondria to damaged alveolar epithelium, restoring ATP and limiting acute lung injury. 42 In the heart, direct mitochondrial transplantation after ischemia-reperfusion improves contractile function and bioenergetics, 48 and oral delivery approaches show promise against progression of ischemic heart disease. 49 Across systems, internalized mitochondria integrate into the host network to reinstate oxidative phosphorylation, reduce oxidative stress, stabilize membrane potential, and enhance survival. 50 , 51 Success depends on donor–recipient compatibility, including mitochondrial membrane potential, cardiolipin integrity, and minimal immune-opsonic modification. 50 Healthy, polarized mitochondria are preferentially incorporated, whereas depolarized or oxidized mitochondria are cleared by mitophagy. 52 Collectively, these findings support a physiological form of mitochondrial transplantation biology with therapeutic potential for metabolic and regenerative medicine. 2.4.2. Stimulation of innate immunity by extracellular mitochondrial DAMPs Loss of mitochondrial integrity exposes molecular patterns that reflect the mitochondrion’s bacterial ancestry. These mtDAMPs potently activate innate immunity, and virtually all immune and vascular cells express receptors that sense mitochondrial distress. 4 , 53 Although the most well-established mitochondrial triggers of inflammation are listed below, the complete spectrum of mtDAMPs remains to be defined. Recent discoveries suggest that non-canonical signals, such as mitochondrial RNA, 54 tRNA fragments, oxidized metabolites, 55 and vesicle-associated proteins, 56 may also engage innate immune sensors, expanding the landscape of mitochondrial immunogenicity. i. Mitochondrial DNA. mtDNA is uniquely enriched in unmethylated CpG motifs, which render it a potent inflammatory ligand when released extracellularly or into the cytosol. 26 , 57 In the extracellular or endosomal space, mtDNA is sensed by TLR9, which triggers NF-κB and IRF7 signaling with type I interferon and proinflammatory cytokine production. 58 If mtDNA escapes from endosomes into the cytosol, it activates the cGAS–STING pathway, fueling persistent interferon responses. 53 Oxidized mtDNA is especially effective in triggering the NLRP3 inflammasome, linking mtROS production to IL-1β and IL-18 secretion. 59 The release of oxidized mtDNA during pyroptotic or lytic cell death amplifies inflammasome activation in surrounding cells. 60 In autoimmune diseases such as systemic lupus erythematosus (SLE), mitochondria contribute to NET formation as well as the release of oxidized mtDNA, a driver of sterile inflammation. 28 ii. Formylated peptides. Mitochondrial disruption can release N-formylated peptides (mtNFP) that act as mtDAMPs. These peptides engage formyl peptide receptor-1 (FPR1) on neutrophils, monocytes, and endothelial cells, triggering chemotaxis, Ca 2 + flux, degranulation, and ROS generation. Experimental models demonstrate that mtNFPs also promote neutrophil recruitment and amplify tissue injury. Biochemically, binding of mtNFPs to FPR1 triggers downstream MAPK signaling (p38, ERK1/2) and shear L-selectin shedding in neutrophils, hallmarks of neutrophil activation. 61 FPR1 is considered the primary receptor for mtNFPs, although other FPR family members may also respond to certain mitochondrial peptides. 62 In vivo, exogenous mtNFPs can induce systemic inflammation, hypotension, vascular leakage, coagulopathy, and/or organ dysfunction, effects that can be attenuated by FPR antagonists. 63 , 64 Recent clinical data indicate elevated circulating mtNFPs in rheumatoid arthritis (RA) or acute respiratory distress syndrome. During lung injuries and inflammatory myopathies, mtNFPs can engage FPR1, contributing to inflammation, barrier disruption, and probably autoimmunity. 65 iii. Cardiolipin and other phospholipids. Under mitochondrial stress or membrane disruption, cardiolipin translocates or becomes exposed on the OMM. Exposed cardiolipin can directly bind NLRP3, acting as a lipid scaffold or docking platform for inflammasome assembly. 17 Certain cardiolipin species, especially saturated forms, have been shown to function as TLR4/MD2 agonists, inducing TNF-α and CXCL10/IP-10 in macrophages. 66 Similarly, oxidized phospholipids derived from mitochondrial or cellular membrane damage such as OxPAPC, may signal via TLR2 (and possibly TLR4) to amplify cytokine release. 67 iv. Mitochondrial ROS and metabolites. Mitochondrial dysfunction often leads to excessive mtROS and leakage of metabolic intermediates, which act as secondary DAMPs. Extracellular ATP, acting through the P2X7 receptor, promotes NLRP3 inflammasome activation and release of IL-1β and IL-18. 68 Meanwhile, succinate accumulation stabilizes HIF-1α and skews macrophage polarization toward increased IL-1β output. 69 These pathways connect mitochondrial metabolic derailment to inflammatory cascades. Table 1 summarizes the contexts in which extracellular mitochondria have been detected, linking their molecular triggers to immune pathways and potential biomarkers that together define a translational use from DAMPs to diagnostics. Mechanisms are representative and not mutually exclusive; biomarkers listed are the most reproducible or translationally validated to date. Table 1. Disease and physiological contexts where extracellular mitochondria act as triggers of innate immune and metabolic signaling Context / Disease Mitochondrial trigger or component Proposed mechanism or pathway Representative biomarker References Healthy / Adaptive physiology mtDNA fragments, intact mitochondria Redox signaling Circulating mtDNA transient elevation 70 Systemic lupus erythematosus Oxidized mtDNA, cardiolipin TLR9–IFN-I response; NLRP3 inflammasome priming Oxidized circulating mtDNA and mtDNA-containing NETs 28 , 71 Rheumatoid arthritis mtDNA, mtNFPs peptides FPR1 and TLR9 ; neutrophil activation; synovial inflammation Plasma mtNFPs; mtDNA; S100A8/A9 72 Idiopathic inflammatory myopathies mtNFPs, mtDNA, GDF-15 mtNFP–FPR1 neutrophil activation; mtDNA–TLR9/cGAS–STING ; IFN signaling mtNFPs, GDF-15 , S100A8/A9 65 , 72 Cardiovascular disease mtDNA, cardiolipin, ROS-damaged mitochondria cGAS–STING and TLR9 endothelium-vascular dysfunction Circulating mtDNA , cardiolipin-EVs 73 – 75 Cancer Tumor-derived mitochondria or mtDNA in EVs cGAS–STING ; metabolic coupling; immune evasion mtDNA-rich EVs 76 , 77 Aging / Frailty Oxidized mtDNA, cardiolipin, mt-lipid peroxides Chronic activation of TLR9/NLRP3/cGAS–STING ; inflammaging Circulating oxidized mtDNA; GDF-15 55 , 78 Spaceflight / Environmental stress Circulating mtDNA, altered mitochondrial gene expression Radiation + microgravity induces mitochondrial stress, systemic inflammation, and metabolic reprogramming Plasma mtDNA; altered mitochondrial transcripts 79 , 80 Open in a new tab Section III. ADAPTIVE IMMUNITY AND ANTI-MITOCHONDRIAL ANTIBODIES Anti-mitochondrial antibodies (AMAs), classically diagnostic for primary biliary cholangitis (PBC), have now been detected in SLE, RA, idiopathic inflammatory myopathies (IIMs), and antiphospholipid syndrome (APS), conditions in which mitochondrial damage and oxidative stress are prominent. 81 – 85 These findings reframe AMAs as sentinels of mitochondrial distress, signaling a breakdown of an otherwise physiological surveillance mechanism that monitors organelle integrity. 3.1. Mechanisms of AMA formation Persistent exposure to extracellular mitochondria and their fragments can prime adaptive immunity. Damaged cells release mitochondria that retain bacteria-like signatures, cardiolipin, formylated peptides, and unmethylated CpG mtDNA, which are taken up by antigen-presenting cells (APCs) and routed into class II pathways for CD4+ T cell help ( Figure 3 ). Mitochondrial material can also be exported via MEVs, further enlarging the extracellular antigen pool and delivery to phagocytes. 86 – 88 Once internalized, mitochondrial proteins contribute to the MHC-II peptide repertoire and license T–B collaboration, with CD40L, IL-21, and BAFF driving B cell proliferation, germinal-center maturation, and class-switch recombination, key steps that convert transient exposure into high-affinity AMA production. Mechanistically, dual BCR/TLR9 engagement by DNA-bearing antigens provides potent co-stimulation to B cells and shapes their differentiation state ( Figure 3 ), offering a plausible bridge from mitochondrial nucleic acids to autoreactive humoral responses. 89 , 90 Figure 3. Triad model of anti-mitochondrial antibody formation. Open in a new tab Chronic exposure to extracellular mitochondria can transform normal organelle turnover into autoimmune activation. Extracellular mitochondrial persistence: Defective mitophagy and efferocytosis result in the accumulation of mitochondria and fragments enriched in cardiolipin, formyl peptides, mitochondrial DNA (mtDNA), and other mitochondrial damage-associated molecular patterns (mtDAMPs). Antigen presentation in an IFN-rich context: Oxidized or vesicle-bound mtDNA sustains type I interferon signaling and antigen-presenting cell activation, promoting CD4+ T cell help. Germinal center and tolerance breakdown: Autoreactive B cells recognizing mitochondrial antigens undergo germinal-center maturation via TLR9 and CD40L/IL-21/BAFF co-stimulation, leading to anti-mitochondrial antibody production. B cells may act in both T cell-dependent and independent manners. Together, mitochondrial persistence, inflammatory presentation, and loss of tolerance form a triad that converts mitochondrial injury from a reparative signal into chronic autoimmunity. A failure of organelle clearance intensifies this cascade. Defective mitophagy and inefficient efferocytosis permit accumulation of damaged mitochondria and prolonged antigen release, while type I interferon-rich inflammation, fueled in part by oxidized mitochondrial DNA, creates a milieu that sustains APC activation and B cell survival. Type I IFN-rich settings are a hallmark of systemic autoimmune disorders such as SLE. In these contexts, oxidized mtDNA potently induces IFN and sustains inflammation, ultimately overwhelming the mechanisms that normally limit immune responses to DNA. 28 , 57 Thus, although direct experimental confirmation is still limited, the most plausible explanation for AMA formation is that it emerges from three converging failures: persistence of extracellular mitochondria due to impaired mitophagy/clearance and MEV-mediated export; enhanced antigen presentation of mitochondrial peptides in an inflamed, IFN-rich context with BCR/TLR9 co-stimulation; and breakdown of B and T cell tolerance within germinal-center ecosystems. 56 , 89 , 90 Conceptually, this triad transforms normal organelle turnover into a self-propagating autoimmune circuit where mitochondrial injury no longer signals repair but fuels disease. While classical models emphasize T cell-dependent maturation, mitochondrial antigens may theoretically also trigger T-independent B cell activation. The repetitive and lipid-rich architecture of mitochondrial membranes, particularly cardiolipin and densely packed protein complexes, could directly crosslink B cell receptors, while co-delivered mtDNA provides endosomal TLR9-mediated co-stimulation, partially substituting for T cell help. 89 , 91 This pathway was originally demonstrated for nucleic acid-containing immune complexes that activate autoreactive B cells through simultaneous engagement of the B cell receptor and TLR9, 92 and is further supported by evidence of BCR–TLR9 synergy in autoimmunity. Similarly, it may underlie early or extrafollicular phases of AMA generation. 93 3.2. Functional and diagnostic relevance of AMAs While the mechanisms underlying AMA formation are still being clarified, accumulating evidence suggests their diagnostic usefulness. Meta-analysis confirms that AMAs, particularly the M2 subtype which targets the E2 subunit of the pyruvate dehydrogenase complex at the inner mitochondrial membrane, offer high sensitivity and specificity for PBC diagnosis (84% and 98%, respectively), 75 , 87 although their applicability for other diseases remains under investigation. However, in PBC, the magnitude of AMA titers does not reliably correlate with disease severity or progression, consequently their titers are not routinely used to monitor disease activity. 94 Anticardiolipin antibodies (aCL, historically including the AMA-M1 specificity) have long been recognized as prothrombotic biomarkers. These autoantibodies are strongly associated with both arterial and venous thrombotic events and represent one of the most common acquired “blood-protein” abnormalities linked to thrombosis. 95 Clinical manifestations range from deep-vein thrombosis and pulmonary embolism to coronary, peripheral, and cerebrovascular thromboses. 95 aCL testing is a key component of APS diagnostics and risk stratification, where a high IgG aCL titer, particularly when combined with lupus anticoagulant and anti-β2-glycoprotein I antibodies, indicates the greatest thrombotic risk. 96 , 97 In SLE, lupus anticoagulant antibodies remain the strongest independent predictor of thrombosis, whereas aCL adds incremental risk mainly when persistent and at a high titer. 96 During SLE, a multitude of AMAs are present that recognize mitochondrial DNA, RNA, and outer-membrane components, and have been associated with nephritis. 83 , 87 A recent SLE cohort study which examines AMA subtypes in 1,114 patients with SLE, measured from the disease onset (within 6 months of diagnosis) up to 21 years of follow-up, indicates that AMAs may predict mortality and cardiovascular disease. 98 In IIMs, AMA positivity (~ 5% of adult IIM cases) has been linked to more severe clinical features, including dysphagia, cardiomyopathy, and chronic muscle weakness, suggesting that AMAs can be used to identify a subset of patients with higher disease burden. 99 – 101 Specifically, a small cohort study suggests that the presence of AMA-M2 directed against the 2-oxoacid dehydrogenase complex is associated with myocarditis, reduced ventricular function, and right atrial enlargement. 102 Overall, AMAs remain robust diagnostic markers of mitochondrial autoimmunity and possess clear clinical utility as biomarkers of thrombotic and cardiovascular risk. Their expanding recognition in association with diverse autoimmune diseases highlights their potential as indicators of mitochondrial injury and immune activation. Further efforts are needed to implement their clinically diagnostic use. Section IV. ROLE OF PLATELETS AND THEIR DERIVED EXTRA-CELLULAR VESICLES IN INFLAMMATION 4.1. Platelets in hemostasis and inflammation Platelets are small anucleate cells derived from bone marrow megakaryocytes, which extend proplatelets that fragment within the circulation to generate mature platelets. 103 During this process, mitochondria from megakaryocytes are transferred along microtubules to daughter platelets. 104 While the bone marrow remains the principal site of thrombopoiesis, studies indicate that the lungs contribute to terminal platelet production, and, in mice, a significant proportion of newly formed platelets may originate from megakaryocytes trapped within the pulmonary capillary bed. 105 Under pathological conditions such as sepsis, megakaryocytes can also be detected in the spleen, where they may produce platelets. 106 Platelets are primarily known for their role in hemostasis and maintenance of vascular integrity. At sites of vascular injury, platelets adhere to the exposed subendothelium, become activated, undergo shape change, and release granule contents. These coordinated events promote αIIbβ3 integrin activation and platelet–platelet aggregation, forming a transient primary hemostatic plug that arrests bleeding. At the same time, exposure of phosphatidylserine (PS) on the activated platelet surface provides a platform to assemble coagulation factor complexes, markedly accelerating thrombin generation which amplifies platelet activation and converts fibrinogen to fibrin, stabilizing the thrombus. 107 When this program fails because of quantitative or qualitative platelet defects, patients exhibit a tendency to increased bleeding. Conversely, hyperreactivity of the program predisposes patients to cardiovascular complications, notably arterial thrombosis leading to myocardial infarction or stroke. In addition to hemostasis, platelets are sentinels that couple innate immune sensing to thrombosis. Their pattern-recognition receptors (e.g., TLRs) detect pathogens and initiate immunothrombosis, fostering fibrin formation and NETs that confine microbes. 108 Upon activation, platelets degranulate to release antimicrobial peptides (thrombocidins, β-defensins) and pro-inflammatory mediators including IL-1β and the chemokines PF4/CXCL4 and CCL5/RANTES, thereby recruiting leukocytes and amplifying host defense. 109 Platelets also represent the most abundant cellular source of the IgG receptor FcγRIIA, enabling the capture, internalization, and presentation of immune complexes to phagocytes. 110 , 111 When dysregulated, platelets are potent drivers of pathological thrombo-inflammation. 112 After myocardial infarction and ischemic stroke, platelet activation promotes pathological formation of NETs, a process linked to poorer clinical recovery in these conditions. 113 , 114 In bacterial sepsis, lipopolysaccharides engage platelet TLR4, initiating disseminated thrombo-inflammation; platelet–neutrophil crosstalk via P-selectin and TLR4 signaling further amplifies NET release. 115 When these responses become excessive, they escalate to disseminated intravascular coagulation with microvascular thrombosis and multi-organ failure. 116 Severe COVID-19 manifests many features of viral sepsis: autopsy series reveal widespread microthrombi across organs, 117 and patient platelets are hyperreactive, aggregating at lower thrombin concentrations, and secrete increased IL-1β and soluble CD40L, changes consistent with cytokine-rich inflammation, endothelial injury, and worse outcomes. 118 Platelets also exacerbate predominantly inflammatory pathologies, including transfusion-related acute lung injury (TRALI), anaphylaxis, atherogenesis, and autoimmune diseases such as SLE and RA. 119 – 123 Collectively, the above observations position platelets as actionable effectors at the immune–thrombotic interface, and attractive targets for therapeutic modulation. 4.2. Platelet-derived extracellular vesicles Platelets constitute a major source of plasma extracellular vesicles (pEVs) by releasing nanoscale, membrane-bounded EVs. 124 pEVs can maintain homeostasis, but also promote signals to other cells via direct receptor interactions, giving them a role at the crossroads of coagulation, membrane repair, inflammation, and immunity. Their bioactive cargo ( Table 2 ) supports roles in hemostasis, tissue repair, immunomodulation, and antimicrobial defense, which may be tunable through the activation of platelet receptors such as glycoprotein VI, C-type lectin-like receptor 2 or the presence of thrombin. 125 Quantitative or qualitative alterations in pEVs are associated with sepsis, autoimmunity, atherothrombosis, and cancer, underscoring their biomedical importance. 126 , 127 Below, we describe two principal subsets, microvesicles and exosomes. Table 2. Cargo of platelet-derived extracellular vesicles Category Key molecules Main functions Predominant functional context References Adhesion receptors Integrin αIIbβ3, GPIbα, P-selectin, PECAM-1 Support anchoring to matrix proteins and activated endothelium. Enable physical interaction with leukocytes. PECAM-1 modulates leukocyte–endothelium interactions. Homeostatic and inflammatory 132 Procoagulant platform Phosphatidylserine, Tissue factor, FVa, FVIII Accelerated FXa/thrombin generation, fibrin formation and clot stabilization. Diffusion from the thrombus, amplifying thrombin generation beyond the contribution of intact platelets. Homeostatic and inflammatory 133 , 134 Inflammatory cargo IL-1β, CD40L, chemokines (CCL5/RANTES, CXCL4/PF4), DAMPs (HMGB1), complement (C5b-9, C3b), NOX-1, microRNAs (miR-223), mitochondria, mtDAMPs Endothelial and leukocyte activation (cytokine, chemokine, DAMPs). ROS production by NOX-1. Reprogramming of genetic networks involved in endothelial activation and inflammation by miR-223 Energy support or DAMPs inflammatory signaling by mitochondria Inflammatory 132 , 133 , 135 – 137 Tissue-repair / trophic factors TGF-β1, PDGF, VEGF Activation of endothelial cells, acceleration of extracellular matrix synthesis and promotion of angiogenesis in the lesional microenvironment. Concentrated pEV preparations have shown reparative potential, improving vascularization, wound healing, and tendon regeneration, and reducing joint inflammation. Homeostatic 133 , 138 , 139 Open in a new tab Microvesicles (ectosomes/microparticles). Strong platelet activation drives outward budding with PS exposure, generating ~ 100 nm–1 μm vesicles carrying platelet cytosol and membrane proteins. Most circulating pEVs are of this type. Many circulating pEVs likely derive from megakaryocytes, since resting platelets shed few vesicles, although robust activation causes abundant shedding. 126 , 127 Exosomes. Platelets form intraluminal vesicles in endosomes and secrete ~ 40–100 nm exosomes marked by tetraspanins (e.g., CD63). 126 Because current methods are rarely able to prove biogenesis unequivocally, it is advisable to avoid “microvesicle/exosome” labels unless dedicated studies confirm vesicle origin; we therefore use pEVs throughout the review. Once released, pEVs are cleared by splenic mononuclear phagocytes, 128 and also target/integrate into endothelium and leukocytes. 126 This is consistent with the half-life of ~ 6 h for transfused pEVs in humans. 129 In mice, biodistribution demonstrates rapid (minutes) uptake, predominantly by neutrophils and platelets, across blood, lymphoid organs, and bone marrow. 130 , 131 Although pEVs can activate recipient cells via receptor engagement or delivery of platelet-derived molecules, the efficiency of internalization and cargo unpacking remains uncertain. 4.2.1. Physiological inflammatory roles of platelet-derived extracellular vesicles pEVs may extend the immune functions of their parent platelets, acting at a distance to coordinate inflammatory responses. Notably, pEVs can be found in bodily fluids such as bone marrow plasma, lymph, and synovial fluid. 126 Several physiological mechanisms explain how pEVs contribute to inflammatory and anti-infective reactions: Leukocyte recruitment and activation. pEVs function as mediators that directly stimulate white blood cells and facilitate their recruitment to inflammatory sites. By engaging P-selectin/PSGL-1, pEVs attach to neutrophils, enhance their adhesion to the endothelium under shear, and may guide trafficking toward the inflammatory site. 140 , 141 In addition, pEVs contain chemokines such as CCL5/RANTES and CXCL4/PF4, as well as the alarmin HMGB1, 132 , 136 which further enhance inflammatory cell recruitment. CD40L/IL-1β-rich pEVs can also activate endothelial cells to upregulate adhesion molecules and secrete chemokines, amplifying local recruitment of immune cells, 142 , 143 while the transfer of GPIbα to leukocytes increases monocyte adhesion within VWF-rich inflamed vessels and favors extravasation. 144 By displaying CD40L at their surface, pEVs can activate dendritic cells and monocytes/macrophages, and stimulate antigen-specific IgG production by B cells, driving increased production of pro-inflammatory cytokines and maturation of antigen-presenting cells, and contributing to the involvement of adaptive immunity. 145 – 147 In parallel, pEVs may support physiological immunothrombosis by triggering NET formation, 148 and by providing procoagulant surfaces enriched in PS which favor fibrin polymerization, 149 as well as tissue factor which could initiate coagulation upon contact with monocytes, 150 supporting the sealing of microbes within a localized thrombus. Direct antimicrobial activity. Platelets store peptides that can kill bacteria and fungi, and a fraction of these effectors is thought to be incorporated into pEVs. At infection sites, pEVs could disseminate concentrated antimicrobial agents and contribute to direct pathogen elimination. 151 , 152 Modulation of immune responses. pEVs can temper exuberant inflammation and foster its resolution. During systemic infection or acute inflammatory disease, pEVs containing miR-223 reduce endothelial ICAM-1 and may limit leukocyte adhesion to the endothelium and help to protect organs from massive immune cell infiltration. 153 , 154 Certain pEVs with microRNA may also promote resolution by biasing macrophages toward M2 phenotypes. 155 , 156 Furthermore, the presence of nucleotidase (CD73) 157 on pEV surfaces can reduce inflammation by cleaving ATP/ADP into cyclic AMP. 158 pEVs can also modulate adaptive immunity, since they preferentially home to lymph nodes and carry active 20S proteasome that contributes to loading exogenous peptides onto MHC-I, promoting CD8+ T cell proliferation. 131 Notably, pEVs bind numerous molecules from the bodily fluid in which they bathe, forming what is called an EV corona. 159 Such molecules may also modulate immune responses. For instance, the interaction between pEVs and secreted phospholipase A 2 , which is abundant in plasma under inflammatory conditions, has been shown to promote the production of lipid mediators that activate leukocytes. 160 4.2.2. Pathological inflammatory roles of platelet-derived extracellular vesicles Because of their cargo, pEVs can amplify inflammation in the vascular environment, including in cardiovascular and autoimmune diseases. pEVs are elevated in patients with cardiovascular risk factors such as diabetes, hypertension, hypercholesterolemia, and obesity. 161 During atherogenesis, pEVs can contribute to the critical recruitment of monocytes into the intima, where they differentiate into macrophages and become foam cells. 162 pEVs promote monocyte–endothelium interactions by inducing ICAM-1 endothelial cell expression, enhancing their chemotaxis, 163 and depositing CCL5/RANTES on the endothelial surface, thereby promoting monocyte arrest. 164 pEVs may further drive atherosclerotic plaque progression by promoting vascular smooth muscle cell (VSMC) activation, proliferation, and migration from the media to the intima, 165 as well as their transition to a pro-inflammatory phenotype, particularly via CD40L and P-selectin. 166 , 167 After plaque rupture, pEVs may promote thrombotic complications by increasing platelet reactivity and fibrin formation. 168 pEVs seem to amplify some thrombotic and inflammatory reactions, making them potential actors of thrombo-inflammatory reaction. Accordingly, patients after myocardial infarction or ischemic stroke show elevated pEVs, sometimes correlating with severity. 169 , 170 pEVs may also contribute to disease pathogenicity during immune reaction to infection or autoimmunity. During viral infections such as dengue or H5N1 influenza, platelet activation via CLEC-2 drives release of pEVs that engage CLEC5A and TLR2 on neutrophils, inducing NETosis that contributes to disease severity. 171 In murine sepsis models and in patients, elevated circulating pEVs correlate with increased NET markers and aggravated endothelial dysfunction, consistent with pEV-driven NETosis injuring the vasculature. 172 A similar pEV–NETs axis has been described in severe COVID-19, where platelet hyperreactivity and heightened pEV levels are associated with NETosis and immunothrombotic coagulopathy. 173 In autoimmunity, pEVs act as antigen sources and immune stimulants. In SLE, opsonized pEVs correlate with disease activity. 174 In RA, synovial pEVs are abundant, activate synovial fibroblasts via IL-1, and correlate with severity. 122 , 175 In APS, pEVs may promote endothelial pyroptosis, 176 a form of cell death that increases tissue factor exposure and thrombin generation, 177 thereby elevating the risk of cardiovascular complications. This interpretation is supported by observations of higher levels of pEVs with tissue factor correlating with thrombotic activity in patients. 178 Section V. PLATELETS AS AN IMPORTANT SOURCE OF MITOCHONDRIA 5.1. Mitochondrial regulation of platelet function Mitochondria in platelets support bioenergetic, signaling, and survival functions essential for hemostasis, thrombosis and inflammation. Although platelets contain only ~ 4–8 mitochondria each, these organelles exert an outsized influence on platelet physiology. Because platelets lack nuclei, they cannot synthesize nuclear-encoded mitochondrial proteins, rendering them particularly susceptible to mitochondrial stress and dysfunction. Over the past two decades, research has revealed that mitochondria are not only ATP generators but also key regulators of calcium homeostasis, redox signaling, apoptosis, inflammatory pathways, and innate immune responses in platelets. 179 , 180 By dynamically balancing glycolysis and OXPHOS, platelet mitochondria match ATP supply to the escalating demands of platelet adhesion, activation, and aggregation. Mitochondria also shape intracellular Ca 2 + signals. 179 , 181 VDACs on the OMM facilitate passage of cytosolic calcium into the intermembrane space, 182 while the mitochondrial calcium uniporter complex on the IMM mediates calcium entry into the matrix. 183 , 184 In the matrix, calcium activates key TCA enzymes, including PDH, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase, accelerating NADH and FADH2 production to fuel the ETC and OXPHOS 185 and enabling ATP production. Mitochondrial calcium also stimulates ROS production, which contributes at physiological levels to platelet activation. 186 When Ca 2 + influx is excessive, mtROS rise pathologically and the mPTP in IMM can open, collapsing the membrane potential and disrupting ATP synthesis. 187 Prolonged opening can provoke the release of mitochondrial calcium, further elevating cytosolic calcium. 187 This promotes PS exposure on the platelet surface, 188 creating a catalytic platform for coagulation factor assembly and thrombin generation 189 and promoting a thrombotic risk environment. Beyond hemostasis and thrombosis, platelet mitochondria also interface with the immune system. Mitochondrial stress and oxidized mtDNA can engage cGAS–STING pathways that facilitate granule exocytosis and P-selectin exposition, thus strengthening platelet–leukocyte interactions, 190 while the NLRP3 inflammasome, present in platelets, induces caspase-1 activation and cleavage of pro–IL-1β and pro–IL-18 for secretion, 191 – 193 thus contributing to inflammatory function of platelets ( Figure 1 ). NLRP3 also contributes to integrin αIIbβ3 outside-in signaling, platelet spreading, aggregation, phosphatidylserine exposure, and thrombus stability, thereby coupling inflammatory sensing to hemostatic output. 194 Through these mechanisms, platelet NLRP3 integrates innate immune signaling with thrombosis, positioning platelets as active immune effector cells in cardiovascular and inflammatory diseases. Finally, mitochondrial support of platelet functions includes not just intracellular, but also extracellular platelet functions, since platelets, out of all cell types, represent the most consistent and abundant source of extracellular mitochondria. 5.2. Platelet-derived extracellular mitochondria Flow cytometry using the mitochondrial dye MitoTracker, or genetically modified mice bearing fluorescent mitochondria, reveals heterogeneity among circulating pEVs, with only a subset containing mitochondria, while others are organelle-free. Fluorescence and electron microscopy have firmly established that activated platelets release respiration-competent mitochondria, both within pEVs and as free organelles, which retain normal oxidative activity. Consistent with this, blood in healthy conditions contains respiration-competent extracellular mitochondria, 39 most likely platelet-derived, whose intact condition supports active expulsion rather than passive leakage. 137 , 195 Strong activation or stress-related stimuli favor mitochondrial externalization. In vitro, thrombin, collagen, immune complexes, and Ca 2 + ionophores elevate intraplatelet Ca 2 + and induce the release of mitochondria-bearing pEVs and even naked organelles. 137 In line with the transfer of organelles from megakaryocytes to platelets that strictly requires cytoskeleton components, mitochondrial release from platelets is actin-dependent and occurs independently of microtubules. 137 It remains unknown, however, whether SNARE proteins, including mitochondria-associated SNARES, participate in mitochondrial release such as seen in mitochondria-derived vesicles. 196 Exported mitochondria can metabolically support immune cells. Intravital imaging shows neutrophil–endothelium interactions in the presence of circulating mitochondria. 137 Neutrophils can internalize pEVs containing mitochondria, thereby increasing their metabolic capacity and inflammatory phenotype. 148 , 160 , 197 Mitochondria uptake is facilitated by 12-HETE, a 12-lipoxygenase product present in pEVs. 160 Following transfer, neutrophils display enhanced activation, adhesion, migration, and NETosis, driven by boosted oxidative phosphorylation and ATP and ROS production ( Figure 4 ), but effects are transient and may reduce bacterial phagocytosis. 148 , 197 Mitochondria released from NETosing neutrophils and TNF-activated endothelial cells are oxidized, a feature that contributes to their pro-inflammatory potential. 28 , 198 Although ROS are generated during platelet activation and mitochondrial release, 71 it remains unknown whether oxidation similarly affects the biological activity of platelet-derived mitochondria or transfer. Extruded mitochondria also serve as substrates for secreted group IIA phospholipase A 2 (sPLA2-IIA), which hydrolyzes mitochondrial membrane and generates lysophospholipids, oxidized fatty acids, and mtDNA that can activate leukocytes. Thus, in the face of danger signals, platelets can externalize mitochondria that, via sPLA2-IIA, amplify local inflammation. 137 , 199 Figure 4. Mitochondrial transplantation, functional maintenance and transfusion risks. Open in a new tab Platelet concentrates provide a sustained reservoir of transferable mitochondria packaged within platelet extracellular vesicles (pEVs) or as “naked” organelles, detectable from day 1 to day 7 after product preparation. These mitochondria enter recipient cells and remain functional, enhancing oxidative capacity and helping maintain metabolic output. In immune cells such as neutrophils, mitochondrial transplantation can activate cells, increasing oxidative phosphorylation, ATP production, and reactive oxygen species (ROS) formation, thereby supporting antimicrobial and inflammatory functions. In rare, specific contexts, a two-hit transfusion-related acute lung injury (TRALI) may occur, with this mitochondrial priming of neutrophils as first-hit, and the transfusion of HNA/HLA antibodies through transfused blood products as second-hit, could precipitate immune cells activation as neutrophil NETosis, contributing to the onset of TRALI. Blue-grey denotes protective effects of extracellular mitochondria, whereas red denotes deleterious effects. 5.3. Platelets as mitochondria donors for therapeutic transplantation The ability of mitochondria to be internalized in cells and support metabolic function has fostered the idea of exploiting EVs as delivery vehicles for mitochondria or pro-metabolic signals to deficient cells. 6 , 200 Mitochondrial transplantation, the transfer of mitochondria encapsulated in natural vesicles, synthetic carriers, or delivered naked, is being evaluated preclinically and clinically to improve mitochondrial mass or function in recipient cells. 6 Across numerous preclinical models, mitochondrial transplantation mitigates injuries affecting the heart, lung, liver, brain, kidney, spinal cord, and skeletal muscle, as well as tumors, inflammatory conditions, and inherited disorders. Reported benefits include restoration of cellular bioenergetics, reduction of oxidative stress, modulation of inflammatory responses, decreased apoptosis, and promotion of tissue regeneration. 6 , 52 As the main source of circulating mitochondria, platelets are promising donors for mitochondrial transplantation. 200 , 201 Indeed, platelet-derived mitochondria can repopulate human cells that have been rendered mitochondria-deficient and restore a respiration activity 202 ( Figure 4 ). Following injury, mitochondria can be internalized by dermal fibroblasts, boosting ATP, cell proliferation, and in vitro wound closure. 203 Mitochondria released from ultrasound-treated platelet concentrates are taken up by endothelial cells, decreasing oxidative stress and apoptosis and promoting endothelial repair. 204 From a cardiovascular standpoint, in an ex vivo heart-preservation model, incubating donor rat hearts with mitochondria isolated from human platelets was associated with a higher mitochondrial membrane potential, increased ATP-synthase activity, greater coronary perfusion flow, and improved cellular viability after prolonged storage, consistent with the transplantation providing myocardial bioenergetic support. 205 More recently, a multicenter randomized study of thirty patients with ST-elevation myocardial infarction (STEMI) tested intracoronary infusion of autologous platelet-derived mitochondria adjunctive to percutaneous coronary intervention. At forty days, the treated group showed an improvement in exercise capacity and left-ventricular ejection fraction compared to controls, with no serious therapy-related adverse events, supporting feasibility and a favorable safety profile. 206 These preliminary clinical data, alongside preclinical evidence, support the potential of platelet-derived mitochondrial transplantation to treat injuries of the heart and vasculature. Beyond the cardiovascular system, platelet-derived mitochondrial transplantation improved mice cognition and reduced neuronal apoptosis in a diabetes-associated model, 207 increased mice survival in sepsis, 208 and mitigated atrophy and fibrosis after rotator-cuff injury in rats. 209 Altogether, although still early, this line of research positions platelets as potential therapeutic vectors in energy-related pathologies. 5.4. Platelet-derived mitochondria in transfusion risks Storage of platelet concentrates in blood banks likewise promotes vesiculation and mitochondrial release. pEVs and mitochondrial loads are detectable from day one to seven after blood product preparation, and are higher with platelet-rich plasma (PRP) than with buffy coat or apheresis, reflecting preparation stress and storage lesions. 210 Although it may be premature to define thresholds that would unequivocally identify platelet concentrates at risk of promoting adverse reactions, several independent studies have compared platelet concentrates transfused without complication to those associated with adverse reactions. Notably, higher extracellular mitochondria, assessed by measuring extracellular mtDNA by quantitative PCR or by flow cytometry with mitochondrial dyes, occur in platelet concentrates linked to transfusion adverse reactions (febrile non-hemolytic responses, urticaria, hypotension). 137 , 210 – 212 Moreover, measurements of extracellular mtDNA and bioactive mediators (e.g., cytokines, CD40L) in platelet concentrates suggest that distinct mechanisms may independently drive adverse reactions, supporting the need for tools and algorithms to stratify high-risk products and elucidate inflammatory pathways. 213 The most severe outcome is TRALI, which classically occurs through a two-hit process. First, recipient leukocytes are primed by clinical stressors (trauma, infection, inflammation), then exposed during transfusion to donor anti-HNA/HLA antibodies that precipitate lung injury. 214 , 215 Recently, it was shown that extracellular mitochondria can provide this first-hit priming. In a murine two-hit TRALI model, mitochondrial DAMPs (mtDNA or mtNFPs) heighten susceptibility to anti-MHC-I (34-1-2s)–mediated lung injury. Administration of purified mitochondria, the TLR9 agonist ODN 2395 (mtDNA mimic), or the dual FPR1/2 agonist WKYMVm (mtNFPs mimic) 18 h before anti-MHC-I induces hypothermia, pulmonary edema, elevated plasma MIP-2, and neutrophil influx. Pretreatment with the TLR9 antagonist ODN 4084F mitigates hypothermia, edema, and MIP-2, while blockade of formyl-peptide receptors with Cyclosporin H or HCH6–1 provides only partial or no protection, indicating a lesser role for N-formyl peptides. Importantly, purified mtDNA alone suffices as the first hit to reproduce the phenotype, confirming a mtDNA–TLR9 priming axis. 216 Thus, circulating mtDAMPs in plasma and in some blood products could act as transferable danger signals that synergize with donor antibodies to trigger TRALI ( Figure 4 ), and TLR9 blockade could be a preventive target. In addition to mitochondria, transfused pEVs can carry pro-inflammatory ligands such as soluble CD40L, which activates the endothelium and leukocytes. In TRALI models, CD40–CD40 signaling on the pulmonary endothelium promotes neutrophil recruitment and alveolo-capillary edema. 217 , 218 Together, mtDAMPs and pEV inflammatory cargo form a hazardous “cocktail” for vulnerable recipients, with manifestations ranging from isolated fever to life-threatening TRALI. These observations support the strict preparation, storage, and quality control of platelet concentrates to limit pEVs and mitochondrial release. 173 Apheresis or buffy-coat methods appear preferable to PRP to reduce the burden of mitochondrial pEVs. 210 Leukoreduction and certain pathogen-inactivation procedures may remove cellular debris, including naked organelles, and measuring mtDNA in older units has been proposed to flag higher-risk products for exclusion. 219 Although rare, TRALI remains a leading cause of transfusion-related mortality; thus, integrating platelet mtDAMPs and co-factors into risk-reduction strategies presents an important opportunity. Section VI. INTEGRATED PERSPECTIVE AND FUTURE DIRECTIONS Stimulation of platelet receptors promotes release of mitochondria, suggesting that deciphering the pathways that regulate release may help identify how to reduce mtDAMPs and define their exact functions. It is necessary to delineate the role of mitochondria in health and diseases, potentially by identifying the key characteristics of pro-inflammatory mitochondria vs those promoting homeostatic metabolism, in order to grasp the role of both intracellular and extracellular mitochondria. Given the presence of AMAs across multiple inflammatory conditions, a more comprehensive profiling of AMA subsets (e.g., anti-cardiolipin, anti-mtDNA, anti-mtRNA, anti–mitofusin-1), combined with routinely measured autoantibodies and machine-learning approaches, 220 could help identify clinically relevant patient clusters, such as in SLE, a disease well known for its heterogeneity. Beyond their utility as biomarkers, AMAs may actively modulate mitochondrial function, tipping the balance from beneficial to pathological effects when present at high levels or depending on antibody isotype (e.g., IgM vs IgG, or IgG subclasses), thereby affecting disease progression. From a translational standpoint, extracellular mitochondria and mitochondrial fragments function as DAMPs and as targets of AMAs, raising potential safety concerns for mitochondria-targeting therapies. Because mtDAMPs can prime or activate innate immune cells and platelets, and are recognized by AMAs, they may critically shape the efficacy and tolerability of mitochondrial transplantation. 221 , 222 In pre-activated inflammatory states, exposure to exogenous mitochondria can amplify effector cascades and, rarely, precipitate severe reactions. The involvement of mtDAMPs in TRALI underscores the need for caution with systemic administration, and for stringent control of product quality, dose, route, and kinetics. Efforts to distinguish damaged or ROS-associated mitochondria from intact mitochondria with less pro-inflammatory potential may improve mitochondrial transfusion. Although there is presently no direct evidence linking AMA positivity to adverse events after mitochondrial transfer or adverse reactions following platelet transfusion, preclinical studies have shown context-dependent innate and adaptive recognition of allogeneic mitochondria, which may trigger mild inflammatory responses, whereas autologous preparations were generally better tolerated. 223 Moreover, even when overt adverse events are absent, the efficiency of mitochondrial transfer may be affected by AMA, especially those directed against the outer mitochondrial membrane, such as anti-cardiolipin or anti-mitofusin-1, as seen in SLE. 224 It is also currently unclear whether some blood donors harbor abnormally elevated levels of AMA, or whether repeated mitochondrial exposure, such as through multiple platelet transfusions or successive mitochondrial transfer procedures, could induce AMA production, thereby negatively affecting long-term therapeutic outcomes. Consequently, protocols should incorporate immunologic profiling, including: (i) systematic AMA screening and, where feasible, cellular anti-mitochondrial reactivity; (ii) preference for autologous sources or optimized allogeneic preparations; (iii) dose/route adjustment, favoring local or regional routes rather than intravenous routes in high-risk patients, and possible targeted premedication and monitoring; and (iv) rational immunomodulation in high-risk cohorts. Such approaches may reduce adverse events while preserving efficacy. Overall, the dual role of extracellular mitochondria as a factor in maintaining metabolic homeostasis as well as a contributor to innate and adaptive immunity ( Figure 5 ) argues in favor of integrating mitochondrial immunology into diagnostics and therapeutic design, alongside rigorous control of transplantation conditions, in order to enable personalized and immunocompatible mitochondrial medicine. Figure 5. The dual benefits and risks of extracellular mitochondria. Open in a new tab (On the left) Under physiological conditions, levels of circulating mitochondria are low and anti-mitochondrial antibodies (AMA) are undetectable; mitochondria circulate freely, enabling intercellular metabolic support. (On the right) When homeostasis is disrupted, e.g., with increased circulating mitochondria and breakdown of immune tolerance, AMA can arise. These antibodies may aid phagocytic clearance of excess mitochondria, but, at high levels, they can engage Fc receptor-expressing effector cells (e.g., circulating cells such as neutrophils, platelets) and, in systemic lupus erythematosus, contribute to elevated cardiovascular risk and mortality. Blue-grey denotes normal conditions without AMA, whereas red denotes deleterious effects of AMA. Box 1. Structure of the review. Fundamental aspects of mitochondrial architecture and cytosolic sensors of mitochondrial integrity Mechanisms of mitochondrial release and the consequences of mitochondrial DAMPs on the innate immune system Interactions with the adaptive immune system, including the generation of anti-mitochondrial antibodies Roles of platelets and platelet-derived extracellular vesicles in immunity Contributions of platelet-derived extracellular mitochondria to health and pathogeneses such as in mitochondrial transplantation, platelet transfusion, thrombo-inflammation, and autoimmunity Concludes with an integrated conceptual framework and future research directions. Acknowledgements: The work was supported in part by the Natural Sciences and Engineering Research Council of Canada (EB), Lupus Research Alliance (519414, CL), National Institute of Health (NIH, R01 HL158606, CL), and the Intramural Research Program of the National Institutes of Health (NIH). The contributions of the NIH author (JC) are considered Works of the United States Government. The findings and conclusions presented in this paper are those of the authors and do not necessarily reflect the views of the NIH or the U.S. Department of Health and Human Services. EB is a recipient of the Merit Award from the Fonds de Recherche en Santé du Québec. Footnotes COI: E.B. holds a patent related to the measurement of anti-mitochondria antibodies in autoimmune diseases. All the other authors have no conflicts to disclose. REFERENCES 1. Andersson SG, Zomorodipour A, Andersson JO, Sicheritz-Pontén T, Alsmark UC, Podowski RM, Näslund AK, Eriksson AS, Winkler HH, Kurland CG. The genome sequence of Rickettsia prowazekii and the origin of mitochondria. Nature. 1998;396:133–140. [ DOI ] [ PubMed ] [ Google Scholar ] 2. Kim J, Kim H-S, Chung JH. Molecular mechanisms of mitochondrial DNA release and activation of the cGAS-STING pathway. Exp Mol Med. 2023;55:510–519. 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