Platelets, which are small blood cells involved in hemostasis and thrombosis, have been found to initiate immune responses (Koupenova et al., 2022). In addition to their crucial role in blood clotting, platelets also contain a range of innate immune receptors and signaling molecules, which can detect pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (Dib et al., 2020; Cognasse et al., 2019). Thus, platelets respond rapidly to infection or tissue injury and mount a protective or immune response (Kim et al., 2018; Mauler et al., 2019). Following activation, platelets produce various immune mediators, including cytokines, chemokines, and antimicrobial peptides, and form platelet-neutrophil and platelet-monocyte aggregates that can amplify the immune response (Hottz et al., 2014; Hottz et al., 2020; Mandel et al., 2022). Dysfunction of platelets is regarded as a hallmark of neurological diseases, such as neurodegenerative diseases, malignant cerebral tumors, acute neurotraumatic insult, and cerebral ischemic/hemorrhagic diseases, etc. (Mendoza-Sotelo et al., 2010; Carrizzo et al., 2014; Fišar et al., 2016; Prodan et al., 2016; Perez et al., 2018; Hishizawa et al., 2019; Dziedzic et al., 2020; Gong et al., 2021; Kim HK. et al., 2022; Sloan et al., 2022; Wang et al., 2023a) ( Table 1 ). Previous studies have found that activated platelets in the pathological environment of the brain cause the overactivation of microglia and astrocytes (Bhat et al., 2017). For instance, platelets obtained from hypertensive rats showed significantly higher levels of soluble CD40 ligand and caused more pronounced activation of glial cells (astrocytes and microglia), triggering the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) inflammatory signaling pathways, which culminated in neuronal injury and elevated levels of apoptotic cells (Bhat et al., 2017). However, platelets and platelet lysates also exert neuroprotective effects due to the neurotrophic, antioxidative, and anti-inflammatory functions of the platelet proteome and platelet-derived extracellular vesicles (EVs) (Nebie et al., 2021; Burnouf and Walker, 2022). A better understanding of the complex roles of platelets will hopefully provide effective therapies for neurological disorders.

Platelets are small subcellular fragments formed from the cytoplasm of bone marrow megakaryocytes (Machlus and Italiano, 2013). Although platelets lack a nucleus and most organelles found in typical cells, they do contain a few specialized subcellular structures, such as organelles, including mitochondria, lysosomes, and peroxisomes (Thon and Italiano, 2012) (Figure 1). α-granules are membrane-bound organelles that contain proteins such as fibrinogen, von Willebrand factor (VWF), and platelet-derived growth factor (PDGF). These protein molecules are released when platelets become activated and play a critical role in hemostasis, wound healing, and angiogenesis (Smith, 2022). For dense granules, small organelles contain molecules such as serotonin, ADP, and ATP. When platelets are activated, these molecules are released to promote platelet aggregation and vasoconstriction (Golebiewska and Poole, 2015). In addition, platelets contain a small number of mitochondria, which provide the energy needed for platelet function (Misztal et al., 2014). Platelet-derived mitochondria, which are regarded as the main source of circulating mitochondria (freeMitos) (Zhao et al., 2017a; Stephens et al., 2020), exert wide biological functions, such as responses of CD4⁺ T cells (Yu et al., 2020), and metabolic remodeling of mesenchymal stem cells (MSCs) (Levoux et al., 2021). Thus, platelets have pivotal roles in many physiological processes, such as angiogenesis (Hayon et al., 2012), innate immunity (Jiang et al., 2022), adaptive immunity (Koupenova et al., 2018), neurogenesis (Delgado et al., 2021), wound healing, and tissue regeneration (Fan Y. et al., 2020). Moreover, increasing evidence has supported that platelets are involved in mediating the pathological processes of central nervous system (CNS) diseases (Mezger et al., 2015).

Mitochondria function as the “power plant” of eukaryotic cells and play an important role in energy metabolism (Friedman and Nunnari, 2014). Beyond this basic function, mitochondria are regarded as essential mediators of multiple biological processes and aggravate the development of diseases (Figure 2). In this review, we will summarize the roles of platelet-derived vesicles, as well as platelet mitochondria in neurological disorders. In addition, platelet mitochondria transplantation shows high potential in the treatment of those diseases by acting as a potent mediator of cell metabolism, apoptosis, inflammatory reactions, and oxidative stress. We will also discuss the advantages and limitations of the use of platelet mitochondria transplantation.

Mitochondrial alterations, such as mitochondrial morphology changes, impaired respiratory chain function, calcium homeostasis disruption, and altered mitochondrial DNA (mtDNA), are hallmarks of CNS disorders (Kilbaugh et al., 2015; Monzio Compagnoni et al., 2020; Ding et al., 2023). Platelets play a crucial role in CNS diseases, and manifold functions of platelets have been found, far more than hemostasis and thrombosis (Figure 2). Platelets play a role in synaptic plasticity, memory, and learning, and those activated by physical activity encourage the development of neurons in certain regions of the brain. Additionally, platelets play a part in the immune response by altering their surface protein profile and releasing pro- and anti-inflammatory substances (Koupenova et al., 2018; Rawish et al., 2020; Ferrer-Raventós and Beyer, 2021). Notably, PLT-mitos also show significant functional alterations in CNS diseases (Bronstein et al., 2015; Donner et al., 2021). Thus, evaluating the functions of PLT-mitos helps the diagnosis and severity evaluation of those diseases.

Various CNS diseases, such as neurodegenerative diseases (such as PD, AD, and HD), cerebral stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are associated with dysfunctions of oxidative stress and inflammatory reactions (Islam, 2017; Khatri et al., 2018; Kumar et al., 2023). PLT-mitos have close relationships with mitochondrial DNA lesions, electron transfer chain impairments, mitochondrial apoptosis, and mitophagy in diverse human diseases (Forrester et al., 2018). Circulating mitochondria released by platelets are generally considered a source of potential DAMPs, promoting inflammation and oxidative stress (Zhang et al., 2010; Forrester et al., 2018; Linge et al., 2018). Extracellular and active mitochondria in the CSF have been detected, and extracellular mitochondria act as a biomarker for the outcome of pathologies such as SAH and delayed cerebral ischemia (Caicedo et al., 2021).

EVs are membrane vesicles released from the cellular plasma membrane (microvesicles or microparticles (MPs)) or endosomal compartments (exosomes) of cells. Following TBI, the injured brains produced cellular microvesicles, which further induced consumptive coagulopathy. Extracellular mitochondria, accounting for 55.2% of these microvesicles, contributed to TBI-induced coagulopathy, oxidative stress, and inflammation by enhancing platelet procoagulant activity (Zhang et al., 2022). Platelets are normally absent in the CNS, while they produce abundant EVs after being activated. The EVs are released into circulation and acquired by vascular endothelial cells through the process of endocytosis (Puhm et al., 2021; Gardin et al., 2022). Platelet-derived EVs exhibit a predictive value for recurrent vascular events in patients after ischemic stroke (Rosińska et al., 2019). Notably, platelets contain enriched mitochondria that may contribute to the local reactive oxygen species pool and remodel phospholipids in the plasma membrane of blood vessels (Aggarwal et al., 2023). Boudreau et al. suggested that respiratory-competent mitochondria are released from activated platelets. Those mitochondria are encapsulated by MPs (mitoMPs) and as freeMitos (Boudreau et al., 2014). Stephens and his colleagues analyzed circulating MPs using flow cytometry and proteomics for identifying the sources of mitoMPs and freeMitos. The results showed that mitochondria-containing MPs that were derived from murine and human beings had positive expressions of CD41 (a platelet marker) and CD144 (the endothelial cell marker), while hematopoietic CD45 labeling was lowly expressed, suggesting that circulating mitochondria mainly originated from platelets, endothelial cells, and leukocytes (Stephens et al., 2020). At the same time, Al Amir Dache Z et al. demonstrated that functional freeMitos are released from resting platelet in a normal physiological state. In addition, normal and tumor cultured cells can also secrete their mitochondria (Al Amir Dache et al., 2020). PLT-mitos share characteristics with bacterial and mitochondrial damage-associated molecular patterns, which are important contributors to sterile inflammation processes (Léger et al., 2022). Therefore, it is believed that freeMitos have the potential for early detection and prognosis of various diseases (Al Amir Dache et al., 2020).

PLT-mitos, whether shuttled by PLT-EVs or as freeMitos, play a role in neurological diseases. For instance, platelet-derived exosomes are significantly elevated in the serum of AD patients (Odaka et al., 2021). Alterations in platelet-derived EVs are also found in other neurodegenerative diseases, such as HD (Denis et al., 2018) and PD (Wang et al., 2023b). In patients with subacute stroke, platelets formed the largest population of vesicles within serial blood samples, and lower levels of platelets vesicles were associated with a worse functional outcome in the first 6 months post-stroke (Jödicke et al., 2021). For stroke patients who underwent the traditional rehabilitation program, the combination of exercise training improved platelet mitochondrial oxidative phosphorylation and electron transport chain, and mitigated plasma myeloperoxidase and interleukin-6 levels (Hsu et al., 2019). Extracellular mitochondria (exMTs) also exert a role in TBI (Zhang et al., 2022). As reviewed by Zhao et al., exMTs are released from injured cerebral cells, endothelial cells, and platelets. These circulating exMTs induce potent procoagulant activity and also aggravate inflammation, oxidative stress, and contribute to secondary tissue injury after the primary traumatic impact (Zhao et al., 2020). Glioblastoma multiforme (GBM) often develops deep venous thrombosis or pulmonary emboli, suggesting that platelets potentially involve in those pathological changes (Riedl and Ay, 2019). Gonzalez-Delgado et al. verified that freeMitos were increased in GBM patients compared with healthy controls. Intravenous delivery of mitochondria resulted in an increased rate of venous thrombosis in a murine model of inferior vena cava stenosis. Mitochondria-induced venous thrombi contain rich neutrophils and more platelets than those in control thrombi. Hence, the authors concluded that mitochondria might play a role in the GBM-induced hypercoagulable state (Gonzalez-Delgado et al., 2023). Overall, freeMitos and mitoMPs in circulation play a pivotal role in neurological diseases. Further investigations are needed to address the specific role of PLT-mitos in CNS diseases.

The functional integrity of mitochondria is regulated by a complex network of molecular mechanisms that control mitochondrial biogenesis, dynamics, quality control, and communication with other cellular compartments. At the transcriptional level, the transcription of mitochondrial genes is regulated by mitochondrial or nuclear transcription factors that bind to the promoters of the mitochondrial genome (Gustafsson et al., 2016). Alterations in the expression of these factors can impact the expression of mitochondrial genes and consequently disrupt mitochondrial function (Bonekamp et al., 2020). In addition, posttranscriptional regulation mechanisms, such as RNA splicing, can modulate the expression of mitochondrial genes, and their deregulation can contribute to mitochondrial dysfunction (Tsuboi et al., 2020). Moreover, proteins that are essential for mitochondrial function, such as enzymes, channels, and transporters, are synthesized in the cytoplasm and subsequently transported into the mitochondria (Busch et al., 2023) (Figure 3).

Studies have revealed that mitochondria are not limited to host cells and can actively move between cells through extracellular vesicles or nanotubes, and the transport of mitochondria plays a crucial role in metabolic homeostasis, the immune response, and stress signaling (Wang ZH. et al., 2022). Replacing damaged or dysfunctional mitochondria with exogenous healthy mitochondria, also called mitochondrial transplantation, has shown promising results (Gollihue and Rabchevsky, 2017). In particular, animal experiments have suggested that mitochondrial transfer is an effective strategy for treating several CNS disorders, such as SCI (Fang et al., 2021), TBI (Bamshad et al., 2023), cerebral stroke (Liu et al., 2019), PD (Moradi Vastegani et al., 2023), and depression (Javani et al., 2022). In 2021, a clinical trial (NCT04998357) was started to confirm the safety of autologous mitochondrial transplantation during brain ischemia.

Recently, increasing evidence has shown that platelet-extracted mitochondria transplantation plays a role in several cellular dysfunctions and diseases (Popov, 2021). Functionally, platelets and their released mitochondria exhibit markers associated with immune tolerance and regulate immune cell proliferation and functions. Platelet mtDNA also expressed embryonic stem cell- and pancreatic islet ß-cell-associated markers. Platelet-releasing mitochondria can migrate to pancreatic islets and be taken up by islet ß cells, leading to the proliferation and enhancement of islet ß-cell functions (Zhao et al., 2017b). Platelet mitochondria can be internalized into human dermal fibroblasts, increase cell proliferation, promote closure of the wound gap, and relieve intracellular and mitochondrial ROS production, thus enhancing wound healing in a cellular model (Kim S. et al., 2022). In primary cardiomyocytes, platelet-derived mitochondria transplantation increased mitochondrial membrane potential and greater ATP synthase activity and citrate synthase activity (Lin et al., 2023). In SH-SY5Y cells subjected to hypoxia/reoxygenation (HR) injury, platelet-derived mitochondria transplantation significantly mitigated mitochondrial malfunction and the mitochondrial apoptotic pathway. This study suggests that platelets may serve as readily available sources of donor mitochondria that afford therapeutic benefits against ischemia/reperfusion injury (Shi et al., 2021). In a diabetes-associated cognitive impairment (DACI) mouse model, platelet-derived mitochondria were internalized into hippocampal neurons 24 h after intracerebroventricular injection. One month later, the cognitive impairment of DACI mice was relieved. Platelet-derived mitochondria also increased mitochondrial number, improved mitochondrial function, suppressed neuronal oxidative stress and apoptosis, and inhibited the accumulation of Aβ and Tau in the hippocampus (Ma et al., 2020). Overall, platelet mitochondria therapy is a promising tool for promoting tissue repair and regeneration. More research is needed to better understand its mechanisms of action and to optimize its use in clinical settings.

Platelet mitochondrial dysfunctions have been uncovered in multiple CNS diseases, which can be caused by genetic mutations in mitochondrial and nuclear DNA, as well as by the pathological environment of a certain disease. Platelet-based liquid biopsy has aroused increasing attention in disease diagnosis, especially in cancer diagnosis (Wang L. et al., 2022). However, there are limited studies available regarding the discovery of platelet-mitos in the diagnosis of CNS disorders. Platelet and mitochondrial dynamics have rapid reactions to the alterations of diseases. Mitochondrial behaviors and changes in size, shape, and location within the cell occur in response to different physiological and pathological cues. These behaviors include mitochondrial fission, fusion, movement, distribution, and degradation, and the balance between them is critical for maintaining mitochondrial function and cellular homeostasis. Platelet mtDNA contains genetic information about diseases, and this might provide a more precise diagnosis of CNS diseases. Second, since platelet mitochondria also function as mediators in the initiation and progression of CNS diseases, mediators and drugs that regulate platelet mitochondrial dysfunction may have more potential in treating those diseases. Third, as increasing evidence has supported that platelet mitochondria transplantation has significant effects in treating cellular dysfunction and diseases, PLT-mitos transfer is a prospective strategy for the treatment of CNS diseases. In comparison to other sources of mitochondria, such as autologous muscle and mesenchymal stem cells, platelets are more accessible and regenerative. Moreover, studies should be performed to improve the isolation method of functional mitochondria from platelets (Vernerova et al., 2021).

Accumulated studies have revealed that platelet mitochondrial alterations have a close relationship with the development of CNS diseases, and evaluating platelet mitochondrial functions helps the prediction of treatment outcomes. Further studies will elucidate the role of platelet-mitos as a rapid and precise method for the diagnostic and therapeutic evaluation of CNS disorders. Moreover, methods for improving platelet-mitos isolation and experiments on the functions of platelet-mitos transplantation in CNS diseases are necessary.