Mitochondrial dysfunction and increased reactive oxygen species production in MECP2 mutant astrocytes and their impact on neurons.

Studies on MECP2 function and its implications in Rett Syndrome (RTT) have traditionally centered on neurons. Here, using human embryonic stem cell (hESC) lines, we modeled MECP2 loss-of-function to explore its effects on astrocyte (AST) development and dysfunction in the brain. Ultrastructural analysis of RTT hESC-derived cerebral organoids revealed significantly smaller mitochondria compared to controls (CTRs), particularly pronounced in glia versus neurons. Employing a multiomics approach, we observed increased gene expression and accessibility of a subset of nuclear-encoded mitochondrial genes upon mutation of MECP2 in ASTs compared to neurons. Analysis of hESC-derived ASTs showed reduced mitochondrial respiration and altered key proteins in the tricarboxylic acid cycle and electron transport chain in RTT versus CTRs. Additionally, RTT ASTs exhibited increased cytosolic amino acids under basal conditions, which were depleted upon increased energy demands. Notably, mitochondria isolated from RTT ASTs exhibited increased reactive oxygen species and influenced neuronal activity when transferred to cortical neurons. These findings underscore MECP2 mutation's differential impact on mitochondrial and metabolic pathways in ASTs versus neurons, suggesting that dysfunctional AST mitochondria may contribute to RTT pathophysiology by affecting neuronal health.

Cardiotoxicity of Anticancer Drugs: Molecular Mechanisms, Clinical Management and Innovative Treatment.

With the continuous refinement of therapeutic measures, the survival rate of tumor patients has been improving year by year, while cardiovascular complications related to cancer therapy have become increasingly prominent. Exploring the mechanism and prevention strategy of cancer therapy-related cardiovascular toxicity (CTR-CVT) remains one of the research hotspots in the field of Cardio-Oncology in recent years. Cardiotoxicity of anticancer drugs involves heart failure, myocarditis, hypertension, arrhythmias and vascular toxicity, mechanistically related to vascular endothelial dysfunction, ferroptosis, mitochondrial dysfunction and oxidative stress. To address the cardiotoxicity induced by different anticancer drugs, various therapeutic measures have been put in place, such as reducing the accumulation of anticancer drugs, shifting to drugs with less cardiotoxicity, using cardioprotective drugs, and early detection. Due to the very limited treatments available to ameliorate anticancer drugs-induced cardiotoxicity, a few innovations are being shifted from animal studies to human studies. Examples include mitochondrial transplantation. Mitochondrial transplantation has been proven to be effective in in vivo and in vitro experiments. Several recent studies have demonstrated that intercellular mitochondrial transfer can ameliorate doxorubicin(DOX)-induced cardiotoxicity, laying the foundation for innovative therapies in anticancer drugs-induced cardiotoxicity. In this review, we will discuss the current status of anticancer drugs-induced cardiotoxicity in terms of the pathogenesis and treatment, with a focus on mitochondrial transplantation, and we hope that this review will bring some inspiration to you.

Unraveling the pathogenesis of viral-induced pulmonary arterial hypertension: Possible new therapeutic avenues with mesenchymal stromal cells and their derivatives.

Pulmonary hypertension (PH) is a severe condition characterized by elevated pressure in the pulmonary artery, where metabolic and mitochondrial dysfunction may contribute to its progression. Within the PH spectrum, pulmonary arterial hypertension (PAH) stands out with its primary pulmonary vasculopathy. PAH's prevalence varies from 0.4 to 1.4 per 100,000 individuals and is associated with diverse conditions, including viral infections such as HIV. Notably, recent observations highlight an increased occurrence of PAH among COVID-19 patients, even in the absence of pre-existing cardiopulmonary disorders. While current treatments offer partial relief, there's a pressing need for innovative therapeutic strategies, among which mesenchymal stromal cells (MSCs) and their derivatives hold promise. This review critically evaluates recent investigations into viral-induced PAH, encompassing pathogens like human immunodeficiency virus, herpesvirus, Cytomegalovirus, Hepatitis B and C viruses, SARS-CoV-2, and Human endogenous retrovirus K (HERKV), with a specific emphasis on mitochondrial dysfunction. Furthermore, we explore the underlying rationale driving novel therapeutic modalities, including MSCs, extracellular vesicles, and mitochondrial interventions, within the framework of PAH management.

A promising therapeutic: Exosome-mediated mitochondrial transplantation.

Mitochondrial dysfunction has been identified as a trigger for cellular autophagy dysfunction and programmed cell death. Emerging studies have revealed that, in pathological contexts, intercellular transfer of mitochondria takes place, facilitating the restoration of mitochondrial function, energy metabolism, and immune homeostasis. Extracellular vesicles, membranous structures released by cells, exhibit reduced immunogenicity and enhanced stability during the transfer of mitochondria. Thus, this review provides a concise overview of mitochondrial dysfunction related diseases and the mechanism of mitochondrial dysfunction in diseases progression, and the composition and functions of the extracellular vesicles, along with elucidating the principal mechanisms underlying intercellular mitochondrial transfer. In this article, we will focus on the advancements in both animal models and clinical trials concerning the therapeutic efficacy of extracellular vesicle-mediated mitochondrial transplantation across various systemic diseases in neurodegenerative diseases and cardiovascular diseases. Additionally, the review delves into the multifaceted roles of extracellular vesicle-transplanted mitochondria, encompassing anti-inflammatory actions, promotion of tissue repair, enhancement of cellular function, and modulation of metabolic and immune homeostasis within diverse pathological contexts, aiming to provide novel perspectives for extracellular vesicle transplantation of mitochondria in the treatment of various diseases.

Stroke studies in large animals: Prospects of mitochondrial transplantation and enhancing efficiency using hydrogels and nanoparticle-assisted delivery.

One of the most frequent reasons for mortality and disability today is acute ischemic stroke, which occurs by an abrupt disruption of cerebral circulation. The intricate damage mechanism involves several factors, such as inflammatory response, disturbance of ion balance, loss of energy production, excessive reactive oxygen species and glutamate release, and finally, neuronal death. Stroke research is now carried out using several experimental models and potential therapeutics. Furthermore, studies are being conducted to address the shortcomings of clinical care. A great deal of research is being done on novel pharmacological drugs, mitochondria targeting compounds, and different approaches including brain cooling and new technologies. Still, there are many unanswered questions about disease modeling and treatment strategies. Before these new approaches may be used in therapeutic settings, they must first be tested on large animals, as most of them have been done on rodents. However, there are several limitations to large animal stroke models used for research. In this review, the damage mechanisms in acute ischemic stroke and experimental acute ischemic stroke models are addressed. The current treatment approaches and promising experimental methods such as mitochondrial transplantation, hydrogel-based interventions, and strategies like mitochondria encapsulation and chemical modification, are also examined in this work.

Mitochondria in Retinal Ganglion Cells: Unraveling the Metabolic Nexus and Oxidative Stress.

This review explored the role of mitochondria in retinal ganglion cells (RGCs), which are essential for visual processing. Mitochondrial dysfunction is a key factor in the pathogenesis of various vision-related disorders, including glaucoma, hereditary optic neuropathy, and age-related macular degeneration. This review highlighted the critical role of mitochondria in RGCs, which provide metabolic support, regulate cellular health, and respond to cellular stress while also producing reactive oxygen species (ROS) that can damage cellular components. Maintaining mitochondrial function is essential for meeting RGCs' high metabolic demands and ensuring redox homeostasis, which is crucial for their proper function and visual health. Oxidative stress, exacerbated by factors like elevated intraocular pressure and environmental factors, contributes to diseases such as glaucoma and age-related vision loss by triggering cellular damage pathways. Strategies targeting mitochondrial function or bolstering antioxidant defenses include mitochondrial-based therapies, gene therapies, and mitochondrial transplantation. These advances can offer potential strategies for addressing mitochondrial dysfunction in the retina, with implications that extend beyond ocular diseases.

Surface Molecularly Engineered Mitochondria Conduct Immunophenotype Repolarization of Tumor-Associated Macrophages to Potentiate Cancer Immunotherapy.

Reprogramming tumor-associated macrophages (TAMs) to an inflammatory phenotype effectively increases the potential of immune checkpoint blockade (ICB) therapy. Artificial mitochondrial transplantation, an emerging and safe strategy, has made brilliant achievements in regulating the function of recipient cells in preclinic and clinic, but its performance in reprogramming the immunophenotype of TAMs has not been reported. Here, the metabolism of M2 TAMs is proposed resetting from oxidative phosphorylation (OXPHOS) to glycolysis for polarizing M1 TAMs through targeted transplantation of mannosylated mitochondria (mPEI/M1mt). Mitochondria isolated from M1 macrophages are coated with mannosylated polyethyleneimine (mPEI) through electrostatic interaction to form mPEI/M1mt, which can be targeted uptake by M2 macrophages expressed a high level of mannose receptors. Mechanistically, mPEI/M1mt accelerates phosphorylation of NF-κB p65, MAPK p38 and JNK by glycolysis-mediated elevation of intracellular ROS, thus prompting M1 macrophage polarization. In vivo, the transplantation of mPEI/M1mt excellently potentiates therapeutic effects of anti-PD-L1 by resetting an antitumor proinflammatory tumor microenvironment and stimulating CD8 and CD4 T cells dependent immune response. Altogether, this work provides a novel platform for improving cancer immunotherapy, meanwhile, broadens the scope of mitochondrial transplantation technology in clinics in the future.

Transplanting mitochondria from gastric epithelial cells reduces the malignancy of gastric cancer.

Mitochondria are essential for energy supplementation and metabolic homeostasis of cancer cells. Using mitochondria transplantation to reduce the malignancy of gastric cancer (GC) cells is herein proposed. In our study normal human gastric mucous epithelium cell line (GES-1) showed a lower mitochondrial membrane potential (MMP) compared to immortalized human vascular endothelial cell line (EAhy 926) and human gastric adenocarcinoma cell line (AGS). The transplantation of GES-1 mitochondria to AGS were confirmed both by confocal microscopy and flow cytometry. After transplanting GES-1 mitochondria, the AGS showed a reduced cell migration, and invasion without affecting cell viability and apoptosis. Investigating the expression of proteins involved in epithelial-mesenchymal-transition (EMT), transplanted GES-1 mitochondria reduced the expression of mesenchymal markers α-SMA, MMP-9, snail, vimentin and N-cadherin, whereas the epithelial markers E-cadherin and clauding-1 were not changed. The proteins implicated in the cell cycle such as cyclin B1 and D1 were decreased. In mice, inoculation with AGS carrying the transplanted GES-1 mitochondria resulted in smaller sized tumors. Further investigating the mitochondrial balance, the transplanted GES-1 mitochondria were more stably preserved compared to endogenous AGS mitochondria. The MMP, ATP production and mitochondrial mass decreased in GES-1 mitochondria and the mitophagic proteins LC3 II and PINK1 were up-regulated. In conclusion the decreased malignancy of AGS was a result of exogenous GES-1 mitochondria transplantation. This suggests for a therapy with low efficiency mitochondria transplantation in the treatment of cancer cells.

Mitochondrial Transplantation Promotes Protective Effector and Memory CD4+ T Cell Response During Mycobacterium Tuberculosis Infection and Diminishes Exhaustion and Senescence in Elderly CD4+ T cells.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is a major global health concern, particularly affecting those with weakened immune systems, including the elderly. CD4+ T cell response is crucial for immunity against M.tb, but chronic infections and aging can lead to T cell exhaustion and senescence, worsening TB disease. Mitochondrial dysfunction, prevalent in aging and chronic diseases, disrupts cellular metabolism, increases oxidative stress, and impairs T-cell functions. This study investigates the effect of mitochondrial transplantation (mito-transfer) on CD4+ T cell differentiation and function in aged mouse models and human CD4+ T cells from elderly individuals. Mito-transfer in naïve CD4+ T cells is found to promote protective effector and memory T cell generation during M.tb infection in mice. Additionally, it improves elderly human T cell function by increasing mitochondrial mass and altering cytokine production, thereby reducing markers of exhaustion and senescence. These findings suggest mito-transfer as a novel approach to enhance aged CD4+ T cell functionality, potentially benefiting immune responses in the elderly and chronic TB patients. This has broader implications for diseases where mitochondrial dysfunction contributes to T-cell exhaustion and senescence.

Neuroprotective effect of autologous mitochondrial transplantation against global ischemia/reperfusion injury in a rat model of cardiac arrest.

BACKGROUND: Mitochondria have emerged as a promising target for ischemic disease. A previous study reported the application of mitochondrial transplantation in focal cerebral ischemia/reperfusion injury, but it is unclear whether exogenous mitochondrial transplantation could be a therapeutic strategy for global ischemia/reperfusion injury induced by cardiac arrest. METHODS: We hypothesized that transplantation of autologous mitochondria would rescue hippocampal cells and alleviate neurological impairment after cardiac arrest. In this study, we employed a rat cardiac arrest-global cerebral ischemia injury model (CA-GCII) and transplanted isolated mitochondria intravenously. Behavior test was applied to assess neurological deficit. Apoptosis and mitochondria permeability transition pore opening in hippocampus was determined using immunoblotting and swelling assay, respectively. RESULTS: Transplanted mitochondria distributed throughout hippocampal cells and reduced oxidative stress. An improved neurological outcome was observed in rats receiving autologous mitochondria. In the hippocampus, mitophagy was enhanced while cell apoptosis was induced by ischemia/reperfusion insult was downregulated by mitochondrial transplantation. Mitochondrial permeability transition pore (MPTP) opening in surviving hippocampal cells was also suppressed. CONCLUSIONS: These results indicated that transplantation of autologous mitochondria rescued hippocampal cells from ischemia/reperfusion injury and ameliorated neurological impairment caused by cardiac arrest.

Safety and efficacy of platelet-derived mitochondrial transplantation in ischaemic heart disease.

BACKGROUND: Acute ST-elevation myocardial infarction (STEMI) remains a globally significant health challenge in spite of improvement in management strategy. Being aware that mitochondrial dysfunction plays a crucial role in ischaemia-reperfusion injury (IRI) modulation, empirical evidence suggests functional mitochondrial transplantation strikes as a reliable therapeutic approach for patients with acute myocardial infarction. METHODS AND RESULTS: We conducted a prospective, triple-blinded, parallel-group, blocked randomised clinical trial to investigate the therapeutic effects and clinical outcomes of platelet-derived mitochondrial transplantation in 30 patients with acute STEMI, such that the 15 subjects in the control group were given standard of care treatment, whereas the subjects in the intervention group received autologous platelet-derived mitochondria through the intracoronary injection. We observed that within 40 days, the intervention group had a slightly greater improvement in the left ventricular ejection fraction (LVEF) compared to the control group and experienced a significant enhancement in the exercise capacity (p < 0.001). Moreover, major adverse cardiac events (MACE), arrhythmia, fever, and tachycardia were compared between the groups and lack of significant difference marks the safety of mitochondrial transplantation (p > 0.05). Furthermore, the two groups were not significantly distinct as regards the average length of stay for a hospitalisation (p > 0.05). CONCLUSION: We suggest platelet-derived mitochondrial transplantation appears as a beneficial and highly promising therapeutic option for patients of ischaemic heart disease (IHD); however, we are aware that further in-depth studies with larger sample sizes along with longer follow-up periods are necessary for validating the clinical implications of our findings.

Mitochondrial homeostasis in odontoblast: Physiology, pathogenesis and targeting strategies.

Caries and pulpitis remain a major global disease burden and affect the quality of life of patients. Odontoblasts are key players in the progression of caries and pulpitis, not only secreting and mineralizing to form dentin, but also acting as a wall of defense to initiate immune defenses. Mitochondrion is an information processor for numerous cellular activities, and dysregulation of mitochondrion homeostasis not only affects cellular metabolism but also triggers a wide range of diseases. Elucidating mitochondrial homeostasis in odontoblasts can help deepen scholars' understanding of odontoblast-associated diseases. Articles on mitochondrial homeostasis in odontoblasts were evaluated for information pertinent to include in this narrative review. This narrative review focused on understanding the complex interplay between mitochondrial homeostasis in odontoblasts under physiological and pathological conditions. Furthermore, mitochondria-centered therapeutic strategies (including mitochondrial base editing, targeting platforms, and mitochondrial transplantation) were emphasized by resolving key genes that regulate mitochondrial function. Mitochondria are involved in odontoblast differentiation and function, and act as mitochondrial danger-associated molecular patterns (mtDAMPs) to mediate odontoblast pathological progression. Novel mitochondria-centered therapeutic strategies are particularly attractive as emerging therapeutic approaches for the maintenance of mitochondrial homeostasis. It is expected to probe key events of odontoblast differentiation and advance the clinical resolution of dentin formation and mineralization disorders and odontoblast-related diseases.

The effects of exercise and mitochondrial transplantation alone or in combination against Doxorubicin-induced skeletal muscle atrophy.

Doxorubicin (DOX) is a chemotherapy drug used to treat various types of cancer, but it is associated with significant side effects such as skeletal muscle atrophy. Exercise has been found to prevent skeletal muscle atrophy through the modulation of mitochondrial pathways. Mitochondrial transplantation (MT) may mitigate toxicity, neurological disorders, kidney and liver injury, and skeletal muscle atrophy. The objective of this study was to evaluate the effects of MT, exercise, and MT with exercise on DOX-induced skeletal muscle atrophy. Male Sprague Dawley rats were randomly assigned to the following groups: control, DOX, MT with DOX, exercise with DOX, and exercise with MT and DOX. A 10-day treadmill running exercise and MT (6.5 µg/100 µL) to tibialis anterior (TA) muscle were administered prior to a single injection of DOX (20 mg/kg). Our data showed that exercise and MT with exercise led to an increase in cross-sectional area of the TA muscle. Exercise, MT and MT with exercise reduced inflammation and maintained mitochondrial enzyme activity. Additionally, exercise and MT have been shown to regulate mitochondrial fusion/fission. Our findings revealed that exercise and MT with exercise prevented oxidative damage. Furthermore, MT and MT with exercise decreased apoptosis and MT with exercise triggered mitochondrial biogenesis. These findings demonstrate the importance of exercise in the prevention of skeletal muscle atrophy and emphasize the significant benefits of MT with exercise. To the best of our knowledge, this is the first study to demonstrate the therapeutic effects of MT with exercise in DOX-induced skeletal muscle atrophy.

Mitochondrial transplantation: A promising therapy for mitochondrial disorders.

As a vital energy source for cellular metabolism and tissue survival, the mitochondrion can undergo morphological or positional change and even shuttle between cells in response to various stimuli and energy demands. Multiple human diseases are originated from mitochondrial dysfunction, but the curative succusses by traditional treatments are limited. Mitochondrial transplantation therapy (MTT) is an innovative therapeutic approach that is to deliver the healthy mitochondria either derived from normal cells or reassembled through synthetic biology into the cells and tissues suffering from mitochondrial damages and finally replace their defective mitochondria and restore their function. MTT has already been under investigation in clinical trials for cardiac ischemia-reperfusion injury and given an encouraging performance in animal models of numerous fatal critical diseases including central nervous system disorders, cardiovascular diseases, inflammatory conditions, cancer, renal injury, and pulmonary damage. This review article summarizes the mechanisms and strategies of mitochondrial transfer and the MTT application for types of mitochondrial diseases, and discusses the potential challenge in MTT clinical application, aiming to exhibit the good therapeutic prospects of MTTs in clinics.

Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease that results in the loss of motor neurons and severe skeletal muscle atrophy. The etiology of ALS is linked to skeletal muscle, which can activate a retrograde signaling cascade that destroys motor neurons. This is why satellite cells and mitochondria play a crucial role in the health and performance of skeletal muscles. This review presents current knowledge on the involvement of mitochondrial dysfunction, skeletal muscle atrophy, muscle satellite cells, and neuromuscular junction (NMJ) in ALS. It also discusses current therapeutic strategies, including exercise, drugs, stem cells, gene therapy, and the prospective use of mitochondrial transplantation as a viable therapeutic strategy.

Pyrroloquinoline quinone promotes human mesenchymal stem cell-derived mitochondria to improve premature ovarian insufficiency in mice through the SIRT1/ATM/p53 pathway.

BACKGROUND: DNA damage and oxidative stress induced by chemotherapy are important factors in the onset of premature ovarian insufficiency (POI). Studies have shown that mitochondria derived from mesenchymal stem cells (MSC-Mito) are beneficial for age-related diseases, but their efficacy alone is limited. Pyrroloquinoline quinone (PQQ) is a potent antioxidant with significant antiaging and fertility enhancement effects. This study aimed to investigate the therapeutic effect of MSC-Mito in combination with PQQ on POI and the underlying mechanisms involved. METHODS: A POI animal model was established in C57BL/6J mice by cyclophosphamide and busulfan. The effects of MSC-Mito and PQQ administration on the estrous cycle, ovarian pathological damage, sex hormone secretion, and oxidative stress in mice were evaluated using methods such as vaginal smears and ELISAs. Western blotting and immunohistochemistry were used to assess the expression of SIRT1, PGC-1α, and ATM/p53 pathway proteins in ovarian tissues. A cell model was constructed using KGN cells treated with phosphoramide mustard to investigate DNA damage and apoptosis through comet assays and flow cytometry. SIRT1 siRNA was transfected into KGN cells to further explore the role of the SIRT1/ATM/p53 pathway in combination therapy with MSC-Mito and PQQ for POI. RESULTS: The combined treatment of MSC-Mito and PQQ significantly restored ovarian function and antioxidant capacity in mice with POI. This treatment also reduced the loss of follicles at various stages, improving the disrupted estrous cycle. In vitro experiments demonstrated that PQQ facilitated the proliferation of MitoTracker-labelled MSC-Mito, synergistically restoring mitochondrial function and inhibiting oxidative stress in combination with MSC-Mito. Both in vivo and in vitro, the combination of MSC-Mito and PQQ increased mitochondrial biogenesis mediated by SIRT1 and PGC-1α while inhibiting the activation of ATM and p53, consequently reducing DNA damage-mediated cell apoptosis. Furthermore, pretreatment of KGN cells with SIRT1 siRNA reversed nearly all the aforementioned changes induced by the combined treatment. CONCLUSIONS: Our research findings indicate that PQQ facilitates MSC-Mito proliferation and, in combination with MSC-Mito, ameliorates chemotherapy-induced POI through the SIRT1/ATM/p53 signaling pathway.

Potential Applications of Mitochondrial Therapy with a Focus on Parkinson's Disease and Mitochondrial Transplantation.

Purpose: Both aging and neurodegenerative illnesses are thought to be influenced by mitochondrial malfunction and free radical formation. Deformities of the energy metabolism, mitochondrial genome polymorphisms, nuclear DNA genetic abnormalities associated with mitochondria, modifications of mitochondrial fusion or fission, variations in shape and size, variations in transit, modified mobility of mitochondria, transcription defects, and the emergence of misfolded proteins associated with mitochondria are all linked to Parkinson's disease. Methods: This review is a condensed compilation of data from research that has been published between the years of 2014 and 2022, using search engines like Google Scholar, PubMed, and Scopus. Results: Mitochondrial transplantation is a one-of-a-kind treatment for mitochondrial diseases and deficits in mitochondrial biogenesis. The replacement of malfunctioning mitochondria with transplanted viable mitochondria using innovative methodologies has shown promising outcomes as a cure for Parkinson's, involving tissue sparing coupled with enhanced energy generation and lower oxidative damage. Numerous mitochondria-targeted therapies, including mitochondrial gene therapy, redox therapy, and others, have been investigated for their effectiveness and potency. Conclusion: The development of innovative therapeutics for mitochondria-directed treatments in Parkinson's disease may be aided by optimizing mitochondrial dynamics. Many neurological diseases have been studied in animal and cellular models, and it has been found that mitochondrial maintenance can slow the death of neuronal cells. It has been hypothesized that drug therapies for neurodegenerative diseases that focus on mitochondrial dysfunction will help to delay the onset of neuronal dysfunction.

Therapeutic potential of mitochondrial transplantation in modulating immune responses post-cardiac arrest: a narrative review.

BACKGROUND: Mitochondrial transplantation (MTx) has emerged as a novel therapeutic strategy, particularly effective in diseases characterized by mitochondrial dysfunction. This review synthesizes current knowledge on MTx, focusing on its role in modulating immune responses and explores its potential in treating post-cardiac arrest syndrome (PCAS). METHODS: We conducted a comprehensive narrative review of animal and human studies that have investigated the effects of MTx in the context of immunomodulation. This included a review of the immune responses following critical condition such as ischemia reperfusion injury, the impact of MTx on these responses, and the therapeutic potential of MTx in various conditions. RESULTS: Recent studies indicate that MTx can modulate complex immune responses and reduce ischemia-reperfusion injury post-CA, suggesting MTx as a novel, potentially more effective approach. The review highlights the role of MTx in immune modulation, its potential synergistic effects with existing treatments such as therapeutic hypothermia, and the need for further research to optimize its application in PCAS. The safety and efficacy of autologous versus allogeneic MTx, particularly in the context of immune reactions, are critical areas for future investigation. CONCLUSION: MTx represents a promising frontier in the treatment of PCAS, offering a novel approach to modulate immune responses and restore cellular energetics. Future research should focus on long-term effects, combination therapies, and personalized medicine approaches to fully harness the potential of MTx in improving patient outcomes in PCAS.

Effects of mitochondrial transplantation on chronic pressure wound healing in a human patient.

BACKGROUND AIMS: Wound healing is a multistage process that requires a concerted effort of various cell types. The intricate processes involved in the healing of wounds result in high energy requirements. Furthermore, mitochondria play a crucial role in the healing process because of their involvement in neo angiogenesis, growth factor synthesis, and cell differentiation. It is unclear how mitochondria transplantation, a promising new approach, influences wound healing. METHODS: In this study, healthy autologous mitochondria obtained from skeletal muscle were injected into chronic pressure wounds as an intervention to promote wound healing. RESULTS: Mitochondrial transplantation accelerated wound healing by reducing wound size, increasing granulation tissue, and hastening epithelialization. CONCLUSIONS: This study is the first to demonstrate the therapeutic efficacy of mitochondrial transplantation in wound healing.

Mitochondria in the Central Nervous System in Health and Disease: The Puzzle of the Therapeutic Potential of Mitochondrial Transplantation.

Mitochondria, the energy suppliers of the cells, play a central role in a variety of cellular processes essential for survival or leading to cell death. Consequently, mitochondrial dysfunction is implicated in numerous general and CNS disorders. The clinical manifestations of mitochondrial dysfunction include metabolic disorders, dysfunction of the immune system, tumorigenesis, and neuronal and behavioral abnormalities. In this review, we focus on the mitochondrial role in the CNS, which has unique characteristics and is therefore highly dependent on the mitochondria. First, we review the role of mitochondria in neuronal development, synaptogenesis, plasticity, and behavior as well as their adaptation to the intricate connections between the different cell types in the brain. Then, we review the sparse knowledge of the mechanisms of exogenous mitochondrial uptake and describe attempts to determine their half-life and transplantation long-term effects on neuronal sprouting, cellular proteome, and behavior. We further discuss the potential of mitochondrial transplantation to serve as a tool to study the causal link between mitochondria and neuronal activity and behavior. Next, we describe mitochondrial transplantation's therapeutic potential in various CNS disorders. Finally, we discuss the basic and reverse-translation challenges of this approach that currently hinder the clinical use of mitochondrial transplantation.