|Year : 2018 | Volume
| Issue : 3 | Page : 84-94
Mitochondrial targeting as a novel therapy for stroke
Eleonora Russo1, Hung Nguyen1, Trenton Lippert1, Julian Tuazon1, Cesar V Borlongan1, Eleonora Napoli2
1 Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida, Morsani College of Medicine, Tampa, FL, USA
2 Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA
|Date of Submission||21-Jul-2018|
|Date of Acceptance||10-Sep-2018|
|Date of Web Publication||09-Oct-2018|
Dr. Cesar V Borlongan
College of Medicine, University of South Florida, Morsani, Tampa, FL
Source of Support: None, Conflict of Interest: None
Stroke is a main cause of mortality and morbidity worldwide. Despite the increasing development of innovative treatments for stroke, most are unsuccessful in clinical trials. In recent years, an encouraging strategy for stroke therapy has been identified in stem cells transplantation. In particular, grafting cells and their secretion products are leading with functional recovery in stroke patients by promoting the growth and function of the neurovascular unit – a communication framework between neurons, their supply microvessels along with glial cells – underlying stroke pathology and recovery. Mitochondrial dysfunction has been recently recognized as a hallmark in ischemia/reperfusion neural damage. Emerging evidence of mitochondria transfer from stem cells to ischemic-injured cells points to transfer of healthy mitochondria as a viable novel therapeutic strategy for ischemic diseases. Hence, a more in-depth understanding of the cellular and molecular mechanisms involved in mitochondrial impairment may lead to new tools for stroke treatment. In this review, we focus on the current evidence of mitochondrial dysfunction in stroke, investigating favorable approaches of healthy mitochondria transfer in ischemic neurons, and exploring the potential of mitochondria-based cellular therapy for clinical applications. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed.
Keywords: Bioenergetics, blood–brain barrier, cerebral ischemia, endothelial cells, impaired mitochondria, neurovascular unit, regenerative medicine, stem cell therapy, transfer of healthy mitochondria, vasculature
|How to cite this article:|
Russo E, Nguyen H, Lippert T, Tuazon J, Borlongan CV, Napoli E. Mitochondrial targeting as a novel therapy for stroke. Brain Circ 2018;4:84-94
| Introduction|| |
Stroke is a leading cause of death and disability worldwide. Although considerable advance in our understanding of the disease has been achieved over the last two decades, the available treatments are limited. Mitochondrial dysfunction has been implicated in the secondary cell death associated with stroke. Accordingly, strategies designed to target mitochondria may prove beneficial for stroke. In this review, we provide an in-depth analysis of the role of mitochondria dysfunction in ischemic injury and examine current mitochondrial pharmacological and nonpharmacological therapeutic approaches. In particular, we explore the potential of mitochondria transfer-based stem cell therapies for the treatment of stroke.
| Current Treatments for Stroke|| |
To date, only one Food and Drug Administration (FDA)-approved drug, alteplase, is available for the treatment of ischemic stroke. Alteplase, a recombinant tissue plasminogen activator, is a thrombolytic agent, and its mechanism of action consists in breaking down the clot from the occluded vessel, allowing the restoration of blood flow. However, the efficacy of alteplase is limited within 4.5 h after stroke onset and therefore not all stroke patients can receive it in a timely manner., In addition, anticoagulant agents increase the risk of hemorrhages., Alternatively, an endovascular thrombectomy may be used as a supplement or substitute option for stroke patients ineligible for intravenous thrombolysis., Other supportive medications for stroke patients include maintenance of normoglycemia and physiological body temperature as well as management of blood pressure. Therefore, advancement in therapeutic options for stroke is an urgent necessity. Increasing evidence suggest an encouraging potential of small molecules for the treatment of stroke. Notably, the PA Stachybotrys microspora triprenyl phenol-7 reduced infarct area, hemorrhages, and improved neurological function in nonhuman primate stroke model., In a mouse stroke model, the small molecule NSI-189 incremented neurogenesis, cell proliferation, and neurotrophic factors, as well as improvement in behavioral function along with the expansion of the time window to a 6-h for delivery after stroke., Hence, these small molecules may represent an additional therapeutic approach to the current stroke treatments.
| Roles of Mitochondria in Stroke|| |
Mitochondria are widely known for their role as “energy powerhouse of the cell,” being the primary generators of adenosine triphosphate (ATP), a high-energy molecule that stores and supplies energy for many biochemical processes. Mitochondria have crucial roles in energy metabolism regulation, cell cycle, survival and death, apoptosis, generation of reactive oxygen species (ROS), and calcium homeostasis., About 90% of the whole cellular energy need is produced by the metabolic processes entailing glycolysis, fatty acid beta-oxidation, Krebs cycle, and oxidative phosphorylation (OXPHOS)., Under physiological conditions, approximately 2% of the total electrons transferred across the mitochondrial respiratory chain (MRC) leak during aerobic respiration, mainly from Complexes I and III, leading to the formation of superoxide anion., Superoxide anion is the precursor of ROS such as hydrogen peroxide and hydroxyl radical, which can damage lipids, nucleic acids, and proteins, becoming critical players in the physiological process of aging as well as in the onset and progression of several diseases including myocardial infarction, inflammatory disorders, some cancers, and atherosclerosis., The human brain is the most energy-consuming organ, with 20% of the total energy produced, being used by only 2% of the body mass. Most of this energy is used for crucial central nervous system functions such as generation action potentials and transmission of information through chemical synapses. In this regard, mitochondrial dysfunction might have a critical role in neurodegeneration and in several diseases such as Alzheimer's, Parkinson's, Huntington's as well as psychiatric disorders such as depression and schizophrenia and neurodevelopmental illnesses like autism spectrum disorder.,,,,, In addition, Anderson–Fabry disease may be associated to a reduction in OXPHOS and energy production due to a mitochondrial dysfunction and it may generate ischemic stroke.,,
Ischemic stroke occurs when a cerebral region is deprived of oxygen due to a decrease in local blood flow resulting from obstruction of a blood vessel such as embolism or thrombus formation. Ischemic stroke leads to deficits in neurological function, disability and, in many cases, death., The risk of stroke increases with age, but there is a rising incidence of stroke cases in young adults that account for the 10%–15% of all the strokes. Stroke in younger people has a higher economic and social impact than in older ones due to a disability in the most fruitful years of life. Intravenous thrombolysis is efficacy within 4.5 h of stroke onset. A thrombectomy may be performed when thrombolytic agents cannot be used, but alternative options are very limited.,, According to several evidence on the central role of mitochondria in neurons metabolism as well as in the ischemic/reperfusion cascade resulting in neuronal death,, this review focuses on the involvement of mitochondria in the pathophysiology of stroke and the promising mitochondria-based regenerative medicine for stroke treatment.
| Mitochondria Dysfunction Inducer of Stress, Disease, and Death|| |
Mitochondria have a central role in cellular biology. MRC is constituted by a series of mitochondrial complexes (Complex I–Complex CV) that serve as sites of electrons transport (Complex I–IV) coupled to ATP production (CV). The OXPHOS machinery is organized into supercomplexes in the inner mitochondrial membrane., Most of the ~ 90 subunits constituting the electron transport chain (ETC) complexes are of nuclear DNA origin, while 13 are encoded by mitochondrial DNA (mtDNA). In the ETC, electrons are transferred from FADH2 and NADH to series of electron acceptors and donors, with molecular oxygen being the last acceptor and pumping protons across the inner membrane., The electrochemical gradient thus generated is used to produce ATP through Complex V., MRC is the central site of premature electron leak to oxygen. The generation of superoxide anion, hydrogen peroxide, and hydroxyl radicals can result in oxidative stress. Therefore, mitochondria are the main ROS producers and consequent oxidative stress is a key factor in degenerative processes. OXPHOS disorders may affect 1–5/10,000 births and each mitochondrial complex may be crucial in the genesis and progression of different diseases. Some of these mitochondrial disorders are characterized by neuronal damage and encephalopathies (coenzyme Q10 deficiency, Complex I–IV deficiencies, Leigh disease, MIRA), epilepsy, seizures and ataxia (MERRF, MIRAS, Leigh disease, Friedreich's ataxia), and stroke-like episodes (MELAS). Therefore, a brief overview of these disorders is imperative.
Complex I, well known as NADH dehydrogenase, is involved in different neurodegenerative disorders characterized by deficits in mitochondrial energy metabolism.,, Complex I is the first protein of the MRC involving the electron transfer from NADH to ubiquinone. Along with this reaction, a premature transfer of electrons to oxygen may happen, leading to superoxide anion production. Therefore, Complex I represents a source of ROS production. ROS directly can damage mitochondrial proteins, mtDNA, and lead to disruption of membrane integrity with consequent depolarization and triggering of the apoptotic pathway.
Although Complex II represents only the 2% of all MRC defects, its deficits extend from cancer to Leigh syndrome, infantile leukodystrophies up to cardiomyopathies. Complex II is involved in apoptosis induction. As such, Complex II detects pH changes generated by apoptosis-inducer transmembrane protein Fas ligand (FasL) leading to ROS production and cellular death.
Similarly, Complex III dysfunction may result in cell death. Pesticide exposure has been associated with inhibition or destruction of Complex III with consequent impairment of electron transport and ROS production leading to apoptotic pathway activation. Interestingly, different studies suggest an association between pesticide exposure and Parkinson's disease. In addition, exercise intolerance and ischemic cardiomyopathy have been correlated with cytochrome b or other Complex III subunits gene mutations.,
Complex IV or cytochrome c oxidase (COX) has the function to reduce oxygen to water by electron transfer from the reduced cytochrome c. Mutations in the mitochondrial COX gene cause a number of rare autosomal recessive diseases. COX deficiencies are associated with Leigh Syndrome, hypertrophic cardiomyopathy and myopathy, and fatal infantile lactic acidosis., Moreover, COX deficit associated to iron-deficiency anemia may exacerbate the oxidative stress.
ATP synthase, also known as Complex V, is the final OXPHOS enzyme that uses the energy of the proton electrochemical gradient to synthesize ATP from ADP and phosphate., ATP synthase plays a role in mitochondrial cristae morphology and in the formation of the permeability transition pore complex (mPTP)., Despite being somewhat uncommon, ATP synthase disorders are highly severe. ATP synthase deficiencies involve structural modifications characterized by energy deprivation., Genetic mutations in mtDNA coding for ATP synthase subunits determine incorrect assembly and/or function of the enzyme. Disorders related to ATP-synthase deficits are neuropathy, ataxia, retinitis pigmentosa (NARP), Leigh syndrome (MILS), and encephalo (cardio) myopathy., On the other hand, quantitative deficits present serious symptoms and usually fatal in newborns with hyperlactacidemia, hypertrophic cardiomyopathy, and high levels of 3-methylglutaconic acid.,
An abnormal ROS production can overload the cerebral antioxidant defense system leading to further cell death and degeneration. Numerous evidence have indicated oxidative stress as a key factor in stroke, pointing to mitochondria as potential target to treat this disease. In addition to mitochondrial dysfunction, alternative mechanisms can contribute to oxidative stress. NADPH oxidases (NOX) in microglia, neurons, and endothelial cells represent significant ROS sources during stroke. NOX2, a member of NOX family located in brain phagocytes, is a key factor in the stroke-dependent ROS production leading to cell death. As a consequence, the inhibition of NOX activity might be suitable therapeutic strategy for the treatment of stroke.
As discussed above, mitochondria may trigger apoptotic cell death. The apoptotic pathway is characterized by several mitochondria-centered events, such as cytochrome c release, modifications in the MRC, loss of mitochondrial membrane potential, impaired cellular redox state, and implicating the action of pro- and anti-apoptotic B-cell lymphoma 2 (Bcl-2) proteins. Bcl-2 family members have a key role in the cytosolic release of mitochondrial molecules that activate the effectors caspases, cysteine proteases involved in degradation, and removal of cellular components. Two different pathways can initiate apoptosis: intrinsic and extrinsic. The intrinsic pathway is triggered by the binding of proapoptotic factors to the outer mitochondrial membrane (OMM) causing the damage of mPTP and, consequently, the release into the cytosol of proapoptotic molecules normally located in the intermembrane space of mitochondria, such as second mitochondria-derived activator of caspases (Smac), apoptosis-inducing factor (AIF), and cytochrome c. In the cytosol, Smac inhibits the inhibitor-of-apoptosis proteins, which role is to inhibit procaspase activation and caspases activity. Instead, AIF can migrate into the nucleus where induces caspase-independent chromatin condensation and large-scale DNA fragmentation following ischemia., In addition, the association of cytochrome c with APAF-1 creates the apoptosome that recruits and active the procaspase-9 in caspase-9. Once activated, caspase-9 can activate effector caspase-3. Consequently, caspase-3 activates endonucleases and proteases which causing breakdown of DNA. This controlled cell death pathway is associated with the expression of ligands for phagocytic receptors, resulting in phagocytosis., On the other hand, extrinsic pathway is triggered after binding of FasL or tumor necrosis factor to their respective receptors and promoting the assembly of the death-induced signaling complex (DISC). DISC activates procaspase-8 to caspase-8, which converge in the activation of caspase-3 and in the final part of the intrinsic pathway. In the same way, cytotoxic T-cells trigger perforin/granzyme-induced apoptosis also activating caspase-3. Apoptosis, along with necrosis and aponecrosis, can be associated to inflammation response. Moreover, an inflammatory response can be also secondary to the cell death damaging the adjacent cells with consequent extension of the primary injury. Conversely, an anti-apoptotic signaling balances the death pathway involving Akt which inhibits proapoptotic factors such as Bcl-2-associated X protein (BAX) and Bcl-2-associated-death promoter (BAD).
Excitotoxicity, characterized by large calcium cellular influx, is associated with stroke as well as traumatic brain injury and neurodegenerative diseases such as multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis, fibromyalgia, Parkinson's disease, and Huntington's disease. The activated calcium/calmodulin phosphatase calcineurin (CaN) determines the activation of proapoptotic factors. In this regard, the translocation to the OMM of activated BAD results in the inhibition of survival proteins Bcl-2 and B-cell lymphoma-extra large inducing BAX to open the mPTP causing the release of cytochrome c and the consequently formation of apoptosome. Moreover, CaN can stimulate mitochondrial fission by dephosphorylating the dynamin-related protein 1 triggering cell death. Even though mitochondrial fission is a normal process in physiological conditions, the presence of spherical mitochondrial lacking of cytochrome c is a hallmark of a pathological apoptotic condition.
| Mitochondria in Regenerative Medicine|| |
Mitochondrial impairment has been shown in stroke, neurodegenerative disorders as well as in aging and other metabolic diseases. Therefore, mitochondrial pharmacological and nonpharmacological therapy could be novel strategies to treat several diseases. Strengths and weaknesses of mitochondria based-regenerative medicine are discussed in this section.
As mentioned above, impaired mitochondrial function is implicated in ROS production., The different pathways of ROS production could be critical therapeutic targets. In this respect, the activation of sirtuin 1 (SIRT1) has been investigated. SIRT1 is a NAD-dependent deacetylase with a main role of sensor of redox state and energy reducing oxidative stress and improving mitochondrial function., It has been shown its crucial function in metabolism of lipids and glucose through insulin signaling in the liver, skeletal muscle, and adipose tissue., SIRT1 induces mitochondrial biogenesis and glucose uptake, through activation of PPARs and PGC1, as well as reduce inflammation and oxidative stress., Resveratrol, an activator of SIRT1, can act like a free radical scavenger. It has been shown that the pretreatment with resveratrol is neuroprotective following cerebral ischemia through SIRT1–UCP2 pathway.
It has long been established that mitochondria are extremely dynamic organelles, undergoing constant morphological remodeling through fission and fusion events crucial for their functions, transport along axons, and survival of the cell. Imbalance in these events underlies several diseases and as such becomes strategic target for new therapies. In this regard, drug inhibitors of fission (e.g., mdivi-1, dynasore, and P110) and activators of fusion, such as leflunomide, have been investigated, and have proved to reduce oxidative stress and offer neuroprotection and improvement of energy metabolism following hypoxia.,,,,,
Purines act as neurotransmitters and their signaling represents the link between neuronal activity energy charge and homeostasis. It has been shown that the modulation of purinergic pathways may be a novel therapeutic strategy for the treatment of stroke. In particular, purinergic receptor agonists regulate the Ca2+ levels reducing the glutamate release and, consequently, the excitotoxicity following stroke. Moreover, the activation of P2Y1 receptor has been associated with increased astrocyte mitochondrial metabolism and reduced infarct size and edema formation. Other studies showed that purinergic modulation resulted in normalization of mPTP with a consequent reduction of apoptosis.,
Large interest is arising for methylene blue, currently approved by the FDA for the treatment of Alzheimer's and Parkinson's diseases, for stroke patients. It has been shown that methylene blue can modulate the electrons flow through the ETC. In particular, being a carrier of electrons between NADH and cytochrome c, it can allow electrons to bypass Complex I and III resulting in decrease of electron leakage and improvement in ATP production along with a consequent reduction of ROS and oxidative stress. Moreover, in an in vitro stroke model, methylene blue increased the activity of Complex IV improving the mitochondrial function. In addition, in a rat stroke model, methylene blue restored cerebral blood flow and glucose uptake to normal conditions as well as reduced the infarct size leading to improved behavioral functions. Taken together, these studies support the efficacy of methylene blue for stroke treatment.
Detrimental effects caused by ROS accumulation following stroke are mitigated by conversion of superoxide to hydrogen peroxide through mitochondrial superoxide dismutase 2 (SOD2 or MnSOD).,, Overexpression of SOD2 and its cytoplasmic counterpart SOD1 (or Cu/Zn SOD) decrease deficits associated with stroke., On the other hand, increase of infarct volumes leads to SOD deficiencies., Despite the beneficial effects related to SOD activity, its therapeutic utilization is hampered by its short half-life, high molecular weight, and the low oral bioavailability. To overcome the issues connected with the pharmacological application of such enzymes, SOD mimetics with lower molecular weight, high diffusion rate and permeability, lack of immunogenicity, and resistance to peroxynitrite inactivation along with elevated efficiency have been developed. Manganese (Mn) exerts a key role in the regulation of the redox activity of SOD., In this regard, Mn (III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTm4PyP) reduced cytochrome c and superoxide radical in a dose-dependent manner in a stroke model. In addition, it decreased active caspase-3 and preserved intracellular calcium level. Similarly, Mn (II) pentaazomacrocyclic mimetic M40403 targets superoxide but, interestingly, it has reported higher redox abilities then endogenous SOD when linked with triphenylphosphonium (TPP) forming the MitoSOD compound. Moreover, reduction of oxidative and nitrosative stress has been obtained with Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP). However, serious side effects such as edema formation and even increased cell death following stroke can occur. In addition, the utility of SOD mimetics in hemorrhagic stroke should be investigated.
An alternative strategy for the reduction of ROS is the use of antioxidants such as coenzyme Q, N-acetylcysteine and Vitamins C and E. Despite the well-established mechanisms of action, few clinical trials have provided evident efficacy of Vitamin E for the treatment of cardiovascular diseases. Interestingly, some antioxidants can directly target mitochondria. In experimental models of cardiac hypertrophy and aging, MitoQ, a derivative of ubiquinone is able to freely access mitochondria and decreased lipid peroxidation.,, In addition, the mitochondrial access of MitoQ has been reported extremely increased when associated with the lipophilic TPP cation. Currently, clinical trials for the treatment of PD or liver damage with MitoQ are in progress.,
Tiron, antioxidant and iron chelator, is another molecule that can penetrate in the mitochondria protecting human dermal fibroblast from photoaging damage., In several in vitro and in vivo models, MitoVit E (or [2-(3,4-dihydro-6-hydroxy-2, 5, 7, 8-tetramethyl-2H-1-benzopyran-2-yl) ethyl] triphenylphosphonium bromide) was 350-fold more potent in reducing oxidative stress than nontargeted antioxidants such as Vitamin E or its water-soluble analog trolox., Similarly, MitoPeroxidase (2-[4-(4-triphenylphosphoniobutoxy) phenyl]-1,2-benzisoselenazol)-3 (2H)-one iodide), a mitochondrially targeted analog of ebselen (glutathione peroxidase analog), protected by oxidant-induced apoptosis by catalyzing the breakdown of H2O2.
Among the mitochondria-targeted antioxidant, glutathione analogs protect the mitochondrial redox system and its signaling ability in cardiovascular diseases. Taken together, these evidence show that mitochondria-targeted antioxidants are more advantageous than the nontargeted ones., The free-radical trapping agent NXY-059 has been reported neuroprotective in stroke animal models. However, no difference between NXY-059-treated and placebo stroke patients in a large-scale clinical trial., Moreover, further investigations are needed for stilbazulenyl nitrone (STAZN) due to its elevated ability in inhibition of lipid peroxidation and its lipophilic characteristics making it highly applicable for brain delivery.,
Exercise may contribute to the recovery from different neurological disorders by inducing mitochondrial biogenesis and boosting OXPHOS capacity., Exercise has been linked to increased mitochondrial biogenesis and density, through AMPK signaling pathway and PGC1 expression modulation, leading to increased mitochondrial respiration and decreased oxidative stress.,,, Moreover, exercise may moderate the age-dependent decline in mitochondrial functions. Similarly, caloric restriction (CR) may increase lifespans and reduce negative outcomes of metabolic disorders. However, few studies in human have reported that CR reduced ROS level and improved mitochondrial functions., It has been shown that CR action may involve Sir2/SIRT1 and AMPK/PGC1 pathways improving mitochondria biogenesis and function.,
| Mitochondria Transfer as New Therapeutic Strategy|| |
The discovery of mitochondrial transfer into ischemic cells paved the way for the treatment of mitochondria dysfunction-related diseases. The demonstration of mitochondria transfer from astrocytes to ischemic neurons supports the concept to use stem cells as source of healthy mitochondria for stroke therapy.
The current stem cells repair mechanisms involve the secretion of growth factors, the direct replacement of injured neuronal cells, as well as the stimulation of migration of the endogenous neural stem cells from the neurogenic niches to the lesion site. The latest findings emphasize the replacement of dysfunctional mitochondria as a tool to restore mitochondrial function and to recover cell damage after stroke.,,, The finding that not only mitochondria but also microvesicles, lysosomes, exosomes, and endosomes can be transferred from stem cells to ischemic host cells, suggest that the stem cells may be considered as organelles donors.
It has been proposed that the transfer of mitochondrial genes may be implicated in restoring mitochondrial function, increasing respiration in cells with impaired mitochondria. However, to date, the mechanism of mitochondria transfer is still uncertain. Evidence show that the mitochondrial transfer may occur through the formation of tunneling nanotubes (TNTs) or extracellular vesicles (EVs), but the passive uptake of mitochondrial is not still confirmed. Several studies have demonstrated that stem cells can donor healthy mitochondria to different recipient cells. In an in vitro ischemic-reperfusion model, mesenchymal stem cells (MSCs) transferred their mitochondria to human umbilical vein endothelial cells (HUVECs) restoring aerobic respiration. In addition, damaged cells can produce phosphatidylserine, inducing the TNTs formation in MSCs promoting mitochondrial transfer. Similarly, TNTs mitochondrial transfer from MSCs to cardiomyocytes improved survival and reduced cellular damage in an in vitro ischemia/reperfusion model and mitochondrial transfer from MSCs to lung epithelium alleviated cigarette smoke damage.
Interestingly, along with the transfer of healthy mitochondria, the protective effect of MSCs seem to involve the endocytosis and degradation of dysfunctional mitochondria reducing the oxidative stress in damaged cells., The mitochondrial transfer may be in response to a “help me” signal from oxidative stress since it rarely occurs in healthy conditions.,, In this regard, it has been reported that the formation nanotubes and vesicles can be associated with the connexins of gap junctions allowing mitochondria transfer. Moreover, overexpression of Miro1, involved in connection and movement of mitochondria through cytoskeleton, increased mitochondrial transfer by TNTs from MSCs to stressed epithelial cells reducing inflammatory cell infiltration, cellular apoptosis, collagen deposition, and hypersecretion of mucus in the lungs.
In cancer cells, mitochondria transfer form MSCs is linked with resistance to doxorubicin and promotion of survival by increment of ATP production (50%) and content (4.5 fold). However, further investigation is granted to better understand the molecular mechanisms of the transfer process, the level of cellular damage that promotes the mitochondrial transfer as well as the signals that allow the interaction between damaged and stem cells.
Although the signaling mechanisms between mitochondria donor and recipient cells are still unclear, the TNTs formation is well-documented in vitro and in vivo studies. The formation of filopodium triggers the TNT formation, but it is retracted releasing an ultrafine structure upon arriving to recipient cell that allows unidirectional or bidirectional mitochondrial transfer.,, Mitochondrial transfer impairment has been reported when stressed cells are exposed to TNT inhibitors supporting the fundamental role of TNTs in this fine mechanism. In addition, stress can modulate TNT formation.
Mitochondrial transfer can occur also by EVs release that may be used as biomarkers for different disease., Despite the limited knowledge about this mechanism, the delivery of mitochondria by EVs promotes the recovery of mitochondrial function.,, Furthermore, cell fusion has been reported as another mechanism of mitochondrial transfer between stem cells and epithelium cells of the respiratory tract and cardiomyocytes.,, Cell fusion has been shown also after bone marrow transplantation in rodent in which leaded with liver regeneration., Extrusion of whole mitochondria or their components has been reported as an alternative mechanism of mitochondria transfer.,
Despite the presence of clinical trials for the use of stem cells for stroke, this therapeutic strategy is still experimental. By restoring cell bioenergetics proliferation, mitochondria transfer could be a promising tool for the treatment of ischemic stroke. Studies in stroke model have shown that targeting TNTs may promote mitochondria transfer., MSCs overexpressing Miro1, a key protein involved in TNT formation, increased mitochondrial transfer reducing neurovascular unit deficits after stroke. To this end, targeting key elements of mitochondria transfer could be a safe and effective therapeutic strategy for stroke.
| Conclusions|| |
ATP and nutrients depletion in the ischemic penumbral implicate the key role of mitochondria in stroke pathology. The rapid degeneration of the penumbral neurovascular unit requires the urgent identification of novel and effective therapeutic strategy for stroke. Recent findings of mitochondria transfer, by TNT formation, EVs or cellular fusion, and its potential to restore mitochondrial function in promoting cell survival in several preclinical trials support stem cell-mediated mitochondria transfer therapies for stroke. Further investigations are needed to advance our knowledge on mitochondria transfer, and consequently, its application for the treatment of stroke and other mitochondrial dysfunction-related diseases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bansal S, Sangha KS, Khatri P. Drug treatment of acute ischemic stroke. Am J Cardiovasc Drugs 2013;13:57-69.
Schiavone S, Trabace L. Small molecules: Therapeutic application in neuropsychiatric and neurodegenerative disorders. Molecules 2018;23:E411.
Sawada H, Nishimura N, Suzuki E, Zhuang J, Hasegawa K, Takamatsu H, et al.
SMTP-7, a novel small-molecule thrombolytic for ischemic stroke: A study in rodents and primates. J Cereb Blood Flow Metab 2014;34:235-41.
Tajiri N, Quach DM, Kaneko Y, Wu S, Lee D, Lam T, et al.
NSI-189, a small molecule with neurogenic properties, exerts behavioral, and neurostructural benefits in stroke rats. J Cell Physiol 2017;232:2731-40.
Napoli E, Song G, Schneider A, Hagerman R, Eldeeb MA, Azarang A, et al.
Warburg effect linked to cognitive-executive deficits in FMR1 premutation. FASEB J 2016;30:3334-51.
Peng YT, Chen P, Ouyang RY, Song L. Multifaceted role of prohibitin in cell survival and apoptosis. Apoptosis 2015;20:1135-49.
Bergman O, Ben-Shachar D. Mitochondrial oxidative phosphorylation system (OXPHOS) deficits in schizophrenia: Possible interactions with cellular processes. Can J Psychiatry 2016;61:457-69.
Wang Y, Mohsen AW, Mihalik SJ, Goetzman ES, Vockley J. Evidence for physical association of mitochondrial fatty acid oxidation and oxidative phosphorylation complexes. J Biol Chem 2010;285:29834-41.
Bovo E, Mazurek SR, de Tombe PP, Zima AV. Increased energy demand during adrenergic receptor stimulation contributes to Ca(2+) wave generation. Biophys J 2015;109:1583-91.
Muller FL, Liu Y, Van Remmen H. Complex III releases superoxide to both sides of the inner mitochondrial membrane. J Biol Chem 2004;279:49064-73.
Du F, Zhu XH, Zhang Y, Friedman M, Zhang N, Ugurbil K, et al.
Tightly coupled brain activity and cerebral ATP metabolic rate. Proc Natl Acad Sci U S A 2008;105:6409-14.
Silzer TK, Phillips NR. Etiology of type 2 diabetes and Alzheimer's disease: Exploring the mitochondria. Mitochondrion 2018. pii: S1567-7249(17)30339-2.
Zeng XS, Geng WS, Jia JJ, Chen L, Zhang PP. Cellular and molecular basis of neurodegeneration in Parkinson disease. Front Aging Neurosci 2018;10:109.
Karabatsiakis A, Böck C, Salinas-Manrique J, Kolassa S, Calzia E, Dietrich DE, et al.
Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression. Transl Psychiatry 2014;4:e397.
Prabakaran S, Swatton JE, Ryan MM, Huffaker SJ, Huang JT, Griffin JL, et al.
Mitochondrial dysfunction in schizophrenia: Evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry 2004;9:684-97, 643.
Napoli E, Wong S, Giulivi C. Evidence of reactive oxygen species-mediated damage to mitochondrial DNA in children with typical autism. Mol Autism 2013;4:2.
Napoli E, Wong S, Hertz-Picciotto I, Giulivi C. Deficits in bioenergetics and impaired immune response in granulocytes from children with autism. Pediatrics 2014;133:e1405-10.
Tuttolomondo A, Pecoraro R, Simonetta I, Miceli S, Arnao V, Licata G, et al.
Neurological complications of Anderson-Fabry disease. Curr Pharm Des 2013;19:6014-30.
Tuttolomondo A, Pecoraro R, Simonetta I, Miceli S, Pinto A, Licata G. Anderson-Fabry disease: A multiorgan disease. Curr Pharm Des 2013;19:5974-96.
Lücke T, Höppner W, Schmidt E, Illsinger S, Das AM. Fabry disease: Reduced activities of respiratory chain enzymes with decreased levels of energy-rich phosphates in fibroblasts. Mol Genet Metab 2004;82:93-7.
Stonesifer C, Corey S, Ghanekar S, Diamandis Z, Acosta SA, Borlongan CV. Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol 2017;158:94-131.
Jauch EC, Saver JL, Adams HP Jr. Bruno A, Connors JJ, Demaerschalk BM, et al.
Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2013;44:870-947.
Kelly-Hayes M. Influence of age and health behaviors on stroke risk: Lessons from longitudinal studies. J Am Geriatr Soc 2010;58 Suppl 2:S325-8.
Singhal AB, Biller J, Elkind MS, Fullerton HJ, Jauch EC, Kittner SJ, et al.
Recognition and management of stroke in young adults and adolescents. Neurology 2013;81:1089-97.
Sun MS, Jin H, Sun X, Huang S, Zhang FL, Guo ZN, et al.
Free radical damage in ischemia-reperfusion injury: An obstacle in acute ischemic stroke after revascularization therapy. Oxid Med Cell Longev 2018;2018:3804979.
Dalkara T, Arsava EM. Can restoring incomplete microcirculatory reperfusion improve stroke outcome after thrombolysis? J Cereb Blood Flow Metab 2012;32:2091-9.
Langhorne P, Bernhardt J, Kwakkel G. Stroke rehabilitation. Lancet 2011;377:1693-702.
Honda HM, Korge P, Weiss JN. Mitochondria and ischemia/reperfusion injury. Ann N
Y Acad Sci 2005;1047:248-58.
Kann O, Kovács R. Mitochondria and neuronal activity. Am J Physiol Cell Physiol 2007;292:C641-57.
Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J 2011;435:297-312.
Shivakumar A, Yogendra Kumar MS. Critical review on the analytical mechanistic steps in the evaluation of antioxidant activity. Crit Rev Anal Chem 2018;48:214-36.
Murphy MP. How mitochondria produce reactive oxygen species. Biochem J 2009;417:1-3.
Yu E, Mercer J, Bennett M. Mitochondria in vascular disease. Cardiovasc Res 2012;95:173-82.
Schägger H, de Coo R, Bauer MF, Hofmann S, Godinot C, Brandt U. Significance of respirasomes for the assembly/stability of human respiratory chain complex I. J Biol Chem 2004;279:36349-53.
Chaban Y, Boekema EJ, Dudkina NV. Structures of mitochondrial oxidative phosphorylation supercomplexes and mechanisms for their stabilisation. Biochim Biophys Acta 2014;1837:418-26.
Thorburn DR. Mitochondrial disorders: Prevalence, myths and advances. J Inherit Metab Dis 2004;27:349-62.
Distelmaier F, Koopman WJ, van den Heuvel LP, Rodenburg RJ, Mayatepek E, Willems PH, et al.
Mitochondrial complex I deficiency: From organelle dysfunction to clinical disease. Brain 2009;132:833-42.
Swerdlow RH. The neurodegenerative mitochondriopathies. J Alzheimers Dis 2009;17:737-51.
Smeitink J, van den Heuvel L, DiMauro S. The genetics and pathology of oxidative phosphorylation. Nat Rev Genet 2001;2:342-52.
Duchen MR. Mitochondria in health and disease: Perspectives on a new mitochondrial biology. Mol Aspects Med 2004;25:365-451.
Dröge W. Free radicals in the physiological control of cell function. Physiol Rev 2002;82:47-95.
Hoekstra AS, Bayley JP. The role of complex II in disease. Biochim Biophys Acta 2013;1827:543-51.
Lemarie A, Huc L, Pazarentzos E, Mahul-Mellier AL, Grimm S. Specific disintegration of complex II succinate: ubiquinone oxidoreductase links pH changes to oxidative stress for apoptosis induction. Cell Death Differ 2011;18:338-49.
Hong S, Kim JY, Hwang J, Shin KS, Kang SJ. Heptachlor induced mitochondria-mediated cell death via impairing electron transport chain complex III. Biochem Biophys Res Commun 2013;437:632-6.
Freire C, Koifman S. Pesticide exposure and Parkinson's disease: Epidemiological evidence of association. Neurotoxicology 2012;33:947-71.
Andreu AL, Hanna MG, Reichmann H, Bruno C, Penn AS, Tanji K, et al.
Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N
Engl J Med 1999;341:1037-44.
Marin-Garcia J, Hu Y, Ananthakrishnan R, Pierpont ME, Pierpont GL, Goldenthal MJ. A point mutation in the cytb gene of cardiac mtDNA associated with complex III deficiency in ischemic cardiomyopathy. Biochem Mol Biol Int 1996;40:487-95.
Shoubridge EA. Cytochrome c oxidase deficiency. Am J Med Genet 2001;106:46-52.
Diaz F. Cytochrome c oxidase deficiency: Patients and animal models. Biochim Biophys Acta 2010;1802:100-10.
Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 2007;83:84-92.
Bonora M, Wieckowsk MR, Chinopoulos C, Kepp O, Kroemer G, Galluzzi L, et al.
Molecular mechanisms of cell death: Central implication of ATP synthase in mitochondrial permeability transition. Oncogene 2015;34:1608.
Paumard P, Vaillier J, Coulary B, Schaeffer J, Soubannier V, Mueller DM, et al.
The ATP synthase is involved in generating mitochondrial cristae morphology. EMBO J 2002;21:221-30.
Rodenburg RJ. Biochemical diagnosis of mitochondrial disorders. J Inherit Metab Dis 2011;34:283-92.
Houstek J, Pícková A, Vojtísková A, Mrácek T, Pecina P, Jesina P. Mitochondrial diseases and genetic defects of ATP synthase. Biochim Biophys Acta 2006;1757:1400-5.
Schon EA, Santra S, Pallotti F, Girvin ME. Pathogenesis of primary defects in mitochondrial ATP synthesis. Semin Cell Dev Biol 2001;12:441-8.
Tuppen HA, Blakely EL, Turnbull DM, Taylor RW. Mitochondrial DNA mutations and human disease. Biochim Biophys Acta 2010;1797:113-28.
Reeve AK, Krishnan KJ, Turnbull D. Mitochondrial DNA mutations in disease, aging, and neurodegeneration. Ann N
Y Acad Sci 2008;1147:21-9.
Radak D, Resanovic I, Isenovic ER. Link between oxidative stress and acute brain ischemia. Angiology 2014;65:667-76.
El-Benna J, Dang PM, Gougerot-Pocidalo MA, Marie JC, Braut-Boucher F. P47phox, the phagocyte NADPH oxidase/NOX2 organizer: Structure, phosphorylation and implication in diseases. Exp Mol Med 2009;41:217-25.
Carbone F, Teixeira PC, Braunersreuther V, Mach F, Vuilleumier N, Montecucco F. Pathophysiology and treatments of oxidative injury in ischemic stroke: Focus on the phagocytic NADPH oxidase 2. Antioxid Redox Signal 2015;23:460-89.
Wang C, Youle R. Cell biology: Form follows function for mitochondria. Nature 2016;530:288-9.
Li J, Yuan J. Caspases in apoptosis and beyond. Oncogene 2008;27:6194-206.
Krautwald S, Ziegler E, Rölver L, Linkermann A, Keyser KA, Steen P, et al.
Effective blockage of both the extrinsic and intrinsic pathways of apoptosis in mice by TAT-crmA. J Biol Chem 2010;285:19997-20005.
Giorgi C, Baldassari F, Bononi A, Bonora M, De Marchi E, Marchi S, et al.
Mitochondrial Ca(2+) and apoptosis. Cell Calcium 2012;52:36-43.
Yang S, Zhao X, Xu H, Chen F, Xu Y, Li Z, et al
. AKT2 blocks nucleus translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) while promoting caspase activation during cardiac ischemia. Int J Mol Sci 2017;18: E565.
Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, et al.
Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 1999;397:441-6.
Lauber K, Bohn E, Kröber SM, Xiao YJ, Blumenthal SG, Lindemann RK, et al.
Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 2003;113:717-30.
Shklyar B, Levy-Adam F, Mishnaevski K, Kurant E. Caspase activity is required for engulfment of apoptotic cells. Mol Cell Biol 2013;33:3191-201.
Kober AM, Legewie S, Pforr C, Fricker N, Eils R, Krammer PH, et al.
Caspase-8 activity has an essential role in CD95/Fas-mediated MAPK activation. Cell Death Dis 2011;2:e212.
Golstein P, Griffiths GM. An early history of T cell-mediated cytotoxicity. Nat Rev Immunol 2018;18:527-35.
Formigli L, Papucci L, Tani A, Schiavone N, Tempestini A, Orlandini GE, et al.
Aponecrosis: Morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol 2000;182:41-9.
Crowley MG, Liska MG, Borlongan CV. Stem cell therapy for sequestering neuroinflammation in traumatic brain injury: An update on exosome-targeting to the spleen. J Neurosurg Sci 2017;61:291-302.
Yamaguchi H, Wang HG. The protein kinase PKB/Akt regulates cell survival and apoptosis by inhibiting bax conformational change. Oncogene 2001;20:7779-86.
Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, et al.
Ca2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999;284:339-43.
Chandra D, Liu JW, Tang DG. Early mitochondrial activation and cytochrome c up-regulation during apoptosis. J Biol Chem 2002;277:50842-54.
Cereghetti GM, Costa V, Scorrano L. Inhibition of drp1-dependent mitochondrial fragmentation and apoptosis by a polypeptide antagonist of calcineurin. Cell Death Differ 2010;17:1785-94.
Gao W, Pu Y, Luo KQ, Chang DC. Temporal relationship between cytochrome c release and mitochondrial swelling during UV-induced apoptosis in living HeLa cells. J Cell Sci 2001;114:2855-62.
Cha MY, Kim DK, Mook-Jung I. The role of mitochondrial DNA mutation on neurodegenerative diseases. Exp Mol Med 2015;47:e150.
Kwong JQ, Beal MF, Manfredi G. The role of mitochondria in inherited neurodegenerative diseases. J Neurochem 2006;97:1659-75.
Ou X, Lee MR, Huang X, Messina-Graham S, Broxmeyer HE. SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress. Stem Cells 2014;32:1183-94.
Yu J, Auwerx J. Protein deacetylation by SIRT1: An emerging key post-translational modification in metabolic regulation. Pharmacol Res 2010;62:35-41.
Liang F, Kume S, Koya D. SIRT1 and insulin resistance. Nat Rev Endocrinol 2009;5:367-73.
Lu M, Sarruf DA, Li P, Osborn O, Sanchez-Alavez M, Talukdar S, et al.
Neuronal sirt1 deficiency increases insulin sensitivity in both brain and peripheral tissues. J Biol Chem 2013;288:10722-35.
Rodgers JT, Lerin C, Gerhart-Hines Z, Puigserver P. Metabolic adaptations through the PGC-1 alpha and SIRT1 pathways. FEBS Lett 2008;582:46-53.
Chong ZZ, Shang YC, Wang S, Maiese K. SIRT1: New avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets 2012;16:167-78.
Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 2005;280:17187-95.
Della-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA. Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience 2009;159:993-1002.
Wang W, Karamanlidis G, Tian R. Novel targets for mitochondrial medicine. Sci Transl Med 2016;8:326rv3.
Reddy PH. Inhibitors of mitochondrial fission as a therapeutic strategy for diseases with oxidative stress and mitochondrial dysfunction. J Alzheimers Dis 2014;40:245-56.
Miret-Casals L, Sebastián D, Brea J, Rico-Leo EM, Palacín M, Fernández-Salguero PM, et al.
Identification of new activators of mitochondrial fusion reveals a link between mitochondrial morphology and pyrimidine metabolism. Cell Chem Biol 2018;25:268-78.e4.
Szabo A, Sumegi K, Fekete K, Hocsak E, Debreceni B, Setalo G Jr., et al.
Activation of mitochondrial fusion provides a new treatment for mitochondria-related diseases. Biochem Pharmacol 2018;150:86-96.
Chauhan A, Vera J, Wolkenhauer O. The systems biology of mitochondrial fission and fusion and implications for disease and aging. Biogerontology 2014;15:1-2.
Lim To WK, Kumar P, Marshall JM. Hypoxia is an effective stimulus for vesicular release of ATP from human umbilical vein endothelial cells. Placenta 2015;36:759-66.
Gerasimovskaya EV, Woodward HN, Tucker DA, Stenmark KR. Extracellular ATP is a pro-angiogenic factor for pulmonary artery vasa vasorum endothelial cells. Angiogenesis 2008;11:169-82.
Lindberg D, Shan D, Ayers-Ringler J, Oliveros A, Benitez J, Prieto M, et al.
Purinergic signaling and energy homeostasis in psychiatric disorders. Curr Mol Med 2015;15:275-95.
Fields RD, Burnstock G. Purinergic signalling in neuron-glia interactions. Nat Rev Neurosci 2006;7:423-36.
Zheng W, Talley Watts L, Holstein DM, Wewer J, Lechleiter JD. P2Y1R-initiated, IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces and partially reverses ischemic neuronal damage in mouse. J Cereb Blood Flow Metab 2013;33:600-11.
Sperlágh B, Illes P. P2X7 receptor: An emerging target in central nervous system diseases. Trends Pharmacol Sci 2014;35:537-47.
Ye X, Shen T, Hu J, Zhang L, Zhang Y, Bao L, et al.
Purinergic 2X7 receptor/NLRP3 pathway triggers neuronal apoptosis after ischemic stroke in the mouse. Exp Neurol 2017;292:46-55.
Jiang Z, Duong TQ. Methylene blue treatment in experimental ischemic stroke: A mini review. Brain Circ 2016;2:48-53.
] [Full text]
Wen Y, Li W, Poteet EC, Xie L, Tan C, Yan LJ, et al.
Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem 2011;286:16504-15.
Poteet E, Winters A, Yan LJ, Shufelt K, Green KN, Simpkins JW, et al.
Neuroprotective actions of methylene blue and its derivatives. PLoS One 2012;7:e48279.
Huang S, Du F, Shih YY, Shen Q, Gonzalez-Lima F, Duong TQ. Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia. Neuroimage 2013;72:237-42.
Sakamoto T, Imai H. Hydrogen peroxide produced by superoxide dismutase SOD-2 activates sperm in Caenorhabditis elegans
. J Biol Chem 2017;292:14804-13.
Van Raamsdonk JM, Hekimi S. Superoxide dismutase is dispensable for normal animal lifespan. Proc Natl Acad Sci U S A 2012;109:5785-90.
Chen H, Yoshioka H, Kim GS, Jung JE, Okami N, Sakata H, et al.
Oxidative stress in ischemic brain damage: Mechanisms of cell death and potential molecular targets for neuroprotection. Antioxid Redox Signal 2011;14:1505-17.
Coucha M, Li W, Hafez S, Abdelsaid M, Johnson MH, Fagan SC, et al.
SOD1 overexpression prevents acute hyperglycemia-induced cerebral myogenic dysfunction: Relevance to contralateral hemisphere and stroke outcomes. Am J Physiol Heart Circ Physiol 2015;308:H456-66.
Muscoli C, Cuzzocrea S, Riley DP, Zweier JL, Thiemermann C, Wang ZQ, et al.
On the selectivity of superoxide dismutase mimetics and its importance in pharmacological studies. Br J Pharmacol 2003;140:445-60.
Batinić-Haberle I, Rebouças JS, Spasojević I. Superoxide dismutase mimics: Chemistry, pharmacology, and therapeutic potential. Antioxid Redox Signal 2010;13:877-918.
Kelso GF, Maroz A, Cochemé HM, Logan A, Prime TA, Peskin AV, et al.
Amitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic. Chem Biol 2012;19:1237-46.
Huang HF, Guo F, Cao YZ, Shi W, Xia Q. Neuroprotection by manganese superoxide dismutase (MnSOD) mimics: Antioxidant effect and oxidative stress regulation in acute experimental stroke. CNS Neurosci Ther 2012;18:811-8.
Hirschberg K, Radovits T, Korkmaz S, Loganathan S, Zöllner S, Seidel B, et al.
Combined superoxide dismutase mimetic and peroxynitrite scavenger protects against neointima formation after endarterectomy in association with decreased proliferation and nitro-oxidative stress. Eur J Vasc Endovasc Surg 2010;40:168-75.
Szabo A, Balog M, Mark L, Montsko G, Turi Z, Gallyas F
Jr., et al.
Induction of mitochondrial destabilization and necrotic cell death by apolar mitochondria-directed SOD mimetics. Mitochondrion 2011;11:476-87.
Sheu SS, Nauduri D, Anders MW. Targeting antioxidants to mitochondria: A new therapeutic direction. Biochim Biophys Acta 2006;1762:256-65.
Hu Q, Ren J, Li G, Wu J, Wu X, Wang G, et al.
The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway. Cell Death Dis 2018;9:403.
Graham D, Huynh NN, Hamilton CA, Beattie E, Smith RA, Cochemé HM, et al.
Mitochondria-targeted antioxidant mitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 2009;54:322-8.
Skulachev VP, Anisimov VN, Antonenko YN, Bakeeva LE, Chernyak BV, Erichev VP, et al.
An attempt to prevent senescence: A mitochondrial approach. Biochim Biophys Acta 2009;1787:437-61.
Ojano-Dirain CP, Antonelli PJ, Le Prell CG. Mitochondria-targeted antioxidant mitoQ reduces gentamicin-induced ototoxicity. Otol Neurotol 2014;35:533-9.
Gane EJ, Weilert F, Orr DW, Keogh GF, Gibson M, Lockhart MM, et al.
The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients. Liver Int 2010;30:1019-26.
Snow BJ, Rolfe FL, Lockhart MM, Frampton CM, O'Sullivan JD, Fung V, et al.
Adouble-blind, placebo-controlled study to assess the mitochondria-targeted antioxidant MitoQ as a disease-modifying therapy in Parkinson's disease. Mov Disord 2010;25:1670-4.
Oyewole AO, Birch-Machin MA. Mitochondria-targeted antioxidants. FASEB J 2015;29:4766-71.
Fang Y, Hu XH, Jia ZG, Xu MH, Guo ZY, Gao FH, et al.
Tiron protects against UVB-induced senescence-like characteristics in human dermal fibroblasts by the inhibition of superoxide anion production and glutathione depletion. Australas J Dermatol 2012;53:172-80.
Mao G, Kraus GA, Kim I, Spurlock ME, Bailey TB, Zhang Q, et al.
Amitochondria-targeted Vitamin E derivative decreases hepatic oxidative stress and inhibits fat deposition in mice. J Nutr 2010;140:1425-31.
Filipovska A, Kelso GF, Brown SE, Beer SM, Smith RA, Murphy MP. Synthesis and characterization of a triphenylphosphonium-conjugated peroxidase mimetic. Insights into the interaction of ebselen with mitochondria. J Biol Chem 2005;280:24113-26.
Mailloux RJ. Application of mitochondria-targeted pharmaceuticals for the treatment of heart disease. Curr Pharm Des 2016;22:4763-79.
Yin X, Manczak M, Reddy PH. Mitochondria-targeted molecules MitoQ and SS31 reduce mutant Huntingtin-induced mitochondrial toxicity and synaptic damage in Huntington's disease. Hum Mol Genet 2016;25:1739-53.
Manczak M, Mao P, Calkins MJ, Cornea A, Reddy AP, Murphy MP, et al.
Mitochondria-targeted antioxidants protect against amyloid-beta toxicity in Alzheimer's disease neurons. J Alzheimers Dis 2010;20 Suppl 2:S609-31.
Bath PM, Gray LJ, Bath AJ, Buchan A, Miyata T, Green AR. Effects of NXY-059 in experimental stroke: An individual animal meta-analysis. Br J Pharmacol 2009;157:1157-71.
Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al.
NXY-059 for the treatment of acute ischemic stroke. N
Engl J Med 2007;357:562-71.
Diener HC, Lees KR, Lyden P, Grotta J, Davalos A, Davis SM, et al.
NXY-059 for the treatment of acute stroke: Pooled analysis of the SAINT I and II trials. Stroke 2008;39:1751-8.
Ley JJ, Vigdorchik A, Belayev L, Zhao W, Busto R, Khoutorova L, et al.
Stilbazulenyl nitrone, a second-generation azulenyl nitrone antioxidant, confers enduring neuroprotection in experimental focal cerebral ischemia in the rat: Neurobehavior, histopathology, and pharmacokinetics. J Pharmacol Exp Ther 2005;313:1090-100.
Becker DA, Ley JJ, Echegoyen L, Alvarado R. Stilbazulenyl nitrone (STAZN): A nitronyl-substituted hydrocarbon with the potency of classical phenolic chain-breaking antioxidants. J Am Chem Soc 2002;124:4678-84.
Steiner JL, Murphy EA, McClellan JL, Carmichael MD, Davis JM. Exercise training increases mitochondrial biogenesis in the brain. J Appl Physiol (1985) 2011;111:1066-71.
Vincent G, Lamon S, Gant N, Vincent PJ, MacDonald JR, Markworth JF, et al.
Changes in mitochondrial function and mitochondria associated protein expression in response to 2-weeks of high intensity interval training. Front Physiol 2015;6:51.
Richter EA, Ruderman NB. AMPK and the biochemistry of exercise: Implications for human health and disease. Biochem J 2009;418:261-75.
Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 2007;104:12017-22.
Lumini JA, Magalhães J, Oliveira PJ, Ascensão A. Beneficial effects of exercise on muscle mitochondrial function in diabetes mellitus. Sports Med 2008;38:735-50.
Huertas JR, Al Fazazi S, Hidalgo-Gutierrez A, López LC, Casuso RA. Antioxidant effect of exercise: Exploring the role of the mitochondrial complex I superassembly. Redox Biol 2017;13:477-81.
Kim Y, Triolo M, Hood DA. Impact of aging and exercise on mitochondrial quality control in skeletal muscle. Oxid Med Cell Longev 2017;2017:3165396.
Redman LM, Ravussin E. Caloric restriction in humans: Impact on physiological, psychological, and behavioral outcomes. Antioxid Redox Signal 2011;14:275-87.
López-Lluch G, Hunt N, Jones B, Zhu M, Jamieson H, Hilmer S, et al.
Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency. Proc Natl Acad Sci U S A 2006;103:1768-73.
Cantó C, Auwerx J. Caloric restriction, SIRT1 and longevity. Trends Endocrinol Metab 2009;20:325-31.
Tang BL. Sirt1 and the mitochondria. Mol Cells 2016;39:87-95.
Hayakawa K, Esposito E, Wang X, Terasaki Y, Liu Y, Xing C, et al.
Transfer of mitochondria from astrocytes to neurons after stroke. Nature 2016;535:551-5.
Lee JY, Xu K, Nguyen H, Guedes VA, Borlongan CV, Acosta SA. Stem cell-induced biobridges as possible tools to aid neuroreconstruction after CNS injury. Front Cell Dev Biol 2017;5:51.
Hayakawa K, Chan SJ, Mandeville ET, Park JH, Bruzzese M, Montaner J, et al.
Protective effects of endothelial progenitor cell-derived extracellular mitochondria in brain endothelium. Stem Cells 2018;36:1404-10.
Chou SH, Lan J, Esposito E, Ning M, Balaj L, Ji X, et al.
Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage. Stroke 2017;48:2231-7.
Lin HY, Liou CW, Chen SD, Hsu TY, Chuang JH, Wang PW, et al.
Mitochondrial transfer from wharton's jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function. Mitochondrion 2015;22:31-44.
Acquistapace A, Bru T, Lesault PF, Figeac F, Coudert AE, le Coz O, et al.
Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells 2011;29:812-24.
Rogers RS, Bhattacharya J. When cells become organelle donors. Physiology (Bethesda) 2013;28:414-22.
Cho YM, Kim JH, Kim M, Park SJ, Koh SH, Ahn HS, et al.
Mesenchymal stem cells transfer mitochondria to the cells with virtually no mitochondrial function but not with pathogenic mtDNA mutations. PLoS One 2012;7:e32778.
Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci U S A 2006;103:1283-8.
Torralba D, Baixauli F, Sánchez-Madrid F. Mitochondria know no boundaries: Mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol 2016;4:107.
Berridge MV, McConnell MJ, Grasso C, Bajzikova M, Kovarova J, Neuzil J. Horizontal transfer of mitochondria between mammalian cells: Beyond co-culture approaches. Curr Opin Genet Dev 2016;38:75-82.
Liu K, Ji K, Guo L, Wu W, Lu H, Shan P, et al.
Mesenchymal stem cells rescue injured endothelial cells in an in vitro
ischemia-reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res 2014;92:10-8.
Han H, Hu J, Yan Q, Zhu J, Zhu Z, Chen Y, et al.
Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro
simulated ischemia/reperfusion model. Mol Med Rep 2016;13:1517-24.
Li X, Zhang Y, Yeung SC, Liang Y, Liang X, Ding Y, et al.
Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage. Am J Respir Cell Mol Biol 2014;51:455-65.
Plotnikov EY, Khryapenkova TG, Vasileva AK, Marey MV, Galkina SI, Isaev NK, et al.
Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. J Cell Mol Med 2008;12:1622-31.
Mahrouf-Yorgov M, Augeul L, Da Silva CC, Jourdan M, Rigolet M, Manin S, et al.
Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ 2017;24:1224-38.
Hayakawa K, Bruzzese M, Chou SH, Ning M, Ji X, Lo EH. Extracellular mitochondria for therapy and diagnosis in acute central nervous system injury. JAMA Neurol 2018;75:119-22.
Maki T, Morancho A, Martinez-San Segundo P, Hayakawa K, Takase H, Liang AC, et al.
Endothelial progenitor cell secretome and oligovascular repair in a mouse model of prolonged cerebral hypoperfusion. Stroke 2018;49:1003-10.
Islam MN, Das SR, Emin MT, Wei M, Sun L, Westphalen K, et al.
Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012;18:759-65.
Ahmad T, Mukherjee S, Pattnaik B, Kumar M, Singh S, Kumar M, et al.
Miro1 regulates intercellular mitochondrial transport and amp; enhances mesenchymal stem cell rescue efficacy. EMBO J 2014;33:994-1010.
Moschoi R, Imbert V, Nebout M, Chiche J, Mary D, Prebet T, et al.
Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood 2016;128:253-64.
Bukoreshtliev NV, Wang X, Hodneland E, Gurke S, Barroso JF, Gerdes HH, et al.
Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells. FEBS Lett 2009;583:1481-8.
Rustom A, Saffrich R, Markovic I, Walther P, Gerdes HH. Nanotubular highways for intercellular organelle transport. Science 2004;303:1007-10.
He K, Shi X, Zhang X, Dang S, Ma X, Liu F, et al.
Long-distance intercellular connectivity between cardiomyocytes and cardiofibroblasts mediated by membrane nanotubes. Cardiovasc Res 2011;92:39-47.
Sun X, Wang Y, Zhang J, Tu J, Wang XJ, Su XD, et al.
Tunneling-nanotube direction determination in neurons and astrocytes. Cell Death Dis 2012;3:e438.
Lou E, Fujisawa S, Morozov A, Barlas A, Romin Y, Dogan Y, et al.
Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. PLoS One 2012;7:e33093.
Mittelbrunn M, Sánchez-Madrid F. Intercellular communication: Diverse structures for exchange of genetic information. Nat Rev Mol Cell Biol 2012;13:328-35.
Pitt JM, Kroemer G, Zitvogel L. Extracellular vesicles: Masters of intercellular communication and potential clinical interventions. J Clin Invest 2016;126:1139-43.
Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A, et al.
Differentiation, cell fusion, and nuclear fusion during ex vivo
repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci U S A 2003;100:2397-402.
Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K, et al.
Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003;425:968-73.
Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, et al.
Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction. Proc Natl Acad Sci U S A 2003;100:12313-8.
Vassilopoulos G, Wang PR, Russell DW. Transplanted bone marrow regenerates liver by cell fusion. Nature 2003;422:901-4.
Wang X, Willenbring H, Akkari Y, Torimaru Y, Foster M, Al-Dhalimy M, et al.
Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003;422:897-901.
Nakajima A, Kurihara H, Yagita H, Okumura K, Nakano H. Mitochondrial extrusion through the cytoplasmic vacuoles during cell death. J Biol Chem 2008;283:24128-35.
Caielli S, Athale S, Domic B, Murat E, Chandra M, Banchereau R, et al.
Oxidized mitochondrial nucleoids released by neutrophils drive type I interferon production in human lupus. J Exp Med 2016;213:697-713.
Napoli E, Lippert T, Borlongan CV. Stem cell therapy: Repurposing cell-based regenerative medicine beyond cell replacement. Adv Exp Med Biol 2018;1079:87-91.
Babenko VA, Silachev DN, Popkov VA, Zorova LD, Pevzner IB, Plotnikov EY, et al
. Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells (MMSC) to neural cells and improves the efficacy of cell recovery. Molecules 2018;23:E687.
|This article has been cited by|
||Targeting Mitochondrial bioenergetics as a promising therapeutic strategy in metabolic and neurodegenerative diseases
| ||Gurjit Kaur Bhatti, Anshika Gupta, Paras Pahwa, Naina Khullar, Satwinder Singh, Umashanker Navik, Shashank Kumar, Sarabjit Singh Mastana, Arubala P. Reddy, P. Hemachandra Reddy, Jasvinder Singh Bhatti |
| ||Biomedical Journal. 2022; |
|[Pubmed] | [DOI]|
||Identification of novel and potential PPAR? stimulators as repurposed drugs for MCAO associated brain degeneration
| ||Halima Usman, Zhen Tan, Mehreen Gul, Sajid Rashid, Tahir Ali, Fawad Ali Shah, Shupeng Li, Jing Bo Li |
| ||Toxicology and Applied Pharmacology. 2022; 446: 116055 |
|[Pubmed] | [DOI]|
||Triage Nurse-Activated Emergency Evaluation Reduced Door-to-Needle Time in Acute Ischemic Stroke Patients Treated with Intravenous Thrombolysis
| ||Xiao Liang, Wenhui Gao, Jiali Xu, Sara Saymuah, Xiaojie Wang, Jing Wang, Wenbo Zhao, Xiurong Xing, Changyuan Wang, Fangyan Liu, Lei Feng, Sijie Li, Feng Zhang |
| ||Evidence-Based Complementary and Alternative Medicine. 2022; 2022: 1 |
|[Pubmed] | [DOI]|
||Mitochondrial Transplantation Attenuates Neural Damage and Improves Locomotor Function After Traumatic Spinal Cord Injury in Rats
| ||Ming-Wei Lin, Shih-Yuan Fang, Jung-Yu C. Hsu, Chih-Yuan Huang, Po-Hsuan Lee, Chi-Chen Huang, Hui-Fang Chen, Chen-Fuh Lam, Jung-Shun Lee |
| ||Frontiers in Neuroscience. 2022; 16 |
|[Pubmed] | [DOI]|
||Oxidative Stress in Ischemia/Reperfusion Injuries following Acute Ischemic Stroke
| ||Anamaria Jurcau, Adriana Ioana Ardelean |
| ||Biomedicines. 2022; 10(3): 574 |
|[Pubmed] | [DOI]|
||Mitochondrial Implications in Cardiovascular Aging and Diseases: The Specific Role of Mitochondrial Dynamics and Shifts
| ||Anastasia V. Poznyak, Tatiana V. Kirichenko, Evgeny E. Borisov, Nikolay K. Shakhpazyan, Andrey G. Kartuesov, Alexander N. Orekhov |
| ||International Journal of Molecular Sciences. 2022; 23(6): 2951 |
|[Pubmed] | [DOI]|
||Role of Creatine Supplementation in Conditions Involving Mitochondrial Dysfunction: A Narrative Review
| ||Robert Percy Marshall, Jan-Niklas Droste, Jürgen Giessing, Richard B. Kreider |
| ||Nutrients. 2022; 14(3): 529 |
|[Pubmed] | [DOI]|
||Normobaric Oxygen (NBO) Therapy Reduces Cerebral Ischemia/Reperfusion Injury through Inhibition of Early Autophagy
| ||Meng Wang,Xiaokun Geng,Chaitu Dandu,Radhika Patel,Yuchuan Ding,Elisha R. Injeti |
| ||Evidence-Based Complementary and Alternative Medicine. 2021; 2021: 1 |
|[Pubmed] | [DOI]|
||Cerebroprotection for Acute Ischemic Stroke: Looking Ahead
| ||Patrick D. Lyden |
| ||Stroke. 2021; |
|[Pubmed] | [DOI]|
||Intranasal administration of mitochondria improves spatial memory in olfactory bulbectomized mice
| ||Natalia V Bobkova, Daria Y Zhdanova, Natalia V Belosludtseva, Nikita V Penkov, Galina D Mironova |
| ||Experimental Biology and Medicine. 2021; : 1535370221 |
|[Pubmed] | [DOI]|
||USP30 protects against oxygen-glucose deprivation/reperfusion induced mitochondrial fragmentation and ubiquitination and degradation of MFN2
| ||Chunli Chen,Haiyun Qin,Jiayu Tang,Zhiping Hu,Jieqiong Tan,Liuwang Zeng |
| ||Aging. 2021; 13(4): 6194 |
|[Pubmed] | [DOI]|
||Extracellular Mitochondria Signals in CNS Disorders
| ||Ji-Hyun Park,Kazuhide Hayakawa |
| ||Frontiers in Cell and Developmental Biology. 2021; 9 |
|[Pubmed] | [DOI]|
||Neuroprotection of Chikusetsu saponin V on transient focal cerebral ischemia/reperfusion and the underlying mechanism
| ||Tiejun Zhang,Zhengjun Li,Zhou Qin,Yi Cao,Tikun Shan,Yuan Fang,Linqiao Tang,Na Jia,Jing Jia,Zhaohui Jin,Ting Xu,Yuwen Li |
| ||Phytomedicine. 2021; : 153516 |
|[Pubmed] | [DOI]|
||Baoyuan Capsule promotes neurogenesis and neurological functional recovery through improving mitochondrial function and modulating PI3K/Akt signaling pathway
| ||Qiaohui Du,Ruixia Deng,Wenting Li,Dong Zhang,Bun Tsoi,Jiangang Shen |
| ||Phytomedicine. 2021; : 153795 |
|[Pubmed] | [DOI]|
||Microvesicles transfer mitochondria and increase mitochondrial function in brain endothelial cells
| ||Anisha DæSouza,Amelia Burch,Kandarp M. Dave,Aravind Sreeram,Michael J. Reynolds,Duncan X. Dobbins,Yashika S. Kamte,Wanzhu Zhao,Courtney Sabatelle,Gina M. Joy,Vishal Soman,Uma R. Chandran,Sruti S. Shiva,Nidia Quillinan,Paco S. Herson,Devika S. Manickam |
| ||Journal of Controlled Release. 2021; |
|[Pubmed] | [DOI]|
||The Beneficial Role of Exercise on Treating Alzheimer’s Disease by Inhibiting ß-Amyloid Peptide
| ||Zi-Xuan Tan,Fang Dong,Lin-Yu Wu,Ya-Shuo Feng,Feng Zhang |
| ||Molecular Neurobiology. 2021; |
|[Pubmed] | [DOI]|
||Targeting the blood-brain barrier for the delivery of stroke therapies
| ||Anisha DæSouza,Kandarp M. Dave,R. Anne Stetler,Devika S. Manickam |
| ||Advanced Drug Delivery Reviews. 2021; |
|[Pubmed] | [DOI]|
||Inter and Intracellular mitochondrial trafficking in health and disease
| ||Santhanam Shanmughapriya,Dianne Langford,Kalimuthusamy Natarajaseenivasan |
| ||Ageing Research Reviews. 2020; : 101128 |
|[Pubmed] | [DOI]|
||Mitochondrial Transfer as a Therapeutic Strategy Against Ischemic Stroke
| ||Wei Chen,Jingjing Huang,Yueqiang Hu,Seyed Esmaeil Khoshnam,Alireza Sarkaki |
| ||Translational Stroke Research. 2020; |
|[Pubmed] | [DOI]|
||Mesenchymal Stem Cell-Mediated Mitochondrial Transfer: a Therapeutic Approach for Ischemic Stroke
| ||Meng Lu,Jindong Guo,Bowen Wu,Yuhui Zhou,Mishan Wu,Maryam Farzaneh,Seyed Esmaeil Khoshnam |
| ||Translational Stroke Research. 2020; |
|[Pubmed] | [DOI]|
||Energy Metabolism Analysis of Three Different Mesenchymal Stem Cell Populations of Umbilical Cord Under Normal and Pathologic Conditions
| ||Eleonora Russo,Jea-Young Lee,Hung Nguyen,Simona Corrao,Rita Anzalone,Giampiero La Rocca,Cesar V. Borlongan |
| ||Stem Cell Reviews and Reports. 2020; |
|[Pubmed] | [DOI]|
||Treadmill exercise attenuates cerebral ischaemic injury in rats by protecting mitochondrial function via enhancement of caveolin-1
| ||Guoyuan Pan,Huimei Zhang,Anqi Zhu,Yao Lin,Lili Zhang,Bingyun Ye,Jingyan Cheng,Weimin Shen,Lingqin Jin,Chan Liu,Qingfeng Xie,Xiang Chen |
| ||Life Sciences. 2020; : 118634 |
|[Pubmed] | [DOI]|
||Stem cell therapy in brain ischemia-the role of mitochondrial transfer
| ||Lei Huang,Cesar Reis,Warren Boling,John H Zhang |
| ||Stem Cells and Development. 2020; |
|[Pubmed] | [DOI]|
||Therapeutic use of extracellular mitochondria in CNS injury and disease
| ||Yoshihiko Nakamura,Ji-Hyun Park,Kazuhide Hayakawa |
| ||Experimental Neurology. 2020; 324: 113114 |
|[Pubmed] | [DOI]|
||The Late-Stage Protective Effect of Mito-TEMPO against Acetaminophen-Induced Hepatotoxicity in Mouse and Three-Dimensional Cell Culture Models
| ||Mohammad Abdullah-Al-Shoeb,Kenta Sasaki,Saori Kikutani,Nanami Namba,Keiichi Ueno,Yuki Kondo,Hitoshi Maeda,Toru Maruyama,Tetsumi Irie,Yoichi Ishitsuka |
| ||Antioxidants. 2020; 9(10): 965 |
|[Pubmed] | [DOI]|
||Selective brain hypothermia-induced neuroprotection against focal cerebral ischemia/reperfusion injury is associated with Fis1 inhibition
| ||Ya-Nan Tang,Gao-Feng Zhang,Huai-Long Chen,Xiao-Peng Sun,Wei-Wei Qin,Fei Shi,Li-Xin Sun,Xiao-Na Xu,Ming-Shan Wang |
| ||Neural Regeneration Research. 2020; 15(5): 903 |
|[Pubmed] | [DOI]|
||Soluble Nogo receptor 1 fusion protein protects neural progenitor cells in rats with ischemic stroke
| ||Hai-Wei He,Yue-Lin Zhang,Bao-Qi Yu,Gen Ye,Wei You,Kwok-fai So,Xin Li |
| ||Neural Regeneration Research. 2019; 14(10): 1755 |
|[Pubmed] | [DOI]|
||Zinc accumulation in mitochondria promotes ischemia-induced BBB disruption through Drp1-dependent mitochondria fission
| ||Zhifeng Qi,Wenjuan Shi,Yongmei Zhao,Xunming Ji,Ke Jian Liu |
| ||Toxicology and Applied Pharmacology. 2019; : 114601 |
|[Pubmed] | [DOI]|
||Neuroprotection by Mesenchymal Stem Cell (MSC) Administration is Enhanced by Local Cooling Infusion (LCI) in Ischemia
| ||Wenjing Wei,Di Wu,Yunxia Duan,Kenneth B. Elkin,Ankush Chandra,Longfei Guan,Changya Peng,Xiaoduo He,Chuanjie Wu,Xunming Ji,Yuchuan Ding |
| ||Brain Research. 2019; : 146406 |
|[Pubmed] | [DOI]|
||Preserving Mitochondrial Structure and Motility Promotes Recovery of White Matter After Ischemia
| ||Chinthasagar Bastian,Jerica Day,Stephen Politano,John Quinn,Sylvain Brunet,Selva Baltan |
| ||NeuroMolecular Medicine. 2019; |
|[Pubmed] | [DOI]|
||Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy
| ||Yuji Kaneko,Jea-Young Lee,Naoki Tajiri,Julian P. Tuazon,Trenton Lippert,Eleonora Russo,Seong-Jin Yu,Brooke Bonsack,Sydney Corey,Alexandreya B. Coats,Chase Kingsbury,Thomas N. Chase,Minako Koga,Cesar V. Borlongan |
| ||STEM CELLS Translational Medicine. 2019; |
|[Pubmed] | [DOI]|
||Mitochondrial dysfunction and role in spreading depolarization and seizure
| ||Patrick Toglia,Ghanim Ullah |
| ||Journal of Computational Neuroscience. 2019; |
|[Pubmed] | [DOI]|