REPORT-SCS: minimum reporting standards for spinal cord stimulation studies in spinal cord injury.

Objective.Electrical spinal cord stimulation (SCS) has emerged as a promising therapy for recovery of motor and autonomic dysfunctions following spinal cord injury (SCI). Despite the rise in studies using SCS for SCI complications, there are no standard guidelines for reporting SCS parameters in research publications, making it challenging to compare, interpret or reproduce reported effects across experimental studies.Approach.To develop guidelines for minimum reporting standards for SCS parameters in pre-clinical and clinical SCI research, we gathered an international panel of expert clinicians and scientists. Using a Delphi approach, we developed guideline items and surveyed the panel on their level of agreement for each item.Main results.There was strong agreement on 26 of the 29 items identified for establishing minimum reporting standards for SCS studies. The guidelines encompass three major SCS categories: hardware, configuration and current parameters, and the intervention.Significance.Standardized reporting of stimulation parameters will ensure that SCS studies can be easily analyzed, replicated, and interpreted by the scientific community, thereby expanding the SCS knowledge base and fostering transparency in reporting.

Perspectives on Data Sharing in Persons With Spinal Cord Injury.

Open data sharing of clinical research aims to improve transparency and support novel scientific discoveries. There are also risks, including participant identification and the potential for stigmatization. The perspectives of persons participating in research are needed to inform open data-sharing policies. The aim of the current study was to determine perspectives on data sharing in persons with spinal cord injury (SCI), including risks and benefits, and types of data people are most willing to share. A secondary aim was to examine predictors of willingness to share data. Persons with SCIs in the United States and Canada completed a survey developed and disseminated through various channels, including our community partner, the North American Spinal Cord Injury Consortium. The study collected data from 232 participants, with 52.2% from Canada and 42.2% from the United States, and the majority completed the survey in English. Most participants had previously participated in research and had been living with an SCI for ≥5 years. Overall, most participants reported that the potential benefits of data sharing outweighed the negatives, with persons with SCI seen as the most trustworthy partners for data sharing. The highest levels of concern were that information could be stolen and companies might use the information for marketing purposes. Persons with SCI were generally supportive of data sharing for research purposes. Clinical trials should consider including a statement on open data sharing in informed consents to better acknowledge the contribution of research participants in future studies.

Proinflammatory and Immunomodulatory Gene and Protein Expression Patterns in Spinal Cord and Spleen Following Acute and Chronic High Thoracic Injury.

Introduction: In addition to paralysis and loss of sensation, high-level spinal cord injury (SCI) causes sympathetic dysfunction that can lead to autonomic dysreflexia (AD) and chronic immune suppression involving splenic leukopenia. Evidence has shown that treatment with either gabapentin or blockade of TNFα mitigates maladaptive plasticity and the underlying hemodynamic dysfunction, spleen atrophy, and immune dysfunction associated with AD. Because significant improvements long term was noted following treatments only during acute stages of recovery, we sought to systematically examine changes in proinflammatory and immunomodulatory cytokines to ascertain the reason. Methods: Adult female Wistar rats underwent complete T4 spinal transection before euthanasia at systematic intervals from 3 days to 8 weeks after injury. Using qRT-PCR and meso scale discovery (MSD) assays, the gene and protein expression of TNFα and IFNγ in the spleen, upper thoracic (T4-9) and lumbosacral (L5-S6) spinal cords were analyzed. Results: We found that spleen atrophy occurs in a biphasic manner compared to naïve controls, with significant decreases in the spleen mass noted at 3 days and 8 weeks after injury. Splenic TNFα mRNA and protein levels did not change significantly over time, while IFNγ gene expression dipped acutely with trends for increased protein levels at more chronic time points. TNFα protein increased significantly only in thoracic spinal cord segments from 3 to 14 days post-injury. IFNγ mRNA and protein levels remained unelevated in injured spinal cords over time, with trends for increased protein levels at 2 and 8 weeks in the lumbosacral segments. Discussion: Novel temporal-spatial cytokine expression profiles reveal that TNFα protein levels are increased solely in upper thoracic segments after high thoracic SCI, while IFNγ remains unaltered. Splenic leukopenia and latent systemic immunosuppression are not associated with altered TNFα or IFNγ expression in the spleen or spinal cord.

LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury.

The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and enhancers of mitochondrial biogenesis, which have been shown to improve pathophysiological outcomes after TBI. However, to date, there is no effective treatment for TBI. Studies have suggested that the deletion of LDL receptor-related protein 1 (LRP1) in adult neurons or glial cells could be beneficial and promote neuronal health. In this study, we used WT and LRP1 knockout (LKO) mouse embryonic fibroblast cells to examine mitochondrial outcomes following exogenous oxidative stress. Furthermore, we developed a novel technique to measure mitochondrial morphometric dynamics using transgenic mitochondrial reporter mice mtD2g (mitochondrial-specific Dendra2 green) in a TBI model. We found that oxidative stress increased the quantity of fragmented and spherical-shaped mitochondria in the injury core of the ipsilateral cortex following TBI, whereas rod-like elongated mitochondria were seen in the corresponding contralateral cortex. Critically, LRP1 deficiency significantly decreased mitochondrial fragmentation, preserving mitochondrial function and cell growth following exogenous oxidative stress. Collectively, our results show that targeting LRP1 to improve mitochondrial function is a potential pharmacotherapeutic strategy against oxidative damage in TBI and other neurodegenerative diseases.

Delivery of mitoceuticals or respiratory competent mitochondria to sites of neurotrauma.

Herein, we review evidence that targeting mitochondrial dysfunction with 'mitoceuticals' is an effective neuroprotective strategy following neurotrauma, and that isolated exogenous mitochondria can be effectively transplanted into host spinal cord parenchyma to increase overall cellular metabolism. We further discuss control measures to ensure greatest potential for mitochondrial transfer, notably using erodible thermogelling hydrogels to deliver respiratory competent mitochondria to the injured spinal cord.

Rat Spinal Cord Injury Associated with Spasticity Leads to Widespread Changes in the Regulation of Retained Introns.

To determine molecular changes that correlate with long-term physiological changes after spinal cord injury associated with spasticity, we used a complete transection model with an injury at sacral spinal level S2, wherein tail spasms develop in rats weeks to months post-injury. Using Illumina and nanopore sequencing, we found that from 12,266 expressed genes roughly 11% (1,342) change expression levels in the rats with spasticity. The transcription factor PU.1 (Spi-1 proto-oncogene) and several of its known regulated genes were upregulated during injury, possibly reflecting changes in cellular composition. In contrast to widespread changes in gene expression, only a few changes in alternative exon usage could be detected because of injury. There were more than 1,000 changes in retained intron usage, however. Unexpectedly, most of these retained introns have not been described yet but could be validated using direct RNA nanopore sequencing. In addition to changes from injury, our model allowed regional analysis of gene expression. Comparing the segments rostral and caudal to the injury site in naïve animals showed 525 differentially regulated genes and differential regional use of retained introns. We did not detect changes in the serotonin receptor 2C editing that were implicated previously in this spinal cord injury model. Our data suggest that regulation of intron retention of polyadenylated pre-mRNA is an important regulatory mechanism in the spinal cord under both physiological and pathophysiological conditions.

Erodible thermogelling hydrogels for localized mitochondrial transplantation to the spinal cord.

We developed a thermal-gelling, erodible hydrogel system for localized delivery of viable mitochondria in vivo, as well as labeled transplanted mitochondria with specific dyes and/or genetically modified mitochondria tagged with red fluorescence protein (RFP). We also employed cell lines to optimize a hydrogel composed of methylcellulose and hyaluronic acid designed to preserve bioenergetics while facilitating mitochondrial release. We further investigated how transplantation of allogeneic or xenogeneic mitochondria into respective cell lines affects host cellular metabolism, as measured by MTS assay. We found that 70% of mitochondria are released from the hydrogel within 20 min at 37 °C, that the respiratory capacity of hydrogel-released mitochondria over 60 min was greater than those without gel, and that MTR-labeling of mitochondria is not indelible. RFP-tagged transgenic mitochondria isolated from modified SH-SY5Y human neuroblastoma cells showed effective uptake into both naïve SH-SY5Y cells and rat PC-12 cells, notably when released from hydrogel. The hydrogel both protected the mitochondria at physiological conditions in vitro while solidifying and diffusing within 60 min locally in situ. To assess metabolic effects, both cell lines were transplanted with different concentrations of SH-SY5Y or PC-12 cell line-derived mitochondria and all resulted in significant increases in metabolism at 6- and 24-hour after transplantation. Alternatively, transplanted mitochondria at highest concentration from rat brain and spinal cord tissues reduced metabolic activities after 24-hour. Along with hydrogel refinements, we are further investigating whether such metabolic changes are due to alterations in cell proliferation or the number of exogenous mitochondria incorporated into individual host cells.

Mitochondria focused neurotherapeutics for spinal cord injury.

The mitochondrion is a double membrane structured organelle involved in a variety of regulatory functions such as calcium signaling, production of adenosine triphosphate, apoptosis, reactive oxygen species generation, cell growth, and cell cycling. Impaired mitochondrial function is evident in various neurological disorders stemming from both acute and chronic neural injury. Herein, we review the role of mitochondrial regulation in maintaining cellular homeostasis, the consequences of their dysfunction in relation to pathophysiology after neurotrauma, approaches being used to promote their bioenergetic integrity for neuroprotection, and multifaceted methods being used to preserve/rescue their function following both traumatic brain and spinal cord injury.

Paradoxical effects of continuous high dose gabapentin treatment on autonomic dysreflexia after complete spinal cord injury.

Spinal cord injury (SCI) can have profound effects on the autonomic and cardiovascular systems, notably with injuries above high-thoracic levels that result in the development of autonomic dysreflexia (AD) characterized by volatile hypertension in response to exaggerated sympathetic reflexes triggered by afferent stimulation below the injury level. Pathophysiological changes associated with the development of AD include sprouting of both nociceptive afferents and ascending propriospinal 'relay' neurons below the injury, as well as dynamic changes in synaptic inputs onto sympathetic preganglionic neurons. However, it remains uncertain whether synapse formation between sprouted c-fibers and propriospinal neurons contributes to the development of exaggerated sympathetic reflexes produced during AD. We previously reported that once daily treatment with the anti-epileptic and neuropathic pain medication, gabapentin (GBP), at low dosage (50 mg/kg) mitigates experimentally induced AD soon after injections, likely by impeding glutamatergic signaling. Since much higher doses of GBP are reported to block the formation of excitatory synapses, we hypothesized that continuous, high dosage GBP treatment after SCI might prevent the formation of aforementioned aberrant synapses and, accordingly, reduce the incidence and severity of AD. Adult female rats implanted with aortic telemetry probes for hemodynamic monitoring underwent T4-transection SCI and immediately received 100 mg/kg (i.p.) of GBP and then every six hours (400 mg/kg/day) for 4-weeks after injury. We assessed daily body weight, mean arterial pressure, heart rate, frequency of spontaneous AD, and hemodynamic changes during colorectal distension (CRD) to establish whether high dose GBP treatment prophylactically mitigates both AD and associated aberrant synaptic plasticity. This regimen significantly reduced both the absolute blood pressure reached during experimentally induced AD and the time required to return to baseline afterwards. Conversely, GBP prevented return to pre-injury body weights and paradoxically increased the frequency of spontaneously occurring AD. While there were significant decreases in the densities of excitatory and inhibitory pre-synaptic markers in the lumbosacral dorsal horn following injury alone, they were unaltered by continuous GBP treatment. This indicates distinct mechanisms of action for acute GBP to mitigate induced AD whereas chronic GBP increases non-induced AD frequencies. While high dose prophylactic GBP is not recommended to treat AD, acute low dose GBP may hold therapeutic value to mitigate evoked AD, notably during iatrogenic procedures under controlled clinical conditions.

Chronic muscle weakness and mitochondrial dysfunction in the absence of sustained atrophy in a preclinical sepsis model.

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of survivors. Our data suggest that sustained mitochondrial dysfunction, rather than atrophy alone, underlies chronic sepsis-induced muscle weakness. This study emphasizes that conventional efforts that aim to recover muscle quantity will likely remain ineffective for regaining strength and improving quality of life after sepsis until deficiencies in muscle quality are addressed.

Intraspinal Plasticity Associated With the Development of Autonomic Dysreflexia After Complete Spinal Cord Injury.

Traumatic spinal cord injury (SCI) leads to disruption of sensory, motor and autonomic function, and triggers structural, physiological and biochemical changes that cause reorganization of existing circuits that affect functional recovery. Propriospinal neurons (PN) appear to be very plastic within the inhibitory microenvironment of the injured spinal cord by forming compensatory circuits that aid in relaying information across the lesion site and, thus, are being investigated for their potential to promote locomotor recovery after experimental SCI. Yet the role of PN plasticity in autonomic dysfunction is not well characterized, notably, the disruption of supraspinal modulatory signals to spinal sympathetic neurons after SCI at the sixth thoracic spinal segment or above resulting in autonomic dysreflexia (AD). This condition is characterized by unmodulated sympathetic reflexes triggering sporadic hypertension associated with baroreflex mediated bradycardia in response to noxious yet unperceived stimuli below the injury to reduce blood pressure. AD is frequently triggered by pelvic visceral distension (bowel and bladder), and there are documented structural relationships between injury-induced sprouting of pelvic visceral afferent C-fibers. Their excitation of lumbosacral PN, in turn, sprout and relay noxious visceral sensory stimuli to rostral disinhibited thoracic sympathetic preganglionic neurons (SPN) that manifest hypertension. Herein, we review evidence for maladaptive plasticity of PN in neural circuits mediating heightened sympathetic reflexes after complete high thoracic SCI that manifest cardiovascular dysfunction, as well as contemporary research methodologies being employed to unveil the precise contribution of PN plasticity to the pathophysiology underlying AD development.

Pharmacological Stimulation of Mitochondrial Biogenesis Using the Food and Drug Administration-Approved ß2-Adrenoreceptor Agonist Formoterol for the Treatment of Spinal Cord Injury.

A hallmark of the progressive cascade of damage referred to as secondary spinal cord injury (SCI) is vascular disruption resulting in decreased oxygen delivery and loss of mitochondria homeostasis. While therapeutics targeting restoration of single facets of mitochondrial function have proven largely ineffective clinically post-SCI, comprehensively addressing mitochondrial function via pharmacological stimulation of mitochondrial biogenesis (MB) is an underexplored strategy. This study examined the effects of formoterol, a mitochondrial biogenic Food and Drug Administration-approved selective and potent ß2-adrenoreceptor (ADRB2) agonist, on recovery from SCI in mice. Female C57BL/6 mice underwent moderate SCI using a force-controlled impactor-induced contusion model, followed by daily formoterol intraperitoneal administration (0.1 mg/kg) beginning 1 h post-SCI. The SCI resulted in decreased mitochondrial protein expression, including PGC-1α, in the injury and peri-injury sites as early as 3 days post-injury. Formoterol treatment attenuated this decrease in PGC-1α, indicating enhanced MB, and restored downstream mitochondrial protein expression to that of controls by 15 days. Formoterol-treated mice also exhibited less histological damage than vehicle-treated mice 3 days after injury-namely, decreased lesion volume and increased white and gray matter sparing in regions rostral and caudal to the injury epicenter. Importantly, locomotor capability of formoterol-treated mice was greater than vehicle-treated mice by 7 days, reaching a Basso Mouse Scale score two points greater than that of vehicle-treated SCI mice by 15 days. Interestingly, similar locomotor restoration was observed when initiation of treatment was delayed until 8 h post-injury. These data provide evidence of ADRB2-mediated MB as a therapeutic approach for the management of SCI.

Effects of Mitochondrial Transplantation on Bioenergetics, Cellular Incorporation, and Functional Recovery after Spinal Cord Injury.

Our previous studies reported that pharmacological maintenance of mitochondrial bioenergetics after experimental spinal cord injury (SCI) provided functional neuroprotection. Recent evidence indicates that endogenous mitochondrial transfer is neuroprotective as well, and, therefore, we extended these studies with a novel approach to transplanting exogenous mitochondria into the injured rat spinal cord. Using a rat model of L1/L2 contusion SCI, we herein report that transplantation of exogenous mitochondria derived from either cell culture or syngeneic leg muscle maintained acute bioenergetics of the injured spinal cord in a concentration-dependent manner. Moreover, transplanting transgenically labeled turbo green fluorescent (tGFP) PC12-derived mitochondria allowed for visualization of their incorporation in both a time-dependent and cell-specific manner at 24 h, 48 h, and 7 days post-injection. tGFP mitochondria co-localized with multiple resident cell types, although they were absent in neurons. Despite their contribution to the maintenance of normal bioenergetics, mitochondrial transplantation did not yield long-term functional neuroprotection as assessed by overall tissue sparing or recovery of motor and sensory functions. These experiments are the first to investigate mitochondrial transplantation as a therapeutic approach to treating spinal cord injury. Our initial bioenergetic results are encouraging, and although they did not translate into improved long-term outcome measures, caveats and technical hurdles are discussed that can be addressed in future studies to potentially increase long-term efficacy of transplantation strategies.

Mitochondrial transplantation strategies as potential therapeutics for central nervous system trauma.

Mitochondria are essential cellular organelles critical for generating adenosine triphosphate for cellular homeostasis, as well as various mechanisms that can lead to both necrosis and apoptosis. The field of "mitochondrial medicine" is emerging in which injury/disease states are targeted therapeutically at the level of the mitochondrion, including specific antioxidants, bioenergetic substrate additions, and membrane uncoupling agents. Consequently, novel mitochondrial transplantation strategies represent a potentially multifactorial therapy leading to increased adenosine triphosphate production, decreased oxidative stress, mitochondrial DNA replacement, improved bioenergetics and tissue sparing. Herein, we describe briefly the history of mitochondrial transplantation and the various techniques used for both in vitro and in vivo delivery, the benefits associated with successful transference into both peripheral and central nervous system tissues, along with caveats and pitfalls that hinder the advancements of this novel therapeutic.

Rapamycin Exacerbates Cardiovascular Dysfunction after Complete High-Thoracic Spinal Cord Injury.

Autonomic dysreflexia (AD) is a potentially life-threatening syndrome in individuals with spinal cord injury (SCI) above the T6 spinal level that is characterized by episodic hypertension in response to noxious stimuli below the lesion. Maladaptive intraspinal plasticity is thought to contribute to the temporal development of AD, and experimental approaches that reduce such plasticity mitigate the severity of AD. The mammalian target of rapamycin (mTOR) has gained interest as a mediator of plasticity, regeneration, and nociceptor hypersensitivity in the injured spinal cord. Based on our preliminary data that prolonged rapamycin (RAP) treatment markedly reduces mTOR activity in the cord weeks after high-thoracic (T4) spinal transection, we sought to determine whether RAP could modulate AD development by impeding intraspinal plasticity. Naïve and injured rats were administered RAP or vehicle every other day, beginning immediately after injury for four weeks, and hemodynamic monitoring was conducted to analyze the frequency of spontaneously occurring AD, as well as the severity of colorectal distention (CRD) induced AD. Results showed that after SCI, RAP significantly exacerbated sustained body weight loss and caused a marked elevation in resting blood pressure, with average daily blood pressure rising above even normal naïve levels within one week after injury. Moreover, RAP significantly increased the frequency of daily spontaneous AD and increased the absolute blood pressure induced by CRD at three weeks post-injury. These dynamic cardiovascular effects were not, however, correlated with changes in the density of nociceptive c-fibers or c-Fos+ neurons throughout the spinal cord, indicating that intraspinal plasticity associated with AD was not altered by treatment. These findings caution against the use of RAP as a therapeutic intervention for SCI because it evokes toxic weight loss and exacerbates cardiovascular dysfunction perhaps mediated by increased peripheral nociceptor sensitivity and/or vascular resistance.

Autonomic dysreflexia after spinal cord injury: Systemic pathophysiology and methods of management.

Traumatic spinal cord injury (SCI) has widespread physiological effects beyond the disruption of sensory and motor function, notably the loss of normal autonomic and cardiovascular control. Injury at or above the sixth thoracic spinal cord segment segregates critical spinal sympathetic neurons from supraspinal modulation which can result in a syndrome known as autonomic dysreflexia (AD). AD is defined as episodic hypertension and concomitant baroreflex-mediated bradycardia initiated by unmodulated sympathetic reflexes in the decentralized cord. This condition is often triggered by noxious yet unperceived visceral or somatic stimuli below the injury level and if severe enough can require immediate medical attention. Herein, we review the pathophysiological mechanisms germane to the development of AD, including maladaptive plasticity of neural circuits mediating abnormal sympathetic reflexes and hypersensitization of peripheral vasculature that collectively contribute to abnormal hemodynamics after SCI. Further, we discuss the systemic effects of recurrent AD and pharmacological treatments used to manage such episodes. Contemporary research avenues are then presented to better understand the relative contributions of underlying mechanisms and to elucidate the effects of recurring AD on cardiovascular and immune functions for developing more targeted and effective treatments to attenuate the development of this insidious syndrome following high-level SCI.

The activity of the serotonin receptor 2C is regulated by alternative splicing.

The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite controlling substances, and possibly anti-spasm agents. Through alternative pre-mRNA splicing and RNA editing, the 5HT2C gene generates at least 33 mRNA isoforms encoding 25 proteins. The 5HT2C is a G-protein coupled receptor that signals through phospholipase C, influencing the expression of immediate/early genes like c-fos. Most 5HT2C isoforms show constitutive activity, i.e., signal without ligand binding. The constitutive activity of 5HT2C is decreased by pre-mRNA editing as well as alternative pre-mRNA splicing, which generates a truncated isoform that switches off 5HT2C receptor activity through heterodimerization; showing that RNA processing regulates the constitutive activity of the 5HT2C system. RNA processing events influencing the constitutive activity target exon Vb that forms a stable double stranded RNA structure with its downstream intron. This structure can be targeted by small molecules and oligonucleotides that change exon Vb alternative splicing and influence 5HT2C signaling in mouse models, leading to a reduction in food intake. Thus, the 5HT2C system is a candidate for RNA therapy in multiple models of CNS disorders.

Optimization of mitochondrial isolation techniques for intraspinal transplantation procedures.

BACKGROUND: Proper mitochondrial function is essential to maintain normal cellular bioenergetics and ionic homeostasis. In instances of severe tissue damage, such as traumatic brain and spinal cord injury, mitochondria become damaged and unregulated leading to cell death. The relatively unexplored field of mitochondrial transplantation following neurotrauma is based on the theory that replacing damaged mitochondria with exogenous respiratory-competent mitochondria can restore overall tissue bioenergetics. NEW METHOD: We optimized techniques in vitro to prepare suspensions of isolated mitochondria for transplantation in vivo. Mitochondria isolated from cell culture were genetically labeled with turbo-green fluorescent protein (tGFP) for imaging and tracking purposes in vitro and in vivo. RESULTS: We used time-lapse confocal imaging to reveal the incorporation of exogenous fluorescently-tagged mitochondria into PC-12 cells after brief co-incubation. Further, we show that mitochondria can be injected into the spinal cord with immunohistochemical evidence of host cellular uptake within 24h. COMPARISON TO EXISTING METHODS: Our methods utilize transgenic fluorescent labeling of mitochondria for a nontoxic and photostable alternative to other labeling methods. Substrate addition to isolated mitochondria helped to restore state III respiration at room temperature prior to transplantation. These experiments delineate refined methods to use transgenic cell lines for the purpose of isolating well coupled mitochondria that have a permanent fluorescent label that allows real time tracking of transplanted mitochondria in vitro, as well as imaging in situ. CONCLUSIONS: These techniques lay the foundation for testing the potential therapeutic effects of mitochondrial transplantation following spinal cord injury and other animal models of neurotrauma.

Prospects for therapeutic mitochondrial transplantation.

Mitochondrial dysfunction has been implicated in a multitude of diseases and pathological conditions- the organelles that are essential for life can also be major players in contributing to cell death and disease. Because mitochondria are so well established in our existence, being present in all cell types except for red blood cells and having the responsibility of providing most of our energy needs for survival, then dysfunctional mitochondria can elicit devastating cellular pathologies that can be widespread across the entire organism. As such, the field of "mitochondrial medicine" is emerging in which disease states are being targeted therapeutically at the level of the mitochondrion, including specific antioxidants, bioenergetic substrate additions, and membrane uncoupling agents. New and compelling research investigating novel techniques for mitochondrial transplantation to replace damaged or dysfunctional mitochondria with exogenous healthy mitochondria has shown promising results, including tissue sparing accompanied by increased energy production and decreased oxidative damage. Various experimental techniques have been attempted and each has been challenged to accomplish successful transplantation. The purpose of this review is to present the history of mitochondrial transplantation, the different techniques used for both in vitro and in vivo delivery, along with caveats and pitfalls that have been discovered along the way. Results from such pioneering studies are promising and could be the next big wave of "mitochondrial medicine" once technical hurdles are overcome.