Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

Balan, Irina; Saladino, Andrew J.; Aarabi, Bizhan; Castellani, Rudolf J.; Wade, Christine; Stein, Deborah M.; Eisenberg, Howard M.; Chen, Hegang H.; Fiskum, Gary

doi:10.1089/neu.2012.2339

Cited by 40 publications

(35 citation statements)

References 58 publications

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“…Axonal shear stretch leads to the opening of voltage-gated calcium channels that, ultimately, precipitates mitochondrial dysfunction, bioenergetic failure, and the release of secondary messengers that end in apoptosis and death (Balan et al, 2013; Glenn et al, 2003; Lifshitz et al, 2003; Marcoux et al, 2008; Ragan et al, 2013; Xu et al, 2010). Thus, mitochondria play a central role in cerebral metabolism and regulation of oxidative stress, excitotoxicity, and apoptosis in acute brain injury; however, the mechanistic response and time course following diffuse TBI, especially in the immature brain at differing developmental stages, has limit investigation (Balan et al, 2013; Gilmer et al, 2010; Lifshitz et al, 2004; Robertson et al, 2009). Furthermore, the challenge of extrapolating adult models of diffuse TBI to pediatric models includes developmental differences in biomechanical properties and biological responses that vary in the infant, toddler, adolescent, and adult (Grate et al, 2003; Ibrahim et al, 2010; S.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury

et al. 2016

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Traumatic brain injury (TBI) is an important health problem, and a leading cause of death in children worldwide. Mitochondrial dysfunction is a critical component of the secondary TBI cascades. The response of mitochondria in the pediatric brain to injury has limited investigation, despite evidence that developing brain’s response differs from the adult, especially in diffuse non-impact TBI. We perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a swine model of diffuse TBI (rapid non-impact rotational injury: RNR), and examined the cortex and hippocampus. A substrate-uncoupler-inhibitor-titration protocol examined the role of the individual complexes as well as the uncoupled maximal respiration. Respiration per mg of tissue was also related to citrate synthase activity (CS) as an attempt to control for variability in mitochondrial content following injury. Diffuse RNR stimulated increased complex II-driven respiration relative to mitochondrial content in the hippocampus compared to shams. LEAK (State 4O) respiration was increased in both hippocampal and cortical tissue, with decreased respiratory ratios of convergent oxidative phosphorylation through complex I and II, compared to sham animals, indicating uncoupling of oxidative phosphorylation at 24 hours. The study suggests that proportionately, complex I contribution to convergent mitochondrial respiration was reduced in the hippocampus after RNR, with a simultaneous increase in complex-II driven respiration. In addition, mitochondrial respiration 24 hours after diffuse TBI that varies by location within the brain. Finally, we conclude that significant uncoupling of oxidative phosphorylation and alterations in convergent respiration through complex I- and complex II-driven respiration reveals therapeutic opportunities for the injured at-risk pediatric brain.

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Section: Introductionmentioning

confidence: 99%

Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury

et al. 2016

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“…A growing body of literature suggests that a main component of this secondary injury cascade is altered mitochondrial bioenergetics and cerebral metabolic crisis (Gilmer et al, 2009; Robertson et al, 2006). Mitochondria play a pivotal role in cerebral metabolism and regulation of oxidative stress, excitotoxicity, and apoptosis (Balan et al, 2013; Gilmer et al, 2009; Lifshitz et al, 2003; Robertson, 2004). Cerebral metabolic crisis displays regional heterogeneity, varies temporally post-injury and with gradation of injury severity, and is often sustained for a prolonged period of time (Lifshitz et al, 2003; Marcoux et al, 2008b; Ragan et al, 2013; Robertson et al, 2006, 2009; Saito et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

Kilbaugh

Karlsson

Byro

et al. 2015

Experimental Neurology

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Traumatic brain injury (TBI) is one of the leading causes of death in children worldwide. Emerging evidence suggests that alterations in mitochondrial function are critical components of secondary injury cascade initiated by TBI that propogates neurodegeneration and limits neuroregeneration. Unfortunately, there is very little known about the cerebral mitochondrial bioenergetic response from the immature brain triggered by traumatic biomechanical forces. Therefore, the objective of this study was to perform a detailed evaluation of mitochondrial bioenergetics using high-resolution respirometry in a high-fidelity large animal model of focal controlled cortical impact injury (CCI) 24 h post-injury. This novel approach is directed at analyzing dysfunction in electron transport, ADP phosphorylation and leak respiration to provide insight into potential mechanisms and possible interventions for mitochondrial dysfunction in the immature brain in focal TBI by delineating targets within the electron transport system (ETS). Development and application of these methodologies have several advantages, and adds to the interpretation of previously reported techniques, by having the added benefit that any toxins or neurometabolites present in the ex-vivo samples are not removed during the mitochondrial is olation process, and simulates the in situ tricarboxylic acid (TCA) cycle by maximizing key substrates for convergent flow of electrons through both complexes I and II. To investigate alterations in mitochondrial function after CCI, ipsilateral tissue near the focal impact site and tissue from the corresponding contralateral side were examined. Respiration per mg of tissue was also related to citrate synthase activity (CS) and calculated flux control ratios (FCR), as an attempt to control for variability in mitochondrial content. Our biochemical analysis of complex interdependent pathways of electron flow through the electron transport system, by most measures, reveals a bilateral decrease in complex I-driven respiration and an increase in complex II-driven respiration 24 h after focal TBI. These alterations in convergent electron flow though both complex I and II-driven respiration resulted in significantly lower maximal coupled and uncoupled respiration in the ipsilateral tissue compared to the contralateral side, for all measures. Surprisingly, increases in complex II and complex IV activities were most pronounced in the contralateral side of the brain from the focal injury, and where oxidative phosphorylation was increased significantly compared to sham values. We conclude that 24 h after focal TBI in the immature brain, there are significant alterations in cerebral mitochondrial bioenergetics, with pronounced increases in complex II and complex IV respiration in the contralateral hemisphere. These alterations in mitochondrial bioenergetics present multiple targets for therapeutic intervention to limit secondary brain injury and support recovery.

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“…Mitochondrial dysfunction may be central to the pathophysiology of TBI through metabolic derangements, oxidative stress, and apoptosis. In fact, a recent study showed mitochondrial ultrastructural alterations at progressive distances from the center of the penumbra in tissue samples from TBI patients [81]. In the setting of TBI, the production of ROS is enhanced [82][83][84], and the neuroprotective systems become overwhelmed and result in oxidative cell damage.…”

Section: Mechanisms Of Neural Injury In the Traumatic Penumbramentioning

confidence: 99%

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

Regner¹,

Meirelles²,

Simon³

2018

Traumatic Brain Injury - Pathobiology, Advanced Diagnostics and Acute Management

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Traumatic brain injury (TBI) is a major cause of morbidity and mortality worldwide. Understanding the pathophysiology of TBI is crucial for the development of more effective therapeutic strategies. At the moment of the traumatic impact, transfer of kinetic forces causes neurologic damage; this primary injury triggers a secondary wave of biochemical cascades, together with metabolic and cellular changes, called secondary neural injury. These areas of ongoing secondary injury, or areas of "traumatic penumbra," represent crucial targets for therapeutic interventions. This chapter is focused on the interplay between progression of parenchymal injury and the neuroprotective and neurorestorative processes that are emerging and developing subsequently to traumatic impact. Thus, we emphasized the role of traumatic penumbra in TBI pathogenesis and suggested a crucial contribution of the neurovascular units (NVUs) and paracrine effects of exosomes and miRNAs in promoting neurological recovery.

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Cellular Alterations in Human Traumatic Brain Injury: Changes in Mitochondrial Morphology Reflect Regional Levels of Injury Severity

Cited by 40 publications

References 58 publications

Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury

Mitochondrial response in a toddler-aged swine model following diffuse non-impact traumatic brain injury

Mitochondrial bioenergetic alterations after focal traumatic brain injury in the immature brain

Traumatic Penumbra: Opportunities for Neuroprotective and Neurorestorative Processes

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