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Mitochondrial Dysfunction After Severe Tbi: a New Translational Target?

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Mitochondrial Dysfunction After Severe Tbi: a New Translational Target? -Edición provisional- MITOCHONDRIAL DYSFUNCTION AFTER SEVERE TBI: A NEW TRANSLATIONAL TARGET? Juan Sahuquillo, MD, PhD1, Marian Vidal-Jorge2, Angela Sánchez-Guerrero2 Department of Neurosurgery1, Neurotraumatology and Neurosurgery Research Unit2 Vall d’Hebron University Hospital Universitat Autònoma de Barcelona, Barcelona, Spain Significant advances in the treatment of TBI have been limited by a lack of knowledge of the biochemical, cellular and molecular changes involved in its pathophysiology. These obstacles have been overcome to a certain degree by new monitoring tools —cerebral microdialysis (MD) and monitoring of partial pressure of oxygen in the brain (PtiO2)— that have allowed clinicians to explore the metabolic disturbances of the injured brain with unprecedented detail. The data gathered by these monitoring tools in the past two decades has provided an opportunity to take a second look at the pathophysiology of TBI, motivating clinical researchers to redefine some of the unchallenged traditional concepts. The hypothesis that mitochondrial dysfunction is at the core of many acute metabolic disorders observed in acute TBI is one of the old concepts that deserves a second look and is the focus of this chapter. New neuromonitoring techniques, including PtiO2 and MD monitoring, are widely used in neurocritical care units, allowing for the quasi-continuous profiling of brain oxygen supply and brain metabolism [1, 2]. Data provided by these tools have cast doubt on the predominant role of ischemia in the pathophysiology of TBI. Many studies have found that the injured brain may experience severe alterations of energetic metabolism in the presence of CBF and oxygen supply well above the ischemic range[3-5]. Vespa et al. found that ischemia (reduced CBF uncoupled with CMRO2) is uncommon in positron emission tomography (PET) and microdialysis measurements taken during the early period after injury [5]. In a cohort of 19 severe TBI patients monitored using strict criteria — defined by MD and PET studies— the frequency of ischemia was found to be only 2.4% by MD criteria and less than 1% when using PET criteria [5]. The same scenario has been observed by our group in a cohort of patients in whom both MD and PtiO2 were monitored. We observed that patients with an adequate oxygen supply may present severe metabolic disturbances with an increase in lactate and in the lactate-pyruvate ratio (LPR) [6]. Several lines of evidence support the idea that cellular energetics are deranged in TBI not because of an inadequate brain O2 supply, but rather on the basis of impaired mitochondrial respiration, either in isolation or in combination with other causes of brain hypoxia. Correspondencia: Juan Sahuquillo, correo-e: [email protected] XV Simposium de neuromonitorización y tratamiento del paciente neurocrítico 2 Mitochondrial dysfunction after severe TBI: a new translational target? NON-ISCHEMIC CAUSES OF BRAIN METABOLIC DYSFUNCTION Some authors have reported that macroscopically normal brain tissue with normal or high PtiO2 in patients with no detectable intracranial or systemic insults may have severe metabolic alterations. Vilalta et al. described a cohort of severe and moderate TBI patients of whom 45% had brain lactate levels above 3 mmol/L, even when the probe was placed in macroscopically non-injured brain tissue[6]. Furthermore, the largest single-center retrospective study published so far showed that a LPR above 25 was a significant independent predictor of unfavorable outcome in TBI[7]. Accumulating evidence in recent years shows that brain metabolism is impaired not only because the delivery of O2 is impaired, but also because the cells are unable to use the available O2. The term cytopathic hypoxia was coined in 1997 to define these changes in mitochondrial respiratory function[8], a type of disorder equivalent to the histotoxic hypoxia defined previously by Siggäard- Andersen[9]. New experimental and clinical data support this early hypothesis and indicate that metabolic failure in the brain is not necessarily mediated by ischemia but may often represent the consequence of mitochondrial damage and disruption in the electron transport chain [6, 10]. Nelson et al. found a high incidence of perturbed energetic metabolism in TBI using machine- learning algorithms and time-series analysis applied to datamining microdialysis data. However, the relationships between MD, ICP and/or cerebral perfusion pressure were found to be weak and did not explain the metabolic disturbances observed, suggesting that factors other than pressure and/or flow variables were the main cause of the metabolic dysfunction[11]. THE SIGGÄARD-ANDERSEN CLASSIFICATION OF TISSUE HYPOXIA REVISITED Connett et al. stated in 1990 that in the discussion of oxygen-limited function it was important that “…both the vocabulary used to discuss the adequacy of 02 supply and the criteria used to detect an inadequate supply be unambiguous and consistent” [12]. The previously discussed evidence reflects an urgent need for a consensus-based classification system that includes all types of brain tissue hypoxia, including failures in the mitochondrial respiratory chain or even more complex situations, such as mitochondrial dysfunction characterized by the uncoupling of the respiratory chain with the production of ATP through the ATPase complex. Such a comprehensive and unambiguous classification system has been available since Siggäard- Andersen first described it in 1995 [9, 13]. These authors described and mathematically modeled all the possible causes of tissue hypoxia and their corresponding pathophysiology, including histotoxic, hypermetabolic and uncoupling hypoxia[9, 13]. The different types of tissue hypoxia described provide the theoretical framework for the characterization of all types of brain hypoxia found in the clinical setting. The Siggäard-Andersen classification system stratifies tissue hypoxia into 7 basic types: 1) ischemic hypoxia, 2) low extractivity hypoxia, 3) shunt hypoxia, 4) dysperfusion hypoxia, 5) histotoxic hypoxia, 6) uncoupling hypoxia, and 7) hypermetabolic hypoxia [9, 13]. It is beyond the scope of this review to examine this classification in detail, but some elements should be highlighted. Low extractivity hypoxia was a new concept introduced by the authors, who defined a new variable, the oxygen extraction tension (Px), that allows the detection of the three potential causes of low extractivity: hypoxemia, anemia, and low half-saturation tension (high-affinity hypoxia). The use of both measured variables (hemoglobin content, PaO2, mixed venous oxygen tension, etc.) and www.neurotrauma.com Juan Sahuquillo, Marian Vidal-Jorge, Ángela Sánchez-Guerrero 3 calculated variables (P50 and Px) simplify the differential diagnosis of the different types of hypoxia and facilitate a pathophysiologically based approach to their management. According to Connett et al., energy production by mitochondria has three stages of control: 1) the phosphorylation state, 2) the redox state, and 3) the concentration of dissolved oxygen [O2][12]. The phosphorylation state, the concentration of ATP, ADP, AMP, PCr and inorganic phosphate (Pi), is believed to be the main regulated variable under most circumstances[12]. Modern neuromonitoring tools, such as MD and PtiO2 monitoring and direct or indirect measurements of global and regional CBF, already allow the implementation of diagnostic algorithms to establish a step-by-step approach to the diagnosis of brain metabolic disturbances and hypoxia [14-16]. MD allows clinicians to estimate the redox state of the cytosol though the LPR, while Clark-type polarographic electrodes, which measure the dissolved oxygen in the brain interstitium (PtiO2), can allow them to accurately measure brain oxygen levels. MITOCHONDRIAL DYSFUNCTION AFTER TBI: AN ELUSIVE TARGET TBI is characterized by a gamut of complex temporal events evolving over hours or even days. Autoregulation impairment, reductions in CBF, low adenosine triphosphate (ATP) levels and energy stores, severe ionic shifts, alterations in the permeability of the blood-brain barrier, and metabolic impairment frequently co-exist in the early phases after injury. Experimental models have shown that mitochondria sustain considerable structural and functional damage at this time and that brain survival is closely linked to mitochondrial homeostasis[17]. Clausen et al. have reported some lines of evidence to support the theory regarding the mitochondrion’s crucial involvement in the pathophysiology of severe TBI. Some of the most relevant points are discussed below [18]. 1. The cerebral metabolic rate of oxygen (CMRO2) is consistently low after severe TBI. In the 1980s, Obrist et al. showed that oxidative metabolism, and therefore CMRO2, was reduced to half the normal levels in severe TBI and that the degree of depression was related to the depth of coma, and therefore to the Glasgow Coma Scale score[19]. It has been proposed that the origin of this metabolic depression could be an injury-induced mitochondrial inhibition. In cardiac ischemia it has been shown that a reversible shutdown inhibition of mitochondrial metabolism is a physiological mechanism of cardioprotection [20]. It has been established experimentally that the reversible inhibition of the proximal respiratory chain by blocking mitochondrial complex I —NADH ubiquinone oxidoreductase, a regulator of NADH/NAD+ redox balance— is a very effective strategy for cardioprotection [20]. 2. Increased levels of the
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