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New Insights into the Mechanisms of Mitochondrial Preconditioning-Triggered. Neuroprotection. Sónia C. Correia1,2, Susana Cardoso1,2, Renato X. Santos1,2, ...
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New Insights into the Mechanisms of Mitochondrial Preconditioning-Triggered Neuroprotection Sónia C. Correia1,2, Susana Cardoso1,2, Renato X. Santos1,2, Cristina Carvalho1,2, Maria S. Santos1,2, George Perry3,4, Mark A. Smith3 and Paula I. Moreira1,5* 1

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal; 2Department of Life Sciences, Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal; 3Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA; 4UTSA Neurosciences Institute and Department of Biology, University of Texas at San Antonio, San Antonio, Texas, USA; 5Institute of Physiology – Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal Abstract: Mitochondria fulfill a number of essential cellular functions, being recognized that the strict regulation of the structure, function and turnover of these organelles is an immutable control node for the maintenance of neuronal integrity and homeostasis. Many lines of evidence posit that mitochondria constitute a convergence point of preconditioning – a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Indeed, it has been described that preconditioning activates an adaptive reprogramming of mitochondrial biology in response to a noxious stress-stimulus, which in turn will contribute to augment both mitochondrial and neuronal tolerance. Mitochondrial reactive species (ROS), mitochondrial ATP-sensitive potassium (mitoKATP) channels and mitochondrial permeability transition pore have been identified as specific mitochondrial mediators and targets of the adaptive program underlying preconditioning. Recent studies further link mitochondrial biogenesis, dynamics and mitophagy to preconditioning, thereby representing novel mechanisms by which preconditioning may mediate brain tolerance. The present review summarizes the current views on how mitochondrial biology is linked to preconditioning-induced neuroprotection. A better understanding of the mitochondrial mechanisms underlying preconditioning will help in the development of novel therapeutic approaches with the primary goal of modulating mitochondria to enhance brain tolerance against neurodegenerative events.

Keywords: Mitochondria, mitochondrial dynamics, mitochondria turnover, neuroprotection, preconditioning, reactive oxygen species. INTRODUCTION Preconditioning is an innate protective and adaptive mechanism, whereby a sublethal insult protects against a subsequent lethal insult, a phenomenon remembering one of Nietszche’s most memorable quotes "What does not kill you, makes you stronger". The first in vivo evidence of preconditioning and tolerance in brain was provided in 1960's [1]. In the late 1980’s, several reports again drew attention to ischemic tolerance in the brain [2,3]. Since then, the preconditioning phenomenon has been confirmed in many animal models of global [4] and focal [5] ischemia, in in vitro brain slice preparations [6], in cultured primary neurons [7], and in human beings in the form of short episodes of ischemia without infarction, known as a transient ischemic attack (TIA) [8]. Brain tolerance can be induced by several distinct preconditioning stimuli, such as ischemia, oxidative stress, hypothermia, hypoxia, and low doses of endotoxin [9]. The existence of multiple, diverse preconditioning stimuli that confer protection result in the well-known phenomenon of "cross-tolerance" [10]. Preconditioning induces two phases of brain tolerance with different temporal profiles and, to some extent, with different mechanisms of protection: early and delayed tolerance. Early tolerance is a short-lasting protection induced within minutes of exposure to preconditioning and wanes within hours. Rapid changes in activity and posttranslational modifications of existing proteins are involved in this phenomenon. Conversely, preconditioning-induced delayed tolerance needs several hours or even days to manifest and requires gene induction and de novo protein synthesis, representing a long-term response through genetic reprogramming [10-13]. Multiple molecular pathways and protective mechanisms have been identified and continue to be studied in an effort to clarify how *Address correspondence to this author at the Center for Neuroscience and Cell Biology, Institute of Physiology- Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal; Tel: +351 239480012; Fax: +351 239480034; E-mail: [email protected]/ [email protected]

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does preconditioning-mediated brain tolerance occurs. In the preconditioning realm, mitochondria have been proposed to be master regulators of preconditioning-triggered endogenous neuroprotection [14]. Mitochondria are ubiquitious and highly dynamic organelles that orchestrate an extensive repertoire of cellular functions. Since neurons are metabolically active cells that have high energy demands at locations distant from the cell body, they are particularly dependent on mitochondrial function. Mitochondria generate energy (ATP) that is essential for the excitability and survival of neurons, and the protein phosphorylation reactions that mediate synaptic signaling and related long-term changes in neuronal structure and function. These organelles are also involved in the regulation of calcium (Ca2+) and redox signaling, developmental and synaptic plasticity, and arbitration of cell survival and death [15,16]. Thus, considering how much neurons depend on mitochondria, it is not surprising to found a strong association between mitochondrialcentered mechanisms and preconditioning-mediated neuroprotection. Accumulating data indicates that transient exposure of mitochondria to physiological or pathological stimuli, intracellular events, or pharmacological agents, induces mitochondrial changes that ultimately protect neurons against a variety of lethal insults [17,18]. Taking in account that mitochondria take a center stage in preconditioning-afforded brain tolerance, this review will highlight the recent advances in understanding the involvement of mitochondrial biology in this phenomenon, emphasizing the role of mitochondrial reactive oxygen species (ROS) and mitochondrial ATP-sensitive potassium (mitoKATP) channels as specific mitochondrial mediators and targets of preconditioning paradigm. We will also address the contribution of mitochondrial biogenesis, dynamics, and autophagic destruction to the maintenance of viable and functional mitochondrial and thereby neuronal homeostasis in the preconditioning paradigm. Deciphering the mechanisms underlying preconditioninginduced brain tolerance could provide new insights, which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration. © 2011 Bentham Science Publishers

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SHEDDING LIGHT ON THE ROLE OF MITOCHONDRIAL REACTIVE OXYGEN SPECIES IN PRECONDITIONING Mitochondria constitute one of the major sources of cellular ROS. While a major increase in mitochondrial ROS generation augments pathological dysfunction of mitochondria potentiating cell death, evidence shows that mild mitochondrial ROS levels are critically involved in preconditioning-mediated brain tolerance [1923]. Ravati and collaborators [20] reported that preconditioning stimulated by moderate ROS levels protects cultured neurons against different damaging agents and subsequent massive oxygen radical formation. Conversely, the presence of a radical scavenger abolishes such ROS-induced neuronal preconditioning [21]. It was also been shown that hydrogen peroxide (H2O2) generation during a brief period of oxygen-glucose deprivation (OGD) is the main trigger involved in the mechanism of preconditioning-induced neuronal protection [24]. Simerabet and collaborators [25] also reported a preconditioning effect following in situ administration of H2O2 inside the brain cortex, emphasizing an involvement of ROS during the triggering phase of cerebral preconditioning. Moreover, several mitochondrial inhibitors have been shown to induce neuronal preconditioning in part by increasing ROS production, whereas scavenging ROS abrogates the neuroprotective effects [26-29]. It is therefore conceivable that mitochondrial ROS produced during the triggering phase of preconditioning stimulate an adaptive program that will augment both mitochondrial and neuronal tolerance. Among the multiple signaling pathways that have been proposed to participate in preconditioning, the induction of the hypoxia signaling pathway with the concomitant stabilization and transcriptional activation of the transcription factor hypoxia-inducible factor (HIF)-1 has emerged as one of the major cellular pathways responsible for brain tolerance. HIF-1 is a heterodimer of two basic helixloop-helix/PAS proteins, HIF-1 and the aryl hydrocarbon nuclear translocator (ARNT or HIF-1). In conditions of normal oxygen (O2), HIF-1 is hydroxylated by prolyl hydroxylase enzymes (PHDs) and rapidly degraded by the ubiquitin-proteasome system. Under hypoxic conditions the HIF-1 subunit is stabilized, dimerizes with ARNT, translocates to the nucleus, and subsequently binds to HIF response elements (HRE), modulating the expression of a wide range of genes involved in angiogenesis, metabolism, apoptosis and cell survival [30]. HIF-1 activation seems to be strictly linked to mitochondrial function. Under hypoxic conditions HIF-1 is stabilized by inhibition of the PHDs through ROS generated by the Qo-site of complex III in the mitochondrial electron transport chain [31]. These ROS are necessary for hypoxic activation since the presence of a mitochondrial-targeted antioxidant during the hypoxic period or mitochondrial DNA depletion abrogates HIF-1 stabilization [32,33]. As referred before, a crosstalk between ROS of mitochondrial origin and HIF-1 has been proposed to underlie brain tolerance mediated by preconditioning [30]. As a matter of fact, hypoxic preconditioning-induced neuroprotection is correlated with ROS generation, subsequent activation of HIF-1 and induction of its downstream specific gene erythropoietin (EPO) [34]. Similarly, low levels of exogenous H2O2 were shown to enhance HIF-1 expression and thereby, protecting neuronal cells against ischemic injury [35]. Collectively, these data point that mitochondrial ROS are required for the initiation and maintenance of neuronal preconditioning. As signaling molecules, mitochondrial ROS seem to be triggers and mediators of neuronal preconditioning by the activation of important signaling pathways involved in brain tolerance, namely HIF-1 signaling pathway. MITOCHONDRIAL ATP-SENSITIVE POTASSIUM CHANNELS AS TRIGGERS AND END EFFECTORS OF NEUROPROTECTION IN PRECONDITIONING MitoKATP channels are localized in the inner mitochondrial membrane and regulate mitochondrial function in several tissues

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including the brain [36-38]. Brain mitochondria contain seven times more mitoKATP channels than liver or heart mitochondria, reflecting the importance of these channels in neuronal functionality and integrity [36]. A great deal of attention has been focused on the role of mitoKATP channels in regulating preconditioning-related adaptive responses, these channels being proposed to be both triggers and end effectors of preconditioning-induced brain tolerance [14,19]. Activation of mitoKATP channels with pharmacological agents mimics the preconditioning-associated protective effects [39,40]. Conversely, physiological or chemical preconditioning is abrogated by mitoKATP channels blockers such as glibenclamide and 5hydroxydecanoate (5-HD) [40]. Some progress has been made to elucidate the mechanisms underlying the role of mitoKATP channels in preconditioning protection. For example, the opening of mitoKATP channels may decrease mitochondrial membrane potential (m), promoting an increase in the electron transport chain rate and, consequently, increasing ATP production [41]. In addition, the activation of mitoKATP channels was reported to induce neuronal protection by attenuating mitochondrial Ca2+ overload and, thus, preventing mitochondrial permeability transition pore (mPTP) induction. Compelling evidence indicates that the inhibition of mPTP opening and its signaling cascade represent crucial events involved in preconditioning-mediated cytoprotection in both heart and brain [19,42-44]. It was proposed a signaling pathway linking mitoKATP and mPTP where increased K + conductance after mitoKATP opening alkalinizes the mitochondrial matrix and increases the generation of H2O2, which in turn activates the mPTP-associated epsilon protein kinase C (PKC). A relationship between mitoKATP channels and ROS has also been postulated, since the protection induced by H2O2 against cerebral ischemiareperfusion injury was blocked by a mitoKATP channels antagonist [25]. Additionally, the antioxidant N-acetyl-cysteine (NAC) blocked the protection induced by diazoxide, a mitoKATP channels opener [25]. This strong and direct relationship between ROS and mitoKATP further confirms a central stage for mitochondria in the neuroprotection induced by cerebral preconditioning [25]. Diazoxide, a selective mitoKATP channels opener, has been suggested to induce mild oxidative stress and preconditioning-like neuroprotection [45] due to the combined effects of mitochondrial membrane depolarization and enhanced ROS production by succinate dehydrogenase (SDH) inhibition [14]. The immediate preconditioning induced by low doses of diazoxide was shown to preserve neuronal and vascular function after cerebral ischemia [46]. BMS191095, another selective mitoKATP channels opener, has been shown to induce both immediate and delayed preconditioning in neurons via mechanisms that involve mitochondrial depolarization and PKC activation, which attenuate free radical production during neuronal stress [47]. In summary, the activation of mitoKATP channels seems to be a key event that elicits neuroprotection by preconditioning and, as such, these channels represent promising therapeutic targets to counteract neurodegeneration. MITOCHONDRIAL BIOGENESIS IN NEURONAL PRECONDITIONING Mitochondria are not synthesized de novo, but arise by growth and division of pre-existing organelles through a process called mitochondrial biogenesis. This is a complex process because mitochondria house proteins encoded by both nuclear and mitochondrial genomes. Due to their ancient bacterial origin, mitochondria possess their own DNA (mtDNA), which encodes 13 respiratory chain protein subunits, and 24 RNA components (22 transfer RNAs and 2 ribosomal RNAs) necessary for mitochondrial protein synthesis and proper functionality. The remaining mitochondrial proteins (~1500) are encoded by the nuclear DNA (nDNA), translated in the cytoplasm and transported into mitochondria. So, new mitochondria result from an intricate and precise crosstalk between the nucleus

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and mitochondria to ensure the coordinated expression of both genomes [48-50]. Noticeably, mitochondrial biogenesis encompasses an amazing degree of plasticity involving variations in mitochondrial size, number, and mass. A wide range of stimuli that induces mitochondrial dysfunction or requires high energy demands, including hypoxia, oxidative stress, caloric restriction and exercise, can trigger mitochondrial biogenesis by interfering with bioenergetics [51]. Regulation of mitochondrial biogenesis involves a choreographed expression of diverse transcriptional activators and transcriptional co-activators. The most prevalent transcription factors activating promoters of mitochondrial genes are the nuclear respiratory factor 1 and 2 (NRF-1 and NRF-2) that work in concert with the transcriptional co-activators of the peroxisome proliferatoractivated receptor -coactivator-1 (PGC-1) family [PGC-1, PGC1 and PRC (PGC-1-related co-activator)] [52]. PGC-1 has been posited as the master regulator of mitochondrial biogenesis. In fact, this transcriptional co-activator is expressed at high levels in mitochondria-rich cells with high energy demands, such as neurons, and is involved in the activation of NRF-2 that, together, co-active NRF-1 [53]. Consequently, NRF-1 activates the mitochondrial transcription factor (TFAM), a factor critical for the initiation of mtDNA transcription, translation and repair. NRF-1 can further regulate the transcription of nuclear genes encoding respiratory complex subunits and other mitochondrial proteins [54,55]. Advances in mitochondrial biology research suggest that mitochondrial biogenesis exquisitely contributes to adaptive responses triggered by preconditioning. In the brain, hypoxic preconditioning was previously shown to stimulate mitochondrial biogenesis Fig. (1) [56]. Gutsaeva and collaborators [56] found that acute transient cerebral hypoxia arouses mitochondrial biogenesis in the subcortex by activating the nuclear-encoded regulatory program for mitochondrial biogenesis, including the NRF-1 transcription factor, the PGC-1 coactivator, and the mitochondrial transcription factor TFAM. Consequently, this program led to a subsequent increase in mtDNA transcription and content, followed by structural evidence of neuronal mitochondrial biogenesis (increased neuronal mitochondrial number and/or volume density), especially in the hippocampus, which is particularly vulnerable to hypoxic injury [56]. Additionally, the authors showed that maintenance of mtDNA and the induction of mitochondrial biogenesis in brain subcortex by hypoxic preconditioning is nitric oxide (NO)-dependent and is mediated by the neuronal nitric oxide synthase (nNOS) isoform [56]. Overall, these cellular responses appear to be part of a regional adaptive program to optimize oxygen utilization, energy production, and/or mitochondrial phenotype during cerebral oxygen limitation [56]. Accordingly, it was also reported a rapid boost in neuronal mitochondrial biogenesis after hypoxic/ischemic brain injury, corroborating the hypothesis that mitochondrial biogenesis is an endogenous neuroprotective response underlying preconditioning [57]. Indeed, it was detected that brain mtDNA content was markedly increased 6 hours after hypoxic/ischemic stimuli, and continued to increase up to 24 hours [57]. Paralleling the temporal change in mtDNA content, an increase in total mitochondrial number and expression of the mitochondrial proteins heat shock protein 60 (HSP60) and cytochrome c oxidase (COX) IV, and mitochondrial transcription factors NRF-1 and TFAM was observed. Meanwhile, no changes were detected in PGC-1 levels [57]. Chen and collaborators [58] observed that PGC-1 is induced after transient global ischemia leading to upregulation of uncoupling protein 2 (UCP2) and superoxide dismutase 2 (SOD2), thereby providing a neuroprotective effect against ischemic injury of the hippocampus by ameliorating oxidative stress. Conversely, the same authors observed that rodents lacking PGC-1 display reduced expression of UCP2 and SOD2 resulting in the exacerbation of oxidative stress and augmentation of delayed neuronal cell death in the hippocampus after transient global ischemia, further emphasizing a role for mitochondrial biogenesis-related signaling pathways in preconditioning [58].

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Accumulating findings repeatedly described neuroprotection by resveratrol, a polyphenolic compound, in neuronal cell cultures, brain slices and animal models. The neuroprotective effects associated to resveratrol are associated with various aspects of mitochondrial function, including mitochondrial biogenesis and ROS detoxification [59-63]. Activation of sirtuin-1 (SIRT1) seems to be in the limelight of the multiple mechanisms that may explain resveratrolinduced neuroprotection [64]. SIRT1 is a member of the sirtuin family of nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylase [65,66]. The presence of NAD+dependent ADP-ribosylase and protein deacetylase activities of sirtuin proteins suggests that they may function as sensors of metabolic or oxidative status of cells [67]. Additionally, SIRT1 binds and deacetylates members of the forkhead box class O (FoxO) family, the tumor suppressor p53, nuclear factor B (NF-B), PPAR, transcriptional co-activator PGC-1 and histones [68]. Although generally described to be a nuclear protein, a recent study demonstrated that SIRT1 is present in the mitochondria where it may locally regulate mitochondrial biogenesis [69]. Resveratrol has been shown to strongly stimulate SIRT1 deacetylase activity in a dosedependent manner by increasing its binding affinity to both the acetylated substrate and NAD+ [70]. In the last years, an important role has been attributed to SIRT1 in preconditioning afforded neuroprotection. Indeed, it was discovered an increase in NAD+/NADH ratio after preconditioning in rat hippocampal slices, which may predict that preconditioning induces SIRT1 activation [71]. An interesting study employing organotypic hippocampal slices as an in vitro model of cerebral ischemia showed that pre-treatment with resveratrol mimics ischemic preconditioning via SIRT1 Fig. (1) [72]. Moreover, SIRT1 inactivation by sirtinol after both resveratrol and ischemic preconditioning culminates in the abrogation of the observed neuroprotection. It was also speculated that resveratrol may exert pharmacological preconditioning by activating PGC-1 [73]. As point out above, SIRT1 physically interacts with and deacetylates PGC-1 at multiple lysine sites consequently increasing its activity [74]. In vivo evidence also confirmed that resveratrol could increase PGC-1 functions by increasing SIRT1 activity [75]. PGC-1, as a stimulator of mitochondrial biogenesis and an important regulator of cellular energy, was shown to regulate mitochondrial density in neurons [76]. It was also found that overexpression of SIRT1 deacetylase activates the transcriptional activity of PGC1 in neurons and increases mitochondrial density. Overexpression of PGC-1 and SIRT1-mediated PGC-1 induction protected neurons from mutant -synuclein- or mutant huntingtin-induced mitochondrial loss [76]. Several other mechanisms and signaling pathways have been proposed to underlie SIRT1 neuroprotection in preconditioning. For instance, under hypoxic conditions, SIRT1 has been shown to modulate the activity of HIFs. Hypoxic preconditioning was shown to upregulate SIRT1 regardless of redox balance, which stabilizes HIF-1, being suggested that SIRT1 acts as a sensor for the maintenance of energy and redox status [77]. Moreover, SIRT1 directly activates HIF-2 [78]. SIRT1-mediated HIF-2 activation is accompanied by a significant increase in the expression of erythropoietin (EPO), an essential regulator of angiogenesis [78]. Previous findings reported that elevation of EPO protein expression during preconditioning plays a key role in neuroprotection [79]. Hence, SIRT1-induced HIF-2 activation and, consequently, increased EPO levels may be crucial in the preconditioning phenomenon by stimulating new blood vessels formation and restoring blood supply to ischemic regions. Deacetylation of FoxO by SIRT1 seems to be another plausible mechanism by which SIRT1 mediates preconditioning-induced neuroprotection. FoxO transcription factors are implicated in apoptosis and autophagy [80]. Recently, Zhan and colleagues [81] demonstrated that the activation of FoxO signaling pathway is intimately involved in hypoxic preconditioning-afforded neuroprotec-

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•Preconditioning •Resveratrol Mitochondrial biogenesis

ROS

SOD

Ac PGC-1α Deacetylation

SIRT1 PGC-1α

PGC-1α target genes nucleus

Fig. (1). Sirtuin-1 (SIRT1)-mediated regulation of mitochondrial biogenesis in neuronal preconditioning. In the brain, hypoxic preconditioning was shown to stimulate mitochondrial biogenesis, mainly by activating peroxisome proliferator-activated receptor -coactivator-1 (PGC-1), a stimulator of this process and an important regulator of cellular energy. Moreover, a crucial role has been attributed to SIRT1 in preconditioning afforded neuroprotection. SIRT1 physically interacts with and deacetylates PGC-1 at multiple lysine sites, consequently increasing its activity. Resveratrol, a potent activator of SIRT1, was reported to mimic ischemic preconditioning via SIRT1. Additionally, pharmacological inhibition of SIRT1 with sirtinol abrogates both resveratrol and ischemic preconditioning-associated neuronal tolerance. Thus, neuronal preconditioning is predicted to potentiate SIRT1 activation, which in turn modulates transcriptional activity of PGC-1, and subsequently induces mitochondrial biogenesis and enhancement of antioxidant defenses (e.g. superoxide dismutase (SOD)), promoting mitochondrial reactive oxygen species (ROS) scavenging.

tion against cerebral ischemia. Since nuclear translocation of FoxO family members and their subsequent transcriptional activity are negatively regulated by phosphatidylinositol 3-kinase (PI3-K)/Aktmediated phosphorylation, the lateral ventricular infusion of LY294002, an inhibitor of PI3-K, before hypoxic preconditioning was shown to block the increase in phosphorylated Akt and FoxOs and increase neuronal damage in hypoxic preconditioned (HPC) animals [81]. Thus, activation of Akt results in the inactivation of FoxOs which may mediate brain tolerance after hypoxic preconditioning. Accordingly, it was shown that SIRT1 could also mediate survival by inhibiting apoptotic cell death pathways. In fact, an in vitro study performed in cerebral endothelial cells showed that SIRT1 governs late DNA fragmentation in apoptosis, activity of Akt1, phosphorylation and cell trafficking of FoxO3a, mitochondrial membrane permeability, cytochrome c release, Bad and caspases 3 and 1 activities [82]. Overall, these findings provide evidence that mitochondrial biogenesis and related signaling pathways are an integral part of the preconditioning scenario, being involved in brain tolerance by modulation of mitochondrial bioenergetics and detoxification of ROS in response to a stressful insult Fig. (1). Furthermore, these data underpin the possibility that the enhancement of mitochondrial biogenesis may represent a beneficial therapeutic strategy for neuronal recovery and survival in neurodegenerative disorders. CONSEQUENCES OF PRECONDITIONING IN MITOCHONDRIAL DYNAMICS AND MORPHOLOGY Mitochondria are highly dynamic organelles and are constantly undergoing fission and fusion, being able to change their shape

from an elongated interconnected network to a fragmented disconnected phenotype, respectively. These two opposing processes are finely orchestrated by at least four conserved dynamin-related GTPases. Mitochondrial fission is regulated by a large cytosolic GTPase that is recruited to the mitochondrial membrane upon a fission-like stimuli, dynamin-like protein 1 (DRP1), and a small mitochondrial molecule located in the outer membrane, denominated human mitochondrial fission protein 1 (hFis1) [83,84]. Mitochondrial fusion requires Mitofusins 1 and 2 (Mfn1, Mfn2) in the outer membrane and optic atrophy protein 1 (OPA1) in the inner membrane to control mitochondrial membrane fusion [85,86]. In neuronal cells, normal mitochondrial fission and fusion has been reported to facilitate mitochondrial biogenesis, repair of defective mitochondrial DNA through mixing and redistribution of mitochondria to sites requiring high-energy production [87-89]. Thus, it is not surprising that an imbalance in fission or fusion processes induces alterations in mitochondrial morphology and bioenergetics, and may thus contribute to neuronal injury during neurodegeneration [89-91]. To date, there are no reports demonstrating a direct link between preconditioning-mediated neuronal survival and mitochondrial dynamics. Meanwhile, it is tempting to speculate that preconditioning could modulate mitochondrial morphology, and, consequently, protect the brain against neurodegenerative insults. As pointed out above, low-grade and tightly controlled mitochondrial ROS generation during the preconditioning phase could trigger endogenous adaptive responses involved in neuronal tolerance. In 2008, Jou [22] presented a bold hypothesis that “minor” mitochondrial ROS formation-induced mitochondrial fission and fusion relo-

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cates mitochondrial network to form a mitochondria free gap, i.e., “a firewall”, which may play a crucial role in mitochondrial ROSmediated protective preconditioning by preventing propagation of those ROS during oxidative insults. On the other hand, it was shown that short-term treatment of endothelial cells with a nonapoptotic concentration of H2O2 caused a transient ROS burst, which, in turn, was correlated with the induction of temporary alterations in mitochondrial morphology and dynamics. Indeed, it was found that the original long interconnected mitochondrial tubules were transiently shortened and weakly fragmented [92], implying a signaling role for such a transient ROS burst. The reestablishment of the tubular phenotype involved upregulation of Mfn1 and DRP1, hence an increase in mitochondrial dynamics, and transcription factor PGG-1, indicating that also new synthesis of mitochondrial components contribute to the restoration of tubular mitochondria [92]. Members of Bcl-2 family of proteins, known conserved regulators of apoptosis, have also been recently implicated in the regulation of mitochondrial dynamics by interfering with both mitochondrial fission and fusion machineries. In mammalian cells, Bax, Bak, Bcl-2, and Bcl-xL have been shown to interact with Mfns [93-95]. Moreover, Bcl-xL was found to interact with DRP1 in neurons and is thought to increase the GTPase activity of DRP1 in vitro [96]. It was also reported that Drp1 is sumoylated during apoptosis in a Bax/Bak-dependent manner, this modification being responsible for a stable association of DRP1 with mitochondrial membranes [97]. Thus, modulation of Bcl-2 family of proteins expression may epitomize another mechanism by which the preconditioning could interfere with mitochondrial dynamics. In fact, preconditioning modifies neuronal expression of apoptosis-related proteins of Bcl-2 superfamily, being shown that hypoxic preconditioning mediates a shift of neuronal Bax/Bcl-2-Bcl-xL ratio favoring the antiapoptotic proteins Bcl-2 and Bcl-xL [98]. Similarly, diazoxide preconditioning was shown to prevent cultured hippocampal neurons apoptosis induced by anoxia-reoxygenation through the up-regulation of Bcl2 and down-regulation of Bax proteins [99]. Interestingly, mitochondrial dynamics also participate in mitochondrial turnover. Evidence from the literature showed that inhibition of fission culminates in disruption of selective degradation of mitochondria by autophagy (mitophagy) and excessive accumulation of dysfunctional mitochondria [100,101]. Indeed, it was found that fission of mitochondria produced metabolically different mitochondrial fragments with different m. The mitochondrial fragment with high m had a high probability of undergoing fusion, whereas the mitochondrial fragment with low m was more likely to be targeted by autophagy [101]. The next section is devoted to discuss mitochondrial selective degradation by autophagy as a possible mechanism underlying preconditioning. Taking into account that changes in mitochondrial morphology appear to affect biological processes, including mitochondrial turnover that is fundamental to proper neuronal function, we hypothesize that preconditioning-induced modulation of mitochondrial dynamics could represent a neuprotective response. IS THERE A ROLE FOR MITOPHAGY IN PRECONDITIONING? Autophagy is a tightly regulated catabolic process, responsible for the degradation and recycling of cellular components including long-lived proteins and organelles via a lysosomal-dependent pathway [102]. This process consists of two discrete but essential steps: formation of autophagosomes that sequester cytosolic constituents, and delivery of autophagic substrates to lysosomes where the contents are degraded [103]. Autophagy can be activated as a cellular response to both extracellular (nutrient deprivation or hypoxia) and intracellular (accumulation of damaged organelles and cytoplasmic components) stress conditions.

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In mammals, autophagy has been shown to be crucial for neuronal homeostasis and acts as a local housekeeping process. Neurons are post-mitotic cells and highly dependent on the endolysosomal pathway for active signaling in the axons and dendrites. Due to these features, neurons require effective protein degradation to prevent accumulation of toxic aggregates, as a quality control for cell survival. Thus, impaired protein degradation can cause the accumulation of abnormal proteins leading to cellular toxicity and, ultimately, to degeneration and death [104,105]. Indeed, conditional inactivation of autophagy pathway genes in the central nervous system (CNS) results in neurodegeneration accompanied by the accumulation of proteinaceous material [106,107]. Furthermore, compelling evidence shows that impaired autophagy contributes to or underlies a wide range of neurodegenerative diseases [108]. At present, many forms of selective autophagy are known [109]. Selective degradation of mitochondria by autophagy, also termed as mitophagy, is of particular significance for the maintenance of healthy cells, in particular non-dividing cells such as neurons, due to several reasons: 1) mitochondria are the main source of energy; 2) mitochondria are one of the major producers and targets of ROS; and 3) dysfunctional mitochondria that are not degraded potentiates the production of ROS and the release of cytochrome c and apoptosis-inducing factor, facilitating apoptosis [110]. Given the importance of mitochondrial homeostasis to proper neuronal function, the maintenance of mitochondrial integrity and clearance of impaired mitochondria by mitophagy are critical events for cell survival. Recent breakthroughs on preconditioning attribute a key role for autophagy in the arbitration of cell survival and death. Balduini and collaborators [111] speculated that preconditioning-mediated upregulation of autophagic pathways may prepare neuronal cells for a lethal stimulus by turning on and sustaining survival programs and postponing the apoptotic program, thereby a larger amount of cells will recover from the insult. In this respect, another study demonstrated that autophagy is really involved in the ischemic preconditioning [112]. The authors found that ischemic preconditioning increases the generation and degradation of autophagosomes, as revealed by increased microtubule-associated protein light chain 3 (LC3)-II protein levels, cathepsin D positive cells, lysosomal activity and autophagic vacuoles [112]. Similarly, it was recently observed that autophagy activation during ischemic preconditioning offers a remarkable tolerance to a subsequent fatal ischemic insult, and the neuroprotective effects associated with preconditioning can be mimicked by autophagy inducers [113]. As a matter of fact, it was observed that ischemic preconditioning is associated with reduced infarct volume, brain edema and motor deficits after subsequent permanent focal ischemia, whereas the autophagy inhibitors 3-methyladenine (3-MA) and bafliomycin A1 (Baf A1) suppressed the neuroprotection induced by preconditioning. In accordance, pretreatment with the autophagy inducer rapamycin increased the protein levels of LC3-II and beclin 1 and induced similar neuroprotective effects to those observed by ischemic preconditioning, namely reduced infarct volume and brain edema [113]. Rapamycin-induced preconditioning was also shown to induce neuroprotection in in vitro models of Parkinson’s disease via autophagy enhancement [114,115]. Tzeng and collaborators [116] also demonstrated that autophagy is intimately involved in hypoxic preconditioninginduced neuroprotection against 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity. At the end of 8 hours of hypoxic preconditioning it was observed an increase in LC3-II levels as well as in the number of autophagosomes. These alterations were also accompanied by increased free radicals generation and nuclear HIF1 localization, being suggested that mitochondrial-derived free radical may trigger autophagy via HIF-1 induction [116]. Furthermore, 8 hours of hypoxic preconditioning significantly decreased mitochondrial mass, pointing for a selective degradation of mitochondria by autophagy [116]. An elevation in mitochondrial

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mass was also observed under 8 hours of hypoxia and subsequent 12 hours of normoxia, reinforcing the notion that hypoxic preconditioning stimulates mitochondrial biogenesis, which seems to be crucial for the survival of cells exposed to a subsequent insult [116]. These authors showed the involvement of autophagy in hypoxic preconditioning by inhibiting autophagy with 3-MA during hypoxia exposure, which resulted in the abrogation of hypoxic preconditioning-afforded neuroprotection [116]. Another study demonstrated that deferoxamine (DFO) protects neurons from rotenoneinduced apoptosis by two interconnected mechanisms, the accumulation of HIF-1 and the induction of autophagy mediated by HIF1 [117]. Indeed, when HIF-1 gene was knockdown, DFOinduced autophagy was suppressed, indicating that DFO-induced autophagy was dependent on the expression of HIF-1. The attenuation of rotenone-induced apoptosis by DFO was also blocked by the suppression of both HIF-1 or autophagy related gene Beclin 1. It was suggested that HIF-1 may up-regulate autophagy via the inhibition of mammalian target rapamycin (mTOR) [118,119] or enhance the expression of its target gene BNIP3 [120]. More recently, Brown and collaborators [121] demonstrated the essential role of the redox sensitive kinase p66shc in determining energy and oxidative status and “cell fate” in neuronal preconditioning. Using an in vitro neuronal culture model, the authors found that both mitogen-activated protein kinase (MAPK) Raf and p66shc kinases are rapidly and intensively activated (phosphorylated) in low-grade oxidative stress conditions induced by preconditioning [121]. Moreover, phosphorylated p66shc was shown to relocate into subcellular organelles including mitochondria and nucleus, which generates a relative lack of cytosolic p66shc, contributing to the downregulation of total ATP content and decrease in ROS production [121]. On the other hand, inhibition of either p66shc or Raf was found to block preconditioning-afforded neuroprotection as well as upregulation of heat shock protein 70 (HSP70), a chaperone known to be involved in preconditioning-associated neuroprotection [121]. Extensive LC3 cleavage and signs of mitophagy were also detected in preconditioned cells. By inhibiting p66shc, LC3 cleavage is significantly enhanced suggesting that without p66shc oxidative and mitochondrial stress can no longer be harnessed into adaptive and pro-survival measures. Without p66shc to dampen the signaling and upregulation of HSP70, oxidative and energetic dysfunctions go unchecked, priming cells to die upon subsequent injury [121]. In face of these findings, the authors hypothesize that the limited autophagy induced by preconditioning aims to sequester damaged organelles and proteins, and ultimately enhances HSP70 induction [121]. This study highlights a specialized role for mitophagy in preconditioning-induced neuroprotection, in which p66sch seems to be a crucial mediator, and therefore raises an intriguing question: What is the intracellular trigger(s) for mitophagy in preconditioning? In our point of view, mitochondrial ROS and mild mitochondrial membrane depolarization may represent two feasible candidates. Mitochondria-derived ROS, at low or moderate levels, may act as signaling molecules and trigger mitophagy throughout redox regulation of Atg4, an essential cysteine protease in the autophagic pathway [122]. As already mentioned, mitochondrial ROS are also implicated in the activation of HIF-1, which in turn has been implicated in the enhancement of autophagy [118-120]. For mitophagy, decreased m has also been proposed to function as a “eat me” signal. Several studies demonstrated that mitochondria depolarize prior to autophagy [101,123,124]. Opening of mitoKATP channels is a mechanism underlying preconditioning-induced neuroprotection and involves a mild mitochondrial depolarization. Thus, it is reasonable to propose that mild mitochondrial depolarization may signal mitochondria for autophagic removal during preconditioning. Altogether these data demonstrate that autophagy (especially mitophagy), as a new-self repairing mechanism, contributes to preconditioning-mediated neuroprotection. Further investigations are

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necessary to clarify the mechanisms by which preconditioning induce mitophagy. CONCLUSION The current state of research supports a role for mitochondrialcentered mechanisms in the adaptive responses provided by preconditioning. Mild levels of mitochondrial ROS are believed to play a critical role in the initiation of neuroprotective signaling cascades. Indeed, mitochondrial ROS modulates the transcriptional activity of HIF-1, a major transcription factor involved in brain tolerance. A number of mechanisms have been purported to regulate ROS generation during preconditioning, including transient opening of mitoKATP channels. Recent findings implicate mitochondrial biogenesis, dynamics and mitophagy in preconditioning, fostering a role for mitochondrial turnover and quality control in this phenomenon. We speculate that reciprocal interactions among mitochondrial biogenesis, dynamics and mitophagy are fundamental events underlying brain cells preconditioning. Thus, future investigations on the role of mitochondrial biogenesis, dynamics and selective degradation of mitochondria by mitophagy may reveal new pathways by which mitochondria is involved in preconditioning-mediated brain tolerance. ACKNOWLEDGMENTS This work is supported by the Fundação para a Ciência e a Tecnologia and Fundo Europeu de Desenvolvimento Regional (PTDC/SAU-NMC/110990/2009). Sónia C. Correia has a PhD fellowship from the Fundação para a Ciência e a Tecnologia (SFRH/BD/40702/2007). REFERENCES [1]

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Received: July 25, 2011

Accepted: August 17, 2011

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