revue neurologique 170 (2014) 390–400

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Mitochondrial diseases

Perspectives of drug-based neuroprotection targeting mitochondria Perspectives de la neuroprotection mitochondriale par des approches pharmacologiques V. Procaccio, C. Bris, J.M. Chao de la Barca, F. Oca, A. Chevrollier, P. Amati-Bonneau, D. Bonneau, P. Reynier * UMR CNRS6214, Inserm1083 and department of biochemistry and genetics, CHU d’Angers, 4, rue Larrey, 49933 Angers, France

info article

abstract

Article history:

Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These

Received 27 January 2014

anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of

Accepted 25 March 2014

mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged

Available online 1 May 2014

mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have

Keywords:

no effective therapies. The development of new metabolic treatments will be useful not only

Mitochondria

for rare mitochondrial disorders but also for the wide spectrum of common age-related

Mitochondrial diseases

neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A

Neurodegenerative disorders

better understanding of the mitochondrial regulating pathways raised several promising

Pharmacological neuroprotection

perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet. # 2014 Elsevier Masson SAS. All rights reserved.

* Corresponding author. E-mail address: [email protected] (P. Reynier). AD, Alzheimer’s disease; AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; ALS, Amyotrophic lateral sclerosis; AMP, Adenosine monophosphate; ATP, Adenosine triphosphate; cAMP, Cyclic AMP; CCCP, Carbonylcyanide m-chlorophenylhydrazone; CNS, Central nervous system; ERR, Estrogen-related receptors; ETC, Electron transport chain; FAD/FADH, Flavin adenine nucleotide; GDAP1, Ganglioside-induced differentiation-associated protein 1; HD, Huntington disease; KTP, Kinetin triphosphate; LHON, Leber hereditary optic neuropathy; MAPK, Mitogen-activated protein kinases; MELAS, Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERRF, Myoclonic epilepsy and ragged red fibers; MFN1/MFN2, Mitofusin; MnSOD, Manganese superoxide dismutase; mtDNA, Mitochondrial genome or DNA; mtPTP, Mitochondrial permeability transition pore; mTOR, Mammalian target of rapamycin; NAD/NADH, Nicotinamide adenine dinucleotide; NARP, Neurogenic muscle weakness, ataxia, and retinitis pigmentosa; nDNA, Nuclear genome or DNA; NMDA, Acide N-methyl-D-aspartic; NOS, Nitric oxide synthase; NRF1/NRF2, Nuclear respiratory factors; OPA1, Optic atrophy 1; OXPHOS, Oxidative phosphorylation; PARL, Presenilins-associated rhomboid-like protein; PD, Parkinson’s disease; PGC-1-a, PPAR gamma coactivator 1-alpha; PINK1, PTEN-induced putative kinase1; PKA, Protein kinase A; PPAR, Peroxisome proliferators-activated receptors; PRC, PGC1-related coactivator; CoQ, Coenzyme Q; RC, Respiratory chain; ROS, Reactive oxygen species; RXR, Retinoid X receptors; SIRT, Sirtuins; TFAM, Mitochondrial transcription factor A; TFB2/TFB2, Transcription factors B1 and B2. http://dx.doi.org/10.1016/j.neurol.2014.03.005 0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.

revue neurologique 170 (2014) 390–400

391

r e´ s u m e´ Mots cle´s :

Des dysfonctions mitochondriales ont e´te´ rapporte´es dans la plupart des maladies mito-

Mitochondrie

chondriales et neurode´ge´ne´ratives. Ces anomalies incluent des de´fauts e´nerge´tiques, une

Maladies mitochondriales

augmentation du stress oxydant lie´ au fonctionnement de la chaıˆne respiratoire, des de´fauts

Maladies neurode´ge´ne´ratives

de la dynamique mitochondriale, une susceptibilite´ accrue a` l’apoptose et une accumulation

Neuroprotection pharmacologique

de mitochondries endommage´es pre´sentant un ADN mitochondrial instable. Des progre`s importants ont e´te´ re´alise´s dans la compre´hension de la pathophysiologie de ces maladies mitochondriales mais la tre`s grande majorite´ de ces pathologies ne dispose pas de traitement. Le de´veloppement de nouvelles approches pharmacologiques est non seulement important pour ces maladies mais aussi pour l’e´ventail de pathologies neurode´ge´ne´ratives associant une dysfonction mitochondriale. La meilleure connaissance des voies de re´gulation mitochondriale a fait e´merger des perspectives prometteuses de neuroprotection. Cette revue se focalise sur les possibilite´s pharmacologiques de moduler la biogene`se mitochondriale, la de´gradation des mitochondries endommage´es par mitophagie, la de´toxification des radicaux libres ainsi que sur des aspects nutritionnels comme le re´gime ce´toge`ne. # 2014 Elsevier Masson SAS. Tous droits re´serve´s.

1.

Introduction

Mitochondrial diseases are often associated with clinical neurological features and are usually seen by a neurologist. Moreover, most of the common neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s diseases (PD), Friedreich’s ataxia (FA), Huntington’s Disease (HD) or Amyotrophic Lateral Sclerosis (ALS) have also been linked to a mitochondrial dysfunction [1]. In the last decade, spectacular progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders. However, the lack of a cure and efficient therapies impair our potential to treat these mitochondrial disorders and special efforts have to be made to validate therapies of mitochondrial disorders. Our ability to treat these disorders is extremely limited by their rarity but more importantly by the heterogeneity of these diseases [2,3]. A limited number of clinical trials have been conducted on putative mitochondrial therapies. Recently, the Cochrane study on mitochondrial disorders judged only twelve clinical trials to be methodologically valid, using a variety of compounds such as coenzyme Q10, creatine monohydrate, dichloroacetate and dimethyglycine [4]. So far, there have been very few randomized, prospective, double-blind, placebo-controlled trials performed in adults or children with mitochondrial diseases but a large number of open-labeled studies with limited probative value [4]. Moreover, several drugs or cofactors have been given in an uncontrolled manner making difficult to assess the efficacy and safety of these drugs. Most of the time these drugs have been used in combination as a ‘‘cocktail’’ and then difficult to assess the efficacy. Following these observations, it was suggested that treatments may have to be tailored for each patient based specifically on their molecular defects and mutation pathophysiology. The development of new metabolic and mitochondrial therapeutics will be useful not only for rare inherited mitochondrial syndromes but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction.

2.

Mitochondria: powerhouse of the cell

Mitochondria are organelles producing the energy required for cellular functions. The mitochondrial respiratory chain or Oxidative Phosphorylation (OXPHOS) is composed of five, multi-enzymatic complexes. Complexes I, II, III, and IV make up the electron transport chain (ETC), while complex V or ATP synthase produces ATP for energy cell requirements (Fig. 1). As a toxic by-product of OXPHOS, the mitochondria generate much of the endogenous cellular reactive oxygen species (ROS). These organelles also contain the mitochondrial permeability transition pore (mtPTP) which initiates cell death through the opening of mtPTP, when mitochondrial energy function declines [5]. Hence, mitochondrial dysfunctions which inhibit OXPHOS and generate ROS production increase the tendency of the cell to undergo apoptosis. Mitochondrial respiratory chain (RC) deficiencies represent one of the major causes of metabolic disorders with an estimated prevalence of 1 in 5000 of the general population [6]. However, these disorders represent a heterogeneous group of genetic diseases, mitochondrial diseases can be caused by genetic defects in mitochondrial DNA (mtDNA) [7] or nuclear DNA (nDNA) genes encoding mitochondrial proteins [8]. The large majority of the mitochondrial proteins is encoded by the nuclear genome, synthesized in the cytoplasm, and then imported into the mitochondria. Hundreds of nuclear genes are required for the synthesis, import and assembly of the respiratory chain complexes, as well as for the maintenance and expression of the mtDNA. In the last few years, the number of identified mutations in nuclear genes responsible for mitochondrial or neurodegenerative diseases has exponentially increased [8].

3.

Mitochondrial genome

The mtDNA is a circular molecule of 16.5 kb that encodes 13 polypeptides, which are essential components of OXPHOS, 12S

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Fig. 1 – Main OXPHOS pharmacological targets. The black arrow symbolizes the electron flow through the complexes I and II to complex IV where the oxygen, the final electrons acceptor, is reduced to water. The ATP synthase (complex V) is responsible for ATP synthesis through the protonic gradient generated by complexes I, III and IV across the mitochondrial inner membrane. In red, OXPHOS dysfunction leads to an increase escape of electrons from complexes I and III that directly react with oxygen, generating the highly toxic superoxide anion, itself metabolized in hydrogen peroxide, radical hydroxyl and water. The different potential targets of pharmacological therapy are shown in blue boxes.

and 16 rRNAs and 22 tRNAs which are part of the mitochondrial protein synthesis machinery required to express the 13 mitochondrial polypeptides. The mtDNA is exclusively maternally-inherited and present in thousands of copies per cell. It also has a very high mutation rate about ten times faster compare to the nuclear DNA (nDNA). As a result, new mtDNA mutations arise frequently in the maternal lineage, initially present as a mixture of the wild-type and mutant mtDNAs, defining the so-called heteroplasmic state. MtDNA mutations are most often heteroplasmic (mixed population of normal and mutant mtDNAs). During cellular divisions, the mutant mtDNAs will be randomly segregated into the daughter’s cells and the percentage of mutant mtDNAs in different cell lineages will drift toward either pure mutant or normal (or homoplasmy). As the percentage of mutant mtDNAs increases in the cell, energy output falls, resulting in mitochondrial dysfunction. Hence, the ratio of mutant to normal mtDNA contributes to the severity of the disease. Few examples of neurological phenotypes include the tRNALys m.8344A > G mutation associated with Myoclonic Epilepsy and Ragged Red Fiber (MERRF) disease; the tRNA Leu(UUR) m.3243A > G mutations associated with Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS); and the ATP6 m.8993T > G and T > C associated with Neurogenic muscle weakness, Ataxia, and Retinitis Pigmentosa (NARP) and Leigh syndrome and the ND4 m.11778G > A mutation associated with Leber Hereditary Optic Neuropathy (LHON) [1]. More than 200 pathogenic mtDNA mutations have now been identified (http://www.mitomap.org).

No satisfactory therapy is presently available for mitochondrial disorders [2,4]. Treatment remains largely symptomatic and does not significantly alter the course of the disease. It includes symptomatic treatments, cofactor supplementation, prevention of oxygen-radical damage to mitochondrial membranes, dietary recommendations, and avoidance of drugs or procedures known to have a detrimental effect. Except rare patients carrying a primary deficiency affecting coenzyme Q10 synthesis, who have been treated successfully with oral ubiquinone, yet none of the current therapies have been convincingly shown to slowdown or prevent the progression of the disease [4].

4. Mitochondrial and neurodegenerative diseases spectrum Mitochondrial disorders are involved in a large spectrum of syndromes usually associated with central or peripheral neurological clinical features. Any organ may be involved but more often they may result in variable multisystem disorders characterized by a wide combination of symptoms affecting different tissues, but predominantly the skeletal muscle and central nervous system (CNS) with a large variety of neurological phenotypes. Clinically, neurological diseases due to mitochondrial dysfunction have usually a delayed onset and a progressive course and can either be stereotypic in their presentation such as optic atrophy in LHON or mitochondrial encephalopathy in Leigh syndrome (LS). Leigh syndrome or subacute necrotizing encephalopathy is one of

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Fig. 2 – Main pharmacological targets. The central picture shows the mitochondrial network of a fibroblast cell, the pink box, the main mitochondrial dysfunctions associated to neurodegeneration and the green box the main neuroprotective mitochondrial targets.

the most common mitochondrial diseases with an estimated incidence of 1:40 000 births. Leigh’s syndrome represents the common clinical end point for the most severe mitochondrial OXPHOS defects. The most common mtDNA mutation occurs in the mitochondrial ATPase 6 (m.8993A > G or m.8993A > C). Other nuclear genetic defects have been described such as nuclear encoded complex I or complex IV genes including SURF-1 mutations [1]. Mitochondrial dysfunction is also implicated in the etiology of a large spectrum of common multifactorial neurodegenerative disorders, often associated with aging. Common neurodegenerative disorders are rarely due to a single gene defect but usually result from a combination of genetic and environmental factors (diet, exercise, hormones, aging). Indeed, aged-related neurodegenerative diseases have been convincingly associated with mitochondrial dysfunction in PD, AD, HD or ALS as extensively reviewed [1]. Bioenergetics defects, altered mitochondrial dynamics, accumulation of abnormal mitochondria, impaired axonal transport and defects in mitochondrial regulatory pathways are regularly reported in mitochondrial and neurodegenerative disorders (Fig. 2). These defects are all potential therapeutic targets and restoring these signaling pathways may be an effective therapeutic modality to reduce neuronal cell death. The concept of mitochondrially-targeted neuroprotection has emerged as an important protective mechanism against the age-dependent mitochondrial decline commonly seen in neurodegenerative disorders (Fig. 2). In addition to ATP production, mitochondria are involved in a

number of critical pathways, including programmed cell death, calcium buffering, lipid metabolism, biosynthesis (steroids, heme, iron-sulfur clusters), and more generally in cell signaling. Hence, mitochondrial homeostasis has to be tightly regulated by multiple signaling pathways that may be targeted for therapeutic purposes.

5. Intervention on mitochondrial energy production and scavenging ROS Pharmacological or metabolic therapeutic strategies may focus on 2 potential goals: producing more ATP and/or reducing the accumulation of mitochondrial ROS by-products of a defective or stalled electron transport chain, a major consequence of a mitochondrial dysfunction. An excess of toxic by-products is indeed considered as deleterious for mitochondrial function and thought to be a key contributor of mitochondrial symptoms. Several open clinical trials have been designed to investigate the usefulness and efficacy of coenzyme Q10 (CoQ10). CoQ10 plays a key role in regulating the electron flow in the electron transport chain, transferring electrons from complex I and II to complex III but has also been shown to act as an antioxidant. Low CoQ10 cellular content appears to be deleterious to mitochondrial functions and dietary supplementation would then be advantageous. Primary CoQ10 deficiency is a rare defect of the electron transport chain due to a blockade of the CoQ10 biosynthetic pathway [9]. This

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disorder clinically heterogeneous affects predominantly brain and muscle with encephalomyopathies, Leigh syndrome, severe multisystem infantile form, pure myopathies or cerebellar ataxia. Patients with such primary deficiency benefit from a CoQ10 supplementation [10]. CoQ10 has been given to other mitochondrial disease patients with varying degrees of success, aiming to enhance electron transfer of the respiratory chain and then ameliorate the symptoms [3]. Idebenone, a synthetic analogue of CoQ10, is a short chain quinone that may penetrate the blood brain barrier more efficiently. Mitochondrial dysfunction and oxidative stress play key roles in neurodegeneration [1]. Friedreich’s ataxia (FA), one of the most common hereditary ataxia is caused by a deficiency in frataxin due to mutations in FXN gene, a regulator of mitochondrial iron processing. Patients with FA manifest cerebellar ataxia, peripheral neuropathy, hypertrophic cardiomyopathy, and diabetes. The idebenone treatment in FA has shown evidence of sustained mitochondrial energy production and clinical improvement with a stabilization of neurological function in pediatric cases when given at high doses, and suggesting that early patient treatment seems to be beneficial to reduce mitochondrial damage [11]. Idebenone has been also assessed in randomized double-blind clinical trials of LHON and has been reported to be beneficial in LHON patients [12,13]. EPI-743 is a synthetic para-benzoquinone analogue, which has been shown to be more active as an antioxidant in cell culture (> 1000-fold) compared to CoQ and idebenone. In two open trials, EPI-743 has been used in patients with Leigh syndrome [14] and LHON [15]. In both open clinical trials, beneficial effects of EPI-743 with better clinical outcomes were reported. An ongoing randomized double-blinded and placebo-controlled clinical trial of EPI-743 aiming to treat children with Leigh syndrome is currently in progress. As an alternative, another option is to modulate the Ca2+ uptake and the mitochondrial permeability transition pore involved in apoptosis, and thus delay cellular loss due to mitochondrial apoptosis, which has been extensively reviewed in [5].

6. Intervention on pathways regulating mitochondrial biogenesis Mitochondrial content and activity are tightly and constantly adapted to cell metabolism through regulating pathways that have been extensively characterized during the last years. Mitochondria are under strong dependency of environmental factors such as quantitative and qualitative nutritional supply, oxygen availability and physical activity. The regulating pathways are constantly adapted to fulfill cell metabolism under those environmental factors. For instance, a sharp increase of mitochondrial mass in the skeletal muscle can be induced by endurance training and mitochondrial disorders are often associated with a compensatory increase of mitochondrial mass. The regulation of mitochondrial biogenesis plays a central role in the pathophysiology of mitochondrial dysfunction. It was recently suggested that the ability of mtDNA mutation carriers to increase their mitochondrial mass and biogenesis may explain the incomplete

penetrance seen in LHON disease [16]. Indeed, the unaffected mutation carriers have a significantly higher mtDNA copy number compared to their affected relatives and healthy controls, the fibroblasts of the unaffected carriers showing the highest capacity for activating mitochondrial biogenesis. Mitochondria of non-proliferative cells have a constant turnover with an estimated half-life of 10 to 25 days [17]. Mitochondrial biogenesis occurs through the fission of preexisting mitochondria followed by growth. Most of the mitochondrial components, such as proteins and lipids, are imported, respectively from the cytosol and the reticulum endoplasmic, but few of them (13 proteins, 22 tRNAs and 2 rRNAs) are also synthesized in situ from the mitochondrial genome. At least three levels of factors regulating mitochondrial biogenesis can be distinguished, those regulating in organella mtDNA expression, those coordinating nuclear and mitochondrial genes expression and those coordinating the mitochondrial metabolism with the general cell and body metabolism. The factors controlling mitochondrial DNA expression are mainly represented by mitochondrial transcription factor A (TFAM), an ubiquitous transcription factor mitochondriallytargeted that promotes both replication and transcription of the mtDNA. TFAM interacts with both promoters of the mitochondrial genome by facilitating the interaction with the RNA polymerase. Other transcription factors, such as TFB1 M and TFB2 M (transcription factors B1 and B2) also contribute to the expression of genes encoded by mtDNA. The overexpression of TFAM enhanced oxidative metabolism and improved memory capacities in aged mice [18]. Another level of regulation involves the ubiquitous transcription factors NRF1 and NRF2 (Nuclear Respiratory Factors 1 and 2) controlling the expression of several nuclear encoded respiratory chain components as well as the expression of TFAM regulating the mtDNA expression, thus assuring the required coordination between the two genomes. Moreover, recent reports have showed that microRNAs also participate to the control of mitochondrial and nuclear gene expression [19]. The third level of regulation, coordinating mitochondrial function to the general cell metabolism is obviously much more complex and significant progresses have been made during the last decade. Involved factors have mainly a tissuespecific expression to fulfill the metabolic functions and requirements of the different organs. At least two main families of regulator intervene at this level, the PPAR gamma coactivator 1 family of transcription coactivators and the sirtuins. PPAR gamma coactivator 1-alpha (PGC-1a) coordinates the mitochondrial biogenesis and the metabolic status of cells (glucose uptake, glycolysis, b-oxydation, thermogenesis, mitochondrial respiratory capacity). It is mainly expressed in brown adipose tissue, skeletal muscles, heart, kidneys and brain. By directly interacting with NRF1, PGC-1a increases the ability of NRF1 to activate its target genes. Another coactivator is PGC-1-related coactivator (PRC), which is ubiquitously expressed, also increases the capacity of NRF1 to activate its targets. A number of studies have demonstrated the implication of PGC-1a/b and downstream targets in the pathogenesis of neurodegenerative disorders. Impaired expression or function of PGC-1a has been shown in cellular and mouse models of HD, PD, AD and ALS and

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several studies have shown that the restoration of PGC-1a was neuroprotective [20,21]. Huntingtin mutant leads to mitochondrial dysfunction and represses transcriptional activity of PGC-1a whereas overexpression of PGC-1a is neuroprotective in the same mouse model [22]. In AD, overexpression of PGC1a protects against Ab accumulation and promotes cell survival [23]. Increasing muscle PGC-1a stimulates mitochondrial biogenesis and improves motor function in ALS mice model [24]. PGC-1a plays an important role against oxidative stress since mice lacking PGC-1a display enhanced hippocampal neurodegeneration when exposed to ROS, the PGC-1a overexpression protecting hippocampal neurons against apoptosis after transient ischemic episodes [25,26]. These results show that PGC-1a expression is a crucial factor for neuroprotection. Sirtuins is a family (SIRT1-7) of proteins mainly composed of NAD-dependent histone deacetylases involved in the regulation of body energy homeostasis, cellular metabolism, response to cellular stress, and cell survival. Sirtuins deacetylate numerous proteins and enzymes involved in various cellular pathways. Most enzymes of the major metabolic pathways are acetylated and reversible lysine acetylation corresponds to a global mechanism coordinating energy metabolism [27]. SIRT1-7 target distinct sets of acetylated protein substrates and are located in distinct sub-cellular compartments [28]. SIRT1, SIRT6 and SIRT7 are found in the nucleus, SIRT2 mainly in the cytosol and SIRT3-5 in the mitochondria. Taken into account their NAD-dependent roles of metabolite sensor and regulator, sirtuins are very promising targets for neuroprotective strategies. SIRT1 controls the activity of various transcription and coactivators including PGC-1a, the tumor suppressor P53 and FOXO proteins. It regulates glucose metabolism, fatty acids oxidation, lipid metabolism, insulin secretion and sensitivity, and modulates oxidative stress. SIRT1 overexpression was shown to reduce the production of Ab and plaques and leads to significant neuroprotection in AD transgenic mice [29]. Inactivation of SIRT2 was found to increase a-synuclein toxicity and the dopaminergic cell death in models of PD [30]. Overexpression of SIRT3 was found to be protective against excitotoxicity in cultured mouse cortical neurons exposed to Acide N-methylD-Aspartic (NMDA) [31]. SIRT1 also controls the deacetylation of PGC-1a, promoting its nuclear translocation. Numerous other factors including hormones, calcium, NO, cAMP, and kinases signaling pathways (PKA; MAPK) also participate at different levels to the regulation of mitochondrial biogenesis by direct or indirect regulation of PGC-1a [21]. AMP-activated kinase (AMPK) upregulates PGC-1a activity by sensing changes in the AMP/ ATP ratio. AMPK serves as an energy sensor for whole body energy regulation. During low energy states, this activation leads to increased glucose transport, fatty acids oxidation and mitochondrial biogenesis via PGC-1a phosphorylation. Activation of AMPK in cellular model of HD was found to be neuroprotective and activation of AMK by its agonist AICAR (5aminoimidazole-4-carboxamide ribonucleoside) reduced Ab production in neuronal cell culture [32]. Taken into account their central role in the control of the metabolic fluxes across the organism, sirtuins have rapidly emerged as therapeutic targets of choice in metabolic

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disorders [33]. Resveratrol, a polyphenol of vegetal origin, stimulates SIRT1 activity at least through AMPK activation and the subsequent oxidized NAD+ coenzyme level. It provides the promising opportunity to influence the general metabolic orientation of an individual while maintaining the global physiological equilibrium. Thus, resveratrol was shown to enhance mitochondrial biogenesis and activity providing protection against obesity and insulin resistance and extending lifespan in rodent models of diet-induced obesity. Resveratrol was shown to improve mitochondrial function and lipid levels in obese patients and ameliorate glycemic control in diabetic patients [34]. Multiple protective properties of resveratrol have been reported, but these effects are highly pleiotropic and strongly tissue- and dose-dependent. Resveratrol was reported to be protective in several models of neurodegenerative disorders [20]. For instance, resveratrol increases the survival of motor neurons in ALS mice, reduces neurodegeneration in AD mice, provides neuroprotection against 3-NP induced motor and behavioral deficits, protects against Ab accumulation, and ameliorates behavioral disorders and mitochondrial dysfunction in HD mice [20]. Several analogues of resveratrol activating SIRT1 are currently evaluated. NAD+ precursors, such as nicotinamide mononucleotide, that increase intracellular NAD+ levels, also represent alternative ways to enhance SIRT1 activity and thus to activate mitochondria. Other sirtuin family members are also potential promising targets of neuroprotection as shown recently for mitochondrially-targeted SIRT3 in HD cell model [35]. Cells expressing huntingtin mutant were found to have reduced SIRT3 expression levels and the SIRT3 activation by the viniferin was mito- and neuroprotective. We have recently shown that low doses of resveratrol using in vivo and in vitro models directly stimulates mitochondrial complex I activity which in turn modulates the mitochondrial NAD+/NADH ratio. Increasing NAD+ concentration leads to SIRT3 activation and finally induces mitochondrial metabolism [36]. The coordinated expression of OXPHOS by nuclear and mitochondrial genomes was recently evidenced to be compromised in aging leading to a pseudo-hypoxic phenotype [37]. A specific loss of mtDNA expression in skeletal muscle, related to a decline of nuclear NAD+ content, was found without any alteration of the nuclear gene expression. This deregulation was reversed in old mice by raising the NAD+ levels restoring mitochondrial function compared to young animals. Interestingly, the pathway mediating this aging-related deregulation was independent of PGC-1a/b but involves the following signaling cascade: Activation of SIRT1 by the nuclear NAD+ leading to a stabilization of HIF-1a (Hypoxia Inducing Factor) that modulated the c-Myc oncogene ability to activate TFAM and thus the mtDNA expression. This study illustrates that mitochondrial regulation pathways are highly pleiotropic and highlights one more time the key role of NAD+/NADH ratio in the cellular and mitochondrial control of metabolism. Several other nuclear receptors acting as transcription factors also participate to mitochondrial biogenesis and activation such as PPAR (peroxisome proliferators-activated receptors) RXR (retinoid X receptors) and ERR (estrogen-related receptors). PPAR mainly regulates genes involved in fatty acids oxidation. The activation of PPARa, PPARd and PPARg

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respectively by fibrates, bezafibrate and rosiglitazone were shown to improve fatty acid oxidation with beneficial effects on energy homeostasis. More generally, PPAR agonists improve PGC-1a and downstream targets expression and several studies have demonstrated a neuroprotective effect, as for instance in the case of the PPARa agonist rosiglitazone which was found to provide neuroprotection in models of PD, ALS, AD and HD [20]. For instance, in HD transgenic mouse model, the treatment with bezafibrate restores PGC-1a, PPAR and downstream genes expression to the levels of wild-type mice with a significant improvement in phenotype and survival. Astrogliosis and neuronal atrophy was attenuated in the striatum with an increase number of mitochondria [38]. Bezafibrate was shown to exert a neuroprotective in a mouse model of encephalopathy due to cytochrome c oxidase deficiency [39]. PPARa and PPARg agonist were also found to protect neurons by modulating mitochondrial dynamics [40].

7. Intervention on the mitochondrial quality control system Mitochondria are highly dynamic organelles that continuously move, fuse and divide in response to variations of cell energy demand [41]. The mitochondrial shape and distribution result from a constant balance between the opposing forces of fusion and fission. The neuronal plasticity is strongly dependent to mitochondrial dynamics. Indeed, it has been shown that dendritic mitochondria play a determinant role in the morphogenesis and plasticity of spines and synapses [42]. Initially described in OPA1-related dominant optic atrophy and in MFN2-related Charcot-Marie-Tooth type 2A, dysfunction of mitochondrial dynamics was progressively found to be altered in models of most neurodegenerative diseases such as AD, PD, and HD [43,44]. Mitochondrial dynamics is mediated by large dynamin GTPases (DRP1, OPA1, MFN1 and MFN2) embedded in mitochondrial membranes [45]. Mitochondrial fission generates new organelles necessary for cellular growth and cell proliferation. It also allows the elimination of damaged mitochondria. Mitochondrial fusion allows a tight complementation between organelles induced by energy requirements at the cellular level. Mitochondrial dynamics is essential in non-proliferating cells such as neurons since it allows the renewal of the damaged mitochondria. Mitochondria are indeed continuously exposed to the stress generated by the production of ROS and they accumulate mtDNA mutations leading to progressive energy production decline. In addition, misfolded proteins, such as huntingtin mutant, asynuclein mutant or b-amyloid peptide, accumulate in mitochondria and cause bioenergetics defects, dysregulation of mitochondrial dynamics and increase sensitivity to apoptosis [46]. The mitochondrial quality control involves:  proteases that eliminate damaged proteins and respond to unfolded protein stress;  the ubiquitin-proteasome system that removes damaged protein from the outer membrane, and;

 the complete elimination of mitochondria through lysosome mediated autophagy/mitophagy. Photodamaged and depolarized mitochondria are submitted to selective mitophagy highly dependent on mitochondrial dynamics. PINK1, a mitochondrially-targeted kinase involved in an inherited form of Parkinson disease, is constitutively repressed and degraded by the rhomboid protease PARL. When mitochondria are depolarized and non-functional, PINK1 accumulates in the outer mitochondrial membrane, tagging damaged mitochondria. Moreover, a strong reduction of mitochondrial membrane potential by CCCP, a mitochondrial uncoupler triggers PINK1 recruitment in the mitochondrial outer membrane [47]. Thus PINK1 acts as a sensor of mitochondrial membrane potential and functionality. PINK1 recruits the E3 ligase Parkin which in turn ubiquitinates the proteins of the mitochondrial outer membrane. Mutations in the E3 ligase Parkin are also linked to a rare inherited form of Parkinson disease. These ubiquitinyled proteins are subsequently degraded by the proteasome system. Such proteasomal degradation of the pro-fusion mitofusins (MFN1 and MFN2) leads to the fragmentation and the isolation of the mitochondria and its subsequent elimination by lysosomalmediated mitophagy. Thus, in non-proliferative cells unable to renew their mitochondrial capital by cell selection, the nonfunctional and damaged mitochondria are selectively eliminated by mitophagy, leaving healthy mitochondria to divide and proliferate through the mechanisms of mitochondrial biogenesis previously discussed. Indeed, the cellular mitochondrial content results from a fine equilibrium between biogenesis and degradation. Interestingly, the two processes are also tightly regulated in a coordinated manner by PGC-1a. In HD mouse model, overexpression of PGC-1a not only stimulated mitochondrial biogenesis, but also upregulate autophagy to eliminate huntingtin mutant aggregates. However, this major PINK1/Parkin pathway for injury-induced mitophagy is not the universal mitophagic pathway and other pathways have been recently described in the mitophagic process based on cell type and type of cell insults [48]. These pathways of mitochondrial renewal play a crucial role in neurodegenerative diseases and may become therapeutic targets of choice for several reasons. Firstly, all genetic defects of mitochondrial dynamics described so far are primarily neurodegenerative diseases with optic atrophy, neurosensorial deafness, peripheral neuropathy or central nervous system involvement. Secondly, mitochondrial dynamics abnormalities were repeatedly seen in aging and in models of most of the common neurodegenerative diseases. This is reinforced by the fact that the PINK1/Parkin pathway was deciphered by studying genes mutated in familial forms of Parkinson disease, bringing to light a central pathomechanism of neurodegeneration. Thirdly, accumulation of abnormal mitochondria has been repeatedly associated to neurodegenerative diseases. MtDNA instability has become a biomarker of choice, easy to investigate, of the damaged mitochondria since aging in non-proliferating cells is often associated with the accumulation of mtDNA mutations [1]. Several studies have shown high mutation rates in specifically affected neurons in Parkinson and Alzheimer’s diseases. Lastly, the existence of a mechanism able to eliminate

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damaged mitochondria allowing the renewal of the cellular mitochondrial pool from healthy mitochondria strongly suggests that the mitochondrial decline associated to aging may be reverted. Hence, combined stimulation of mitophagy and mitochondrial biogenesis of functional mitochondria may represent a promising therapeutic strategy in treatment and prevention of common neurodegenerative diseases. Drugs enhancing the activity of the PINK1/Parkin pathway begin to be developed as recently reported by Hertz et al. [49] who showed that the ATP analog kinetin triphosphate (KTP) increased PINK1 activity, leading to higher levels of Parkin recruitment to depolarized mitochondria. More generally, the use of candidate drugs triggering mitophagy appears as a promising protective target in many neurodegenerative models [50]. Such innovative therapeutic strategies interfering with autophagy were recently reported in mitochondrial neurodegenerative diseases using rapamycin, a specific inhibitor of the mTOR (mammalian Target Of Rapamycin), able to activate mitophagy. In a cell model carrying an heteroplasmic mtDNA mutation (m.11778G > A) responsible for LHON, rapamycin induced the colocalization of mitochondria with autophagosomes resulting in a reduction of the mutant load and leading to partial restoration of ATP levels [51]. Rapamycin, was also found to prevent brain lesions, to attenuate disease progression and finally to enhance survival of a mouse model of Leigh syndrome due to mitochondrial complex I defect [52]. However, in this later study, the mechanism of action was rather found to be due to a metabolic shifting than to autophagic-mediated rescue of mitochondrial function. Concerning the mitochondria responsible for ATP production in the synapses, the axonal transport must intercalate between these coupled processes of mitochondrial biogenesis and degradation. Indeed, the mitochondrial biogenesis and mitophagy both take place in the cellular body of neurons requiring an anterograde transport of healthy mitochondria toward the synapse and a retrograde transport of aged mitochondria backward to the cellular body. Again, the mitochondrial dynamics and the level of mitochondrial membrane potential are involved in mitochondrial transport in addition to energy-dependent kinesins that drive mitochondria along the microtubules. This complex interdependency between mitochondrial dynamics, biogenesis, transport and degradation is emphasized by clinical expression resulting from mutations in MFN2 (fusion protein of the mitochondrial outer membrane), OPA1 (fusion protein of the mitochondrial inner membrane) and GDAP1 (outer membrane protein involved in mitochondrial fission) that predominantly affect neurons with the longest axons such as peripheral and optic nerves.

8. Intervention on mitochondrial metabolism and mtDNA mutant load through dietary measures A series of nutritional strategies have been used in an attempt to modulate mitochondrial dysfunction and to force oxidative metabolism. It includes L-arginine treatment, dietary measures such as ketogenic diet, vitamins and nutritional supplements.

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L-arginine has been proposed as a treatment for MELAS m.3243A > G syndrome patients during the acute stroke phase or long term use [53,54]. The logic of this approach is that the stroke-like episodes of MELAS syndrome are the result of mitochondrial production of superoxide anion which destroys NO (Nitric Oxide) in vascular endothelial and smooth muscle cells. Since NO is a vasodilator, loss of NO would result in chronic vasoconstriction and transient ischemia. As the substrate of NOS, L-arginine should stimulate NOS, to generate more NO and alleviate the vasoconstriction. The NO diffuses out of the mitochondrion and cell where it causes relaxation of the vascular smooth muscle cells resulting in vasodilation and increases tissue oxygenation. L-arginine is administrated either by intravenous injections (0.5 g/kg/day) during crises or orally between crises at 0.15-0.3 g/kg/day [54]. Arginine supplementation of these patients inhibits the recurrence of stroke [53] or ameliorates endothelial function [55]. However, the cells containing a higher percent mutation are expected to produce less ATP and produce more free radicals triggering mitochondrial apoptosis. Hence, this system can be compromised by genetic defects that inhibit the ETC and increase ROS production, since mitochondrial O2.S reacts with NO to generate peroxynitrite (ONOO ), inactive as a vasodilator. This may explain why the mtDNA tRNALeu(UUR) nt 3243A > G mutation which causes MELAS [56] is associated with vasoconstriction and stroke-like localized ischemia. Other supplements given to mitochondrial disease patients in order to increase respiratory chain efficiency [57] are carnitine that facilitate the fatty acids import and mitochondrial catabolism, niacin, the precursor of NAD that carry the electrons to the RC, the FAD precursor riboflavin, the other coenzyme carrying electron toward the RC, and thiamine that facilitates the pyruvate dehydrogenase activity. Dichloroacetate (DCA), a structural analogue of pyruvate, is another activator of pyruvate deshydrogenase that enhance oxidative respiration of carbohydrates limiting the anaerobic glycolysis and lactate accumulation. This strategy had limited success in ameliorating clinical symptoms. Moreover, adverse events with a high incidence of drug-induced peripheral neuropathy were reported in a group of DCA treated patients carrying the 3243A > G mutation [3]. Lastly, supplementation with creatine, that facilitates the ATP storage through the creatine phosphokinase system mainly in skeletal muscle and brain, was evaluated in controlled clinical trials [3]. Although no adverse effects were observed, most of these studies did not show significant clinical benefit. The Ketogenic Diet (KD) is a high-fat diet in which carbohydrates are almost eliminated from the regimen. The efficacy of Ketogenic Diet (KD) in intractable epilepsy in children or adult patients has been proven for almost a century but the neuroprotective properties of KD still remain to be understood [58]. KD was shown to be safe and improve the outcome of patients with mitochondrial disorders associated with intractable epilepsy [59]. In addition, KD reduces the percentage of deleted mtDNA molecules in cells carrying large-scale heteroplasmic deletions after 5 days of treatment [60]. Shifting the levels of heteroplasmy towards the normal

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mtDNA (or heteroplasmy shifting) has become the goal of a large variety of invasive or non-invasive methods. A small decrease of the mutant load in cells may be enough to rescue the phenotype if you pass under the pathogenic threshold of the mtDNA mutation. Moreover, the ketone bodies (b-hydroxybutyrate and acetoacetate) are used preferentially by the mitochondrial respiration bypassing the glycolytic pathway and then selecting cells with wild-type mtDNA molecules. A key aspect of the KD is the restriction in carbohydrates and energy mainly derived from ketone bodies and not from glycolysis. The role of glucose deprivation has been investigated with the use of 2deoxy-D-glucose (2-DG) a glucose analogue not metabolized by glycolysis and then mimicking caloric restriction. Treatment using 2-DG is neuroprotective in a mouse model of AD, increasing ketone metabolism, enhancing mitochondrial bioenergetics with a significant reduction of b-amyloid accumulation [61]. There is increasing evidence that the KD may produce beneficial effects to patients with AD, PD or other neurodegenerative disorders. Such diet may have profound effects on neuronal plasticity and glutamate-mediated toxicity, reducing inflammation, improving bioenergetics with more ATP produced and reducing ROS production, maybe through the induction of uncoupler proteins [58]. Concerning the influence of nutritional conditions on mitochondrial metabolism, it is interesting to notice that caloric restriction prolongs lifespan in several organisms reducing oxidative stress and improving antioxidant enzymes [62].

9.

Conclusion

The neurodegenerative diseases are closely linked to ageing and to the parallel decline of mitochondrial functions. The mitochondrial therapeutic targets discussed in this review such as the control of mitochondrial content and plasticity, the modulation of metabolic fluxes, and the improvement of mitochondrial renewal are all interdependent. A tight coordination of the different therapeutic strategies is likely to synergistically improve energy metabolism. However, the beneficial effect of increasing respiratory chain efficiency may be counteracted by the increased oxidative stress generated by a potential electron overflow in the mitochondria. This suggests the importance to include anti-oxidants in therapeutic strategies to improve mitochondrial function. We have learnt from inherited mitochondrial diseases that only a slight increase of mitochondrial efficiency is somewhat sufficient to alleviate the clinical expression of the diseases. This suggests that such mitochondria-targeted therapies could efficiently slow down the outcome of common neurodegenerative disorders. However, there is a pressing need for advancing mitochondrial therapeutics and identify biomarkers of mitochondrial dysfunction to evaluate the treatment efficacy in future clinical trials. Pilot studies focused on candidate drugs should give the groundwork for larger and long term randomized international and multicenters placebo-controlled trials. Lastly, we must keep in mind that many compounds including pesticides, anti-retroviral agents, antibiotics, analgesics, chemotherapies and cholesterol-lowering drugs have

been reported to induce mitochondrial dysfunction. Moreover, mitochondrial toxicity has been suggested to represent a major cause of concern in preclinical and clinical therapeutic studies [63]. Thus, the prevention of such mitochondrial toxicity remains undoubtedly a major element of prevention in the management of neurodegenerative diseases.

Disclosure of interest The authors declare that they have no conflict of interest concerning this article.

Acknowledgments This work was supported by grants from the following research institutions: Re´gion Pays de la Loire, Association Franc¸aise contre les Myopathies (AFM HAO2013, No. 17122), Fondation pour la Recherche Me´dicale (FRM DPM20121125554), Union Nationale des Aveugles et De´ficients Visuels, Retina France, Ouvrir les Yeux, and Association contre les Maladies Mitochondriales.

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