REVIEW ARTICLE

Mitochondrial Dysfunction in Central Nervous System White Matter Disorders Laia Morat o,1,2 Enrico Bertini,3 Daniela Verrigni,3 Anna Ardissone,4 Montse Ruiz,1,2 Isidre Ferrer,5,6 Graziella Uziel,4 and Aurora Pujol1,2,7 Defects of mitochondrial respiration and function had been proposed as a major culprit in the most common neurodegenerative diseases, including prototypic diseases of central nervous system (CNS) white matter such as multiple sclerosis. The importance of mitochondria for white matter is best exemplified in a group of defects of the mitochondria oxidative metabolism called mitochondria leukoencephalopathies or encephalomyopathies. These diseases are clinically and genetically heterogeneous, given the dual control of the respiratory chain by nuclear and mitochondrial DNA, which makes the precise diagnosis and classification challenging. Our understanding of disease pathogenesis is nowadays still limited. Here, we review current knowledge on pathogenesis and genetics, outlining diagnostic clues for the various forms of mitochondria disease. In particular, we underscore the value of magnetic resonance imaging (MRI) for the differential diagnosis of specific types of mitochondrial leukoencephalopathies, such as genetic defects on SDHFA1. The use of novel technologies for gene identification, such as whole-exome sequencing studies, is expected to shed light on novel molecular etiologies, broadening prenatal diagnosis, disease understanding, and therapeutic options. Current treatments are mostly palliative, but very promising novel gene and pharmacologic therapies are emerging, which may also benefit a growing list of secondary mitochondriopathies, such as the peroxisomal disease adrenoleukodystrophy. GLIA 2014;00:000–000

Key words: mitochondria, myelin, leukoencephalopathy, MRI, SDHAF1

The Importance of Mitochondria in Central Nervous System White Matter

T

he pivotal role of mitochondrial dysfunction in neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), or amyotrophic lateral sclerosis (ALS) has been amply documented (Beal, 2005; Gibson et al., 2010). Dysfunction of the mitochondria, the powerhouse of the cell, is usually coupled to oxidative stress. Most of the motor disability that occur in these diseases can be attributed to axonal loss or degeneration. Axons in the white matter have an extremely high-energy demand, required to maintain the ionic gradient and to keep the structural integrity necessary to support neurotransmission. This high energy demand of myelinated axons is pri-

marily met by ATP-producing axonal mitochondria (Court and Coleman, 2012). In addition to neurons, the different glial cells also rely on mitochondria function. For instance, mitochondrial b-oxidation results in the production of acetylCoA, which is essential for the build-up of cholesterol and other complex lipids that are required in the myelination process. Indeed, when mitochondrial function is disrupted, oligodendrocyte differentiation, viability (Schoenfeld et al., 2010; Silva et al., 2009), and capacity to form myelin sheaths (Ziabreva et al., 2010) are compromised. Moreover, mitochondrial dysfunction in Schwann cells (SC) triggers abnormal lipid metabolism, depletion of myelin lipid components, and disruption of axon–SC interactions, which eventually trigger axonal degeneration and demyelination (Viader et al., 2013).

View this article online at wileyonlinelibrary.com. DOI: 10.1002/glia.22670 Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com). Received Aug 31, 2013, Accepted for publication Mar 21, 2014. Address correspondence to Aurora Pujol, Neurometabolic Diseases Laboratory, IDIBELL, Hospital Duran i Reynals, Gran Via 199, 08908 L’Hospitalet de Llobregat, Barcelona, Spain. E-mail: [email protected] From the 1Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain; 2Center for Biomedical Research on Rare Diseases (CIBERER), ISCIII, Spain; 3Unit for Neuromuscular and Neurodegenerative Diseases, Laboratory of Molecular Medicine, Bambino Ges u Children’s Hospital, IRCCS, Rome, Italy; 4Department of Child Neurology The Foundation “Carlo Besta” Neurological Institute (IRCCS), Milan, Italy; 5Institute of Neuropathology, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Spain; 6Center for Biomedical Research on Neurodegenerative Diseases (CIBERNED), ISCIII, Spain; 7Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Spain. Additional Supporting Information may be found in the online version of this article.

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Myelin is not only essential for saltatory conduction but also to preserve the architecture (Viader et al., 2013) and to provide metabolic support to axons (Funfschilling et al., 2012; Nave, 2010). The relationship of astrocytes with white matter integrity is best exemplified in inherited leukodystrophies such as Alexander’s disease and megalencephalic leukoencephalopathy with subcortical cysts (MLC1) caused by mutations in genes encoding astrocyte-specific proteins (Molofsky et al., 2012). Remarkably, essential roles of astrocytes such as support of neurotransmission or supply of energy substrates to neurons are regulated by mitochondria. For example, energy produced in the mitochondria of the astrocytes is necessary to avoid excitotoxicity. In the astrocytic end-feet, ATP is mostly consumed by the Na1/K1 pump, which take up K1 released by axons after each depolarization and re-establishes the Na1 gradient necessary for glutamate uptake (Cambron et al., 2012). Moreover, the mitochondrial enzymes glutamate dehydrogenase and pyruvate carboxylase are key players in the glutamate–glutamine cycle, important not only to prevent excitotoxic damage but also to provide glutamine to the neurons as an energetic substrate (Stobart and Anderson, 2013). Mitochondrial creatine kinase in the astrocytes is pivotal for the generation of phosphocreatine, a metabolic buffer that is transported from mitochondria to high-energy consuming areas in the cytosol (Cambron et al., 2012). Astrocytes also provide energy to neurons in the form of lactate, which requires NADH for its synthesis, which in turn is regulated by the mitochondrial malate-aspartate shuttle (Hirrlinger and Dringen, 2010). Indeed, aralar mice (deficient for the mitochondrial malate-aspartate carrier) present impaired neuronal development (Gomez-Galan et al., 2012) and hypomyelination (Ramos et al., 2011). Similarly, patients with mutations in the mitochondrial aspartate-glutamate carrier isoform 1 (AGC1) present a severe hypomyelination (Wibom et al., 2009). In neurons, AGC1 transports aspartate from mitochondria to the cytosol to synthesize N-acetylaspartate (NAA), which will be transferred to oligodrendrocytes in order to supply acetyl groups for the synthesis of myelin lipids. Finally, mitochondria also play a key role in microglial cells, the active immune defence of the central nervous system. In several neurological diseases, infiltration of macrophages into the central nervous system (CNS) and activation of resident microglia is largely observed. The nature of the damage and the capacity of response of these cells determine whether they will adopt a neuroprotective role or in contrast, a phenotype that will exacerbate tissue injury. In microglial cells, intracellular reactive oxygen species (ROS)—produced mainly by the plasma membrane-bound enzyme NADPH oxidase—are crucial for the pro-inflammatory response (Block 2

et al., 2007). ROS and reactive nitrogen species (RNS) produced by activated macrophages and microglia may directly damage axonal mitochondria, which in turn, mediates focal axonal degeneration in a mouse model of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS) (Nikic et al., 2011). Moreover, a growing bulk of evidence indicates that mitochondria are also essential for the synthesis of pro-inflammatory mediators since their production is regulated by mitochondrial ROS (Bulua et al., 2011; Naik and Dixit, 2011; Voloboueva et al., 2013; Zhou et al., 2011a) and mitochondrial fission events (Park et al., 2013). Mitochondrial KATP channels in activated microglia have been proposed as regulators of mitochondrial membrane potential and mainly responsible for adoption of a specific phenotype to respond to the surrounding signals. Activation of these mitochondrial channels alleviates rotenone-induced mitochondrial membrane potential loss, ROS production, and release of pro-inflammatory mediators (Rodriguez et al., 2013; Zhou et al., 2008). Thus, mitochondrial dysfunction in neurons, oligodendrocytes, astrocytes, or even microglia can disrupt the delicate equilibrium of the white matter in the nervous system.

From Mitochondrial Dysfunction to White Matter Disease Three main homeostatic disruptions can combine to threaten mitochondria viability: oxidative stress, ATP reduction, and Ca21 overload (Court and Coleman, 2012). Firstly, ROS are the partially reduced intermediate of oxygen. These include both radical and non-radical species, such as superoxide anion (O22), hydrogen peroxide (H2O2), or hydroxyl radical (HO), with O22 being the precursor of most ROS. Mitochondria can generate ROS from different redox centers in the respiratory chain, in particular from complex I and complex III (Murphy, 2009). However, redox homeostasis is guaranteed if an adequate pool of endogenous cellular enzymatic and non-enzymatic antioxidants is present. Enzymatic antioxidants include superoxide dismutases (SODs), catalases, and glutathione peroxidases (GSH-Px), while non-enzymatic antioxidants include glutathione (GSH), vitamin C, and vitamin E. Many enzymatic antioxidants, such as the thioreductases (Murphy, 2012), are located in the mitochondrial matrix. Thus, oxidative stress occurs when the equilibrium between ROS production and antioxidant capacity is disrupted (Halliwell, 2007). In this scenario, ROS may cause oxidative damage to biological molecules (DNA, RNA, lipids, and proteins) by altering their function or structure. Moreover, lipid peroxidation results in the formation of reactive lipids that can readily react with proteins, generating secondary oxidation products. It is of note that ROS can directly oxidize mitochondrial DNA (mtDNA) molecules. Volume 00, No. 00

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Furthermore, mitochondria in neurons are especially vulnerable to oxidative damage due to the high rate of oxidative metabolic activity, the relatively poor expression of enzymatic antioxidant defenses, the high abundance of peroxidizable polyunsaturated fatty acids in neuron membranes, the high membrane surface to cytoplasm ratio and their nonreplicative nature (Galea et al., 2012; Lee et al., 2012). Secondly, mitochondrial ATP synthesis may be compromised if the respiratory chain complexes (responsible for generating the electrochemical gradient across the inner membrane) or the ATP synthase machinery are affected, as occurs when these proteins are oxidized or when the encoding genes are mutated (Lopez-Erauskin et al., 2013; Wallace et al., 2010). As mentioned before, neurons need ATP to support neurotransmission (synthesis, release, and recycling of neurotransmitters), but ATP is also required for transporting vesicles and organelles along the axon and for ATP dependent pumps to maintain proper ionic homeostasis. Thirdly, decreased activity of the Na1/K1-ATPases due to energy failure leads to Na1 influx, membrane depolarization, and opening of voltage-gated Ca21 channels. In addition, the direction of the Na1/Ca21 exchanger is reversed, resulting in Ca21 influx. Moreover, excessive activation of glutamate receptors under excitotoxic conditions, in particular NMDA receptors, promotes an extra influx of Ca21 (Mehta et al., 2013). Mitochondria play a crucial buffering role when cytosolic Ca21 rises over the physiological range, uptaking the ion through selective uniporters. However, a chronic increase in cytosolic Ca21overloads the mitochondrial buffering capacity and induces mitochondrial membrane depolarization and ROS production. Furthermore, excessive cytosolic Ca21 activates Ca21-dependent protease calpains that mediate cleavage of the axonal cytoeskeleton, leading to necrosis or apoptosis (Mammucari et al., 2011; Wang et al., 2012) and eventually provoking caspase-dependent or-independent oligodendrocyte death (Sanchez-Gomez et al., 2003). The combination of oxidative damage, reduction in ATP and Ca21 dysregulation may induce opening of the mitochondrial permeability transition pore (mPTP) (LopezErauskin et al., 2012; Rasola and Bernardi, 2011). Remarkably, opening of the mPTP abolishes the inner mitochondrial membrane potential, which interferes with the activity of the electron transport chain, which in turn induces the generation of ROS, decreases the production of ATP, and promotes the release of Ca21 into the cytosol, exacerbating the initial damage. Finally, the mPTP opening may induce apoptotic cell death if sufficient ATP is available, or will prime the cell to enter the necrotic process (Lopez-Erauskin et al., 2012; Stavrovskaya and Kristal, 2005). Therefore, combination of redox imbalance, energetic deficit, and Ca21 dyshomeostasis compromises mitochondrial Month 2014

function affecting white matter integrity, eventually leading to a pathological scenario. In this review, we classify mitochondrial disorders that effect white matter into two main groups: (i) primary mitochondrial diseases, which are caused by mutations in genes encoding mitochondria components or in genes directly involved in mitochondrial function (see Table 1) and (ii) secondary mitochondrial diseases, in which mitochondria are genetically intact but lose functionality early in the pathogenic cascade, greatly impacting cellular homeostasis and fostering disease progression. A prototypical disease of this category is multiple sclerosis (Campbell et al., 2012; Lassmann, 2013). Primary Mitochondrial Diseases Mitochondrial disorders represent the most common group of inborn errors of metabolism. The term “mitochondrial syndrome” includes a heterogeneous group of disorders with multisystemic, clinically variable phenotypes. However, a predominance of neurological symptoms is often found, such as optic atrophy, ataxia, seizures, dementia, stroke-like episodes, extrapyramidal features, or neuropathy; this reflects the elevated dependence of CNS on mitochondria. These syndromes can be classified into three main groups: (i) maternally inherited defects in the mtDNA; (ii) diseases caused by mutations in the nuclear DNA (nDNA) that directly or indirectly affect the respiratory chain, and (iii) diseases related to defects of mtDNA maintenance (DiMauro et al., 2013) (see Table 1). As treating all mitochondrial disorders are beyond the aim of this review, we will focus on mitochondrial disorders with a major involvement of the white matter. Although encephalopathy characterized by deep gray matter involvement is one of the more prevalent clinical features, in recent years, white matter involvement has been increasingly recognized as a common feature in patients with mitochondrial diseases (Wong, 2012). Leukoencephalopathy has been described in mitochondrial syndromes associated with mtDNA, such as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) (Fig. 1) or Kearns–Sayre’s syndrome (KSS), as well as in diseases caused by mutations in nuclear genes involved in the maintenance of mtDNA such as mitochondrial neurogastrointestinal encephalopathy (MNGIE) and Alpers syndrome. Mutations in nuclear-encoded respiratory chain complexes resulting in Leigh’s disease or in mitochondrial tRNA synthetases causing leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) or leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) have also been associated with white matter involvement. Finally, diseases linked to defects in mitochondrial dynamics or mitochondrial quality control such as dominant 3

TABLE 1: A Classification of Primary Mitochondrial Diseases

Primary mitochondrial diseases with white matter/axon involvement Altered function

Disease

Mutated gene

Disorders of mtDNA defects Protein synthesis

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) Myoclonic epilepsy with ragged red fibers (MERRF)

OXPHOS subunit

Leber’s hereditary optic neuropathy (LHON)

Large scale deletions

Maternally inherited leigh syndrome (MILS) Kearns–Sayre syndrome (KSS)

tRNALeu

(UUR)

tRNALys MT-ND1, MT-ND2, MT-ND4, MT-ND4L, MT-ND5, MT-ND6 MT-ATP6

Disorders of nDNA defects Respiratory chain subunit

Leigh syndrome (LS)

NDUFA1, NDUFA2, NDUFA10, NDUFA11, NDUFS1, NDUFS2, NDUFS3, NDUFS4, NDUFS7, NDUFS8, NDUFV1, SDHA

Respiratory chain ancillary proteins

Leigh syndrome (LS)

NDUFAF2, NDUFAF5, NDUFAF6, SURF1, COX10, COX15

Metabolic enzymes

Leigh syndrome (LS)

PDHA1

mtRNA translation

Leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL) Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) Combined oxidative phosphorylation deficiency 1 (COXPD1) Combined oxidative phosphorylation deficiency 2 (COXPD2) Combined oxidative phosphorylation deficiency 3 (COXPD3) Combined oxidative phosphorylation deficiency 4 (COXPD4)

EARS2

Charcot–Marie–Tooth type 2A and type 6 (CMT2A, CMT6) Charcot–Marie–Tooth type 4 (CMT4) Dominant optic atrophy (DOA) Hereditary spastic paraplegia type 3A (SPG3A) Hereditary spastic paraplegia type 4 (SPG4) Hereditary spastic paraplegia type 7 (SPG7) Hereditary spastic paraplegia type 10 (SPG10) Hereditary spastic paraplegia type 13 (SPG13) Hereditary spastic paraplegia type 20 (SPG20) Hereditary spastic paraplegia type 31 (SPG31) Fatal infantile encephalomyopathy

MFN2

Mitochondrial dynamics and mitochondria quality control

4

DARS2 GFM1 MRPS16 TSFM TUFM

GDAP1 OPA1 ATL1 SPAST SPG7 KIF5A HSPD1 SPG20 REEP1 DNM1L

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TABLE 1: Continued

Primary mitochondrial diseases with white matter/axon involvement Altered function

Disease

Mutated gene

Alpers syndrome (AS)

POLG

Defects of mtDNA maintenance Replication machinery Defects involving the dNTP pool

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) Navajo neurohepatopathy (NNH) Infantile encephalomyopathy

optic atrophy (DOA) (mutations in OPA1), Charcot–Marie– Tooth Types 2A and 6A (mutations in mitofusin 2), or Hereditary Spastic Paraplegia 7 (mutations in SPG7) present particularly impact on axons, highlighting its dependence on mitochondria (Court and Coleman, 2012).

Molecular Mechanisms of Primary Mitochondrial Leukoencephalopathies The neurobiology of white matter damage underlying these disorders still remains largely elusive; however growing evidences support the hypothesis that respiratory chain deficiency, which leads to inefficient electron transport, increased ROS production and oxidative damage, a drop in ATP levels and Ca21 dysregulation, are common factors observed in all mitochondrial diseases, regardless of the specific etiology. Many of the evidences that support this hypothesis have been obtained in in vitro studies, most often in non-neural cell types. For instance, fibroblasts from MELAS patients present oxidative stress associated to a decrease in the mitochondrial membrane potential and an activation of the mPTP that promotes excessive mitophagy and deficient autophagic flux (Cotan et al., 2011). Also, evidence of impaired Ca21 handling has been detected in fibroblasts with mutations associated with MELAS (Moudy et al., 1995), complex I deficiency (Visch et al., 2004; Willems et al., 2008), or cybrid embryonic stem cell lines carrying different mitochondrial DNA mutations (Trevelyan et al., 2010). Studies in cybrid lines from Leber’s hereditary optic neuropathy (LHON) patients suggest that ROS production associated to complex I deficiency may modulate neuron differentiation (Wong et al., 2002) and disrupt glutamate transport in primary rat retinal cultures which in its turn might explain the selective retinal ganglion cell death (Beretta et al., 2004, 2006). Although primary cultures from patients or cybrid cell lines are generally the only available tool to dissect the molecular mechanism of these diseases, similarities between these in vitro models and Month 2014

TYMP MPV17 SUCLA2, SUCLG1, RRM2B

the highly complex nervous system are expected, based on the universality of mitochondria functions. For instance, a defective antioxidant response and hydroxy-20 -deoxyguanosine, a marker for oxidative damage of DNA/RNA has been detected in brain samples of MELAS patients (Katayama et al., 2009), underscoring the hypothesis that defective mitochondrial oxidative phosphorylation, leading to an imbalance in the ROS/ ATP/Ca21 triad may underlie these disorders also in the brain. Whether white matter alterations are a direct consequence of mitochondrial defects within a specific cell type, or a more complex process due to disrupted homeostasis from compromised oligodendrocytes, neurons, astrocytes, or even microglia, and their metabolic interplay, is a question that may be answered using proper animal models, or also, patient-specific induced pluripotent stem (iPS) cell lines properly differentiated into specific neural cells. Although we are still at the beginning of the in vivo era in primary mitochondrial diseases, some promising results have been already obtained. For instance, inactivation of NDUFS4 selectively in neurons and glia has been used to dissect the molecular events associated to neuronal death in Leigh syndrome. These animals have aberrant mitochondria in the brain, concomitant with oxidative damage to proteins and a progressive glial activation that induces neuronal death (Quintana et al., 2010). In the Pol-gamma-Mutator mice, the animal model for Alper’s syndrome, ROS production induced by mtDNA mutagenesis triggers neural stem cells dysfunction (Ahlqvist et al., 2012). Moreover, a newly described animal model for LHON exhibits smaller caliber optic nerve fibers with neuronal accumulation of abnormal mitochondria, axonal swelling, and demyelination. It is worth noting that in these animals, oxidative stress, rather than energy deficiency, appears to be the key factor in the pathogenesis since ROS production is not associated with a diminution of ATP production (Lin et al., 2012). Further advances in understanding mitochondrial leukoencephalopathies will surely benefit from the analysis of bona-fide animal models, required for the 5

FIGURE 1: MELAS patient showing atrophy of the cerebral cortex, caudate, putamen, and thalamus, together with reduced cerebral white matter, periventricular demyelination, and enlargement of the lateral ventricles (A,B). A clear demyelination of the cerebellar white matter is observed (C). Variable neuron loss (D), spongiosis (E) and focal necrosis in the cerebral cortex (F), cystic necrosis in the white matter (G), mineralization of thalamic neurons (H), and neuron loss and marked astrocytic gliosis in the cerebellar cortex (I). Myelin loss (J), spongiosis, and vascular proliferation are present in the white matter (K). Images (A–C) correspond to Kl€ uver–Barrera stain. Images (D–K) are hematoxylin and eosin stain.

validation of in vitro results and the dissection of molecular mechanisms in the brain cells, but also for paving the way to preclinical tests and eventually clinical trials in patients.

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Diagnosis of Mitochondrial Leukoencephalopathies Two major clinical presentations are reported in childhood mitochondrial leukoencephalopaties: (i) psychomotor delay

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since the first months of life with failure to thrive, growth impairment, rapidly progressive course resulting in severe spastic quadriparesis and cognitive impairment or (ii) acute onset after a period free of symptoms, with focal motor signs, sometimes seizures, slowly progressive course, and motor impairment more severe than cognitive impairment. In several infantile mitochondrial diseases, damage to diffuse white matter is reported as a predominant radiological feature, with little or no involvement of the brainstem or deep gray structures. The premature, diffuse white matter damage is most likely due to an early impairment of mitochondrial oxidative phosphorylation and energy production that is crucial both for active myelination and for the maintenance of compact myelin. In the late onset, adult mitochondrial diseases, usual presentations involve white matter alteration in subcortical and periventricular areas, with a major involvement of the deep gray matter, cerebral or cerebellar atrophy. Diagnosis of primary mitochondrial diseases remains a challenge for neurologists. Family history can provide clues about the etiology of the disorder: maternal inheritance is indicative of mtDNA origin, while parental consanguinity is suggestive of an autosomal recessive inheritance. Moreover, some mitochondrial leukoencephalopathies are associated with specific mutations in mtDNA (i.e., KSS, MELAS) or nuclear genes (i.e., MNGIE, Alpers’syndrome), thus facilitating the molecular diagnosis by sequencing the genes more commonly associated with these particular diseases. In contrast, diagnosis of Leigh syndrome does not provide any hint about which genome or mutations are implicated. In these cases, complementary approaches such as whole-exome or mito-exome sequencing will facilitate diagnosis by finding novel mutant genes (Garone et al., 2013). Lactic acidosis is a common feature observed among patients with mitochondrial diseases (DiMauro et al., 2013). The use of proton spectroscopy, 1H-MRS, to accurately detect increases of lactate in the brain, has revealed very useful for leukoencephalopathies. However, a lactate peak may also be found in the active phase of acute ischemic or inflammatory lesions, and the absence of lactate peak, as it occurs in MNGIE syndrome (see below), does not rule out the diagnosis. More specific is the finding of a high peak of succinate, a hallmark of complex II deficiency due to SDHAF1 mutations (see Fig. 2). In recent years, magnetic resonance imaging (MRI) has emerged as a precious tool for the differential diagnosis of some particular mitochondrial leukoencephalopathies (Van der Knaap and Valk, 2005). Beside patients with “MELAS like” phenotypes presenting with focal cortical and subcortical lesions mimicking cerebral strokes, in the majority of mitochondrial leukoencephalopathies white matter is diffusely affected. In some patients within the abnormal white matter, minute cysts develop leading Month 2014

to the aspect of diffuse vacuolization resembling to the MRI features of vanishing white matter disorder. In other patients, MRI shows large and confluent cysts replacing most of the cerebral white matter. Both the massive destruction and the tiny vacuolization probably result from energy failure for the processes needed for the maintenance of compacted myelin. Pathologic features are similar to the spongiotic degeneration characteristic of the lesions in the gray matter with capillary proliferation, myelin splitting, myelin loss, presence of macrophage, and prominent gliosis (Naidu et al., 2005). Severe and progressive abnormalities of white matter have been described in patients harboring mutations in genes encoding complex I, complex II, and complex IV assembly factors. Nevertheless, MRI image also reveals involvement of deep gray nuclei as it is expected in Leigh disease. For instance, patients harboring mutations in NDUFS1 or NDUFV1 (structural complex I subunits) show a marked swelling of the white matter and whole brain with secondary macrocephaly, resembling Alexander leukodystrophy (Loeffen et al., 2000; Schuelke et al., 1999) or a vacuolating leukodystrophy with peculiar MRI (Bugiani et al., 2004; Ferreira et al., 2011; Hoefs et al., 2010; Pagniez-Mammeri et al., 2010). Complex I deficency associated to mutations in NUBPL (an iron sulfur cluster assembly factor for complex I), results in a peculiar MRI pattern with abnormalities in the cerebellar cortex, deep cerebral white matter, and corpus callosum (Kevelam et al., 2013). Mutations in the complex II subunit SDHAF1 (complex II deficiency) often present with a recognizable MRI pattern, abnormal hyperintense T2 signals showing involvement of the middle cerebellar peduncles (brachium pontis) (Ghezzi et al., 2009) (Fig. 2 and Supp. Info. Fig. 1) and an accumulation of succinate as observed by in vivo proton MR spectroscopy (Fig. 2G). Another peculiar MRI pattern is seen in patients with mutations in COX6B1, a cytochrome oxidase (complex IV) assembling gene. These patients show progressive, diffuse leukodystrophy changes in the cerebellum, pyramidal tracts, and supratentorial white matter. Later in disease progression, the patients develop white matter vacuolization from the peritrigonal toward the frontal areas and ex vacuo dilatation of the lateral ventricles (Massa et al., 2008). The group of mitochondrial leukoencephalopathies caused by mutations in genes encoding aminoacyl-tRNA synthase (DARS2 and EARS2) and proteins participating to the elongation machinery (EFG1 and EFTu) also exhibit characteristic MRI patterns. Patients with LBSL (caused by mutations in the gene DARS2) (Van der Knaap and Scheper, 2010) present MRI abnormalities in the dorsal columns and the corticospinal tracts, the pyramids, the cerebellar peduncles, the intraparenchymal tract of the V cranial nerve, the posterior arm of the internal capsule, and the splenium of 7

FIGURE 2: Patient affected by homozygous mutation in SDHAF1 at 22 months. FLAIR signal of sagittal (A), coronal (B), and axial (C–G) MR images. Notice the involvement of the corpus callosum (A), the characteristic hyperintense areas involving the middle cerebellar peduncles (brachium pontis) (C), the typical vacuolization features of the white matter with central cavitations, and an outer hyperintense rim (D–F). 1H MRS regional representation of spectra obtained in vivo. Voxels are referred to an axial brain image at the center. The results of voxels that analyze areas of the white matter are red and the spectra that analyze areas of the cortex are in black. Notice that red voxels better visualize the lactate double inverted peak (retention time 1.3 ppm, arrow head) and succinate peak (retention time 2.40 ppm, arrow). The latter is characteristic of this type of leukodystrophy (G).

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FIGURE 3: Characteristic aspects of the brain MR images in a patient with a mutation in DARS and a LBSL. T2 weighted axial images (A,D); sagittal T1 and T2 weighted images (B,E), and close-up axial T2 weighted images (C,F) to show details of cerebellum and brainstem. Notice the typical hyperintense abnormal signal involving the dorsal and ventral areas of the brainstem (C) and also involving the trigeminal nerves at the level of the pons (F). In addition to these specific MRI abnormalities, for LBSL patients the white matter is diffusely involved sparing the subcortical U-fibers (A, D). There is also involvement of the corpus callosum (B) and spinal cord (E).

the corpus callosum; the U-fibers are spared (Fig. 3). In contrast, LTBL (caused by mutations in mutations in the EARS2 gene) is characterized by early-onset leukoencephalopathy with thalamus and brainstem involvement, hallmarked by unique MRI features, high lactate, and a biphasic clinical course presentation (Supp. Info. Fig. 2). The peculiar MRI pattern consistently spares the periventricular rim but affects the deep cerebral white matter including corpus callosum, thalamus, basal ganglia, midbrain, pons, medulla oblongata, and the cerebellar white matter (Steenweg et al., 2012). Additional specific MRI patterns are observed in patients harboring mutations in the mitochondrial elongation factors EFG1 and EFTu, in which involvement of the basal ganglia is prominent, although the disease is dominated by devastating progressive cavitating leukodystrophy and micropolygyria (Valente et al., 2007). Finally, patients with MNGIE also display a unique MRI pattern. This leukoencephalopathy show T2 hyperintensities in the pons, basal ganglia, and centrum semiovale with Month 2014

sparing of the U-fibers, with absence of lactate peak in MRS (Schupbach et al., 2007) (Supp. Info. Fig. 3). Secondary Mitochondrial Dysfunction in White Matter Diseases Although from a classical point of view, mitochondrial disorders refer to inherited disease resulting from mutations in mtDNA or nDNA that encodes essential components of mitochondria function, secondary mitochondrial damage is a culprit in the pathogenesis of an ever-increasing number of diseases, which may be genetic or multifactorial. Here we select two examples that illustrate how secondary mitochondrial dysfunction may contribute to white matter damage and axon degeneration. The diseases we discuss are the well-known prototypic white matter disease MS and the rare, inherited condition Xlinked adrenoleukodystrophy (X-ALD, OMIM: 300100). MS is traditionally considered an inflammatorymediated demyelinating disease of the CNS. However, MS is increasingly viewed as a neurodegenerative disease in which 9

axonal damage, neuronal death, and atrophy of the CNS are the principal causes of irreversible neurological disability in patients. Although the mechanisms of neurodegeneration in MS are poorly understood, several lines of evidence point to secondary mitochondrial dysfunction as a key player in the process (Lassmann, in press (a,b); Lassmann and van Horssen, 2011; Mao and Reddy, 2010; Su et al., 2013). One of the first hints of mitochondrial dysfunction in MS is the dramatic decline of NAA. NAA is produced by neuronal mitochondria and is commonly used as a marker of neuronal integrity (Fu et al., 1998). The decrease in NAA is detected both in acute lesions and chronic white matter lesions, suggesting chronic mitochondrial dysfunction in MS (Bjartmar et al., 2000). Remarkably, altered mitochondrial function in astrocytes compromises the glycogenolysis and lactate synthesis that are needed not only to supply energy to axons but also for the neuronal synthesis of NAA, required for the formation and turnover of the myelin in the oligodendrocytes (Cambron et al., 2012). Recent insights also list oxidative stress as an important element in the pathogenesis of MS. Extensive oxidative damage to proteins, lipids, and nucleotides occurs in active demyelinating MS lesions, predominantly in reactive astrocytes and macrophages (van Horssen et al., 2008). Further studies detected oxidative damage in mtDNA, disrupted activity of mitochondrial enzymes in affected tissues (Lu et al., 2000) and reduced mitochondrial gene expression in non-affected tissues (Dutta et al., 2006). Strikingly, mitochondrial dysfunction related to oxidative damage and mediated by activated macrophages and microglia is present in all lesions at all disease stages (Lassmann, in press (a); Lassmann and van Horssen, 2011). In animal models of MS, it has been reported that macrophages/microglia exert detrimental roles such as toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and ROS, and recruitment and reactivation of T lymphocytes in the CNS. Microglia can activate the apoptotic program in neurons and oligodendrocytes either by inflammatory molecules such as interferon-gamma (IFN-c) or tumor necrosis factor alpha (TNF-a) or by the release of ROS that promote the opening of the mPTP and release of apoptotic mediators (Kalman et al., 2007). Indeed, in cyclophilin D (a key protein for opening the mPTP) knockout mice, induction of EAE showed reduced axonal damage, increased resistance to oxidative stress, and improved Ca21 handling (Forte et al., 2007). Nevertheless, few studies have addressed the specific impact of mitochondrial function in microglia in MS pathology. For instance, treatment of EAE mice with the mitochondrial KATP channel activator diazoxide, diminishes the activation of microglia/ macrophages and ameliorates the disease progression (Virgili et al., 2011). Recently, in vivo imaging using the EAE mouse 10

model revealed that the appearance of abnormal intra-axonal mitochondria preceded changes in axon morphology. Moreover, this study concluded that macrophage-derived ROS triggered mitochondrial pathology and initiated axonal damage (Nikic et al., 2011). Substantial evidences demonstrate that excitotoxicity contributes to oligodendrocyte death, demyelination, and tissue damage in MS (Matute et al., 2001; Srinivasan et al., 2005; Vallejo-Illarramendi et al., 2006). Remarkably, mitochondrial dysfunction in axons, astrocytes, and oligodendrocytes compromises the function of mitochondrial enzymes and ATP-dependent pumps, indispensable for the control of glutamate metabolism (Cambron et al., 2012). In support to this hypothesis, clinical and pathological features of EAE model such as oligodendrocyte death, axonal damage, or inflammation are alleviated by treatment with glutamate receptor antagonists (Cambron et al., 2012; Kanwar et al., 2004; Pitt et al., 2000; Smith et al., 2000). The impact of mitochondria in oligodendrocyte death can be also addressed in the cuprizone model of demyelination (Matsushima and Morell, 2001). Cuprizone operates by decreasing the activity of the respiratory chain in oligodendrocytes, involving ROS production (Pasquini et al., 2007). This mitochondrial injury leads to the release of the apoptosis-inducing factor (AIF), which translocates into the nucleus, induces DNA damage, and activates poly(ADP-ribose) polymerase (PARP) proteins. In an attempt to repair the damage, PARP activation exacerbates energy deficiency and eventually triggers caspaseindependent apoptosis. Furthermore, treatment with PARP inhibitors protects mice against cuprizone-induced demyelination in the brain (Lassmann et al., 2012; Veto et al., 2010). Finally, another hypothesis proposes that redistribution of mitochondria in demyelinated axons may participate in the pathogenesis of MS. After demyelination, disruption of the nodes of Ranvier is accompanied by an increase in mitochondrial density, likely an adaptive mechanism to address increased energy demand. Thus, demyelinated axons are more reliant on mitochondria and consequently more sensitive to mitochondrial dysfunction and axonal demise. This adaptive mechanism is a double-edged sword in acute lesions, where activated microglia produces high amounts of ROS and ignites a vicious cycle of mitochondrial dysfunction (Campbell et al., 2012). It’s worth to highlight that, non-focal diffuse changes in the MS brain, such as mitochondrial dysfunction and axonal damage are associated with disease progression and prove to be better correlates of disability than the total lesion load (Stadelmann, 2011). Studies using the X-ALD mouse model contributed to understanding how oxidative damage and mitochondrial dysfunction may cause axonal degeneration (Ferrer et al., 2010; Volume 00, No. 00

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Fourcade et al., in press; Galea et al., 2012; Launay et al., 2013; Singh and Pujol, 2010). The clinical presentation is highly variable, and is characterized by central inflammatory demyelination and/or spastic paraparesis compatible with dying back axonal degeneration in spinal cords (Ferrer et al., 2010; Kemp et al., 2001; Moser et al., 2007). There is no phenotype/genotype correlation, suggesting the incidence of modifying epigenetic/environmental/ stochastic factors playing a role. The disease is caused by inactivation of the ABCD1 gene, a peroxisomal transporter that imports very-long-chain fatty acids (VLCFAs) for degradation by b-oxidation. VLCFAs can interfere with OXPHOS proteins and mitochondria respiration, increasing ROS production (Fourcade et al., 2008; Lopez-Erauskin et al., 2013). Oxidative damage to OXPHOS subunits, Krebs cycle proteins, or even to the pore component cyclophilin D induces a generalized bioenergetic failure, in terms of ATP drop, decreased NADH, and impairment of pyruvate kinase (Lopez-Erauskin et al., 2013, in press; Galino et al., 2011). These abnormalities are found concomitant to repressed mitochondrial biogenesis (Morato et al., 2013) and proteasome and immunoproteasome dysfunction (Launay et al., 2013), and preceding axonal degeneration in the Abcd1 null mice. The proof of concept that oxidative stress and global mitochondria dysfunction underlies axonal degeneration is provided by the halting of axonal damage with an antioxidant cocktail (Galino et al., 2011; Lauritzen et al., 2001; Lopez-Erauskin et al., 2011) and with the mitochondrial booster pioglitazone (Morato et al., 2013). As a result of these studies, two phase II clinical trials for these drugs are ongoing or planned.

Mitochondrial Therapy Although primary and secondary mitochondrial disorders have different etiology, they share the common consequences of mitochondrial damage. Thus, therapeutic interventions that promote mitochondrial function by correcting oxidative damage, boosting ATP production, or regulating mPTP opening are considered in pathologies with primary or secondary mitochondrial involvement (Andreux et al., 2013; Smith et al., 2012). Mitigating Oxidative Stress and Energetic Failure The first therapeutic approach to mitochondrial disorders was the use of compounds that enhance respiratory chain function by mitigating oxidative stress and the bioenergetic crisis. Several clinical trials have been performed to evaluate the potential of antioxidant therapies, such as coenzyme Q10 (CoQ10) or lipoic acid, and compounds that increase the ATP availability, such as creatine. Additionally, drugs that promote the elimination of noxious compounds have also been tested, such as dichloroacetate, which keeps pyruvate dehydrogenase Month 2014

in the active form and facilitates lactate oxidation. Some clinical trials with the abovementioned compounds have led to unclear results (Kerr 2009; Pfeffer et al., 2012); however, coadministration of creatine, CoQ10, and lipoic acid (Rodriguez et al., 2007) displayed positive effects, suggesting that combinatory therapy with this family of compounds should be taken under consideration. Along the same lines, treatment with a cocktail of antioxidants halted axonal degeneration and the associated disability in a mouse model of X-ALD (LopezErauskin et al., 2011). Importantly, treatment with the antioxidant compound vitamin E or with idebenone, a synthetic analog of CoQ10, have showed promising results in patients with Leigh syndrome and LHON, respectively (Carelli et al., 2011; Klopstock et al., 2011; Martinelli et al., 2012; Pfeffer et al., 2013). It is worth to highlight the successful results obtained with idebenone in the two independent clinical studies in LHON. The conclusion of a retrospective review of idebenone-treated patients with LHON (Carelli et al., 2011) and of a double-blind, randomized placebo-controlled phase II clinical trial (NCT00747487) is that an early and prolonged idebenone treatment may significantly improve the frequency of visual recovery (Klopstock et al., 2011). In addition, a recent observational follow-up study proved that the therapeutic effect of the 24-week-treatement (Klopstock et al., 2011) was maintained 30 months after the therapy was terminated (NCT01421381) (Klopstock et al., 2013). The authors suggest that during the period of treatment the drug preserved retinal ganglion cell function and thus protects from further irreversible retinal ganglion cell loss. Moreover, idebenone has yielded positive results in Friedreich’s ataxia, especially in younger patients treated with higher doses, although the greatest beneficial effects have been observed in cardiac function rather than in the neurological parameters (Parkinson et al., 2013). Finally, genetic or pharmacological blocking of cyclophilin D also prevented mitochondrial dysfunction and cell demise in MS (Forte et al., 2007) and X-ALD (Lopez-Erauskin et al., 2012).

Targeting Mitochondria Strategies designed for delivering the abovementioned drugs directly into the mitochondria, such as the use of lipophilic cations (such as triphenylphosphonium or TPP), or peptides that drive the drug into the mitochondria (SS and MPPS peptides), are the focus of many recent efforts. Mitochondria targeting allows a high concentration of the compounds to reach the organelle, increasing their potency and minimizing extra-mitochondrial metabolism. To date, the use of mitochondria-targeted drugs, such as MitoQ (a CoQ10 derivative conjugated to TPP) or SS-31 peptides have been successful in animal models of neurodegenerative diseases such as 11

PD (Ghosh et al., 2010) and ALS (Petri et al., 2006), thus paving the way to use this strategy in mitochondrial diseases. Activating Stress Response Pathways An intriguing therapeutic approach comprises compounds that activate signaling pathways involved in the modulation of mitochondrial content and their activity in response to environmental challenges, such as increased oxidative stress or changes in nutrient availability. Activation of the cellular antioxidant response, for example through the NRF2/ARE pathway, has been attempted in white matter disorders. In a mouse model of MS, activation of NRF2 ameliorates the disease course and preserves the integrity of myelin, axons, and neurons (Linker et al., 2011). Moreover, two phase III clinical trials using the activator of NRF2, dimethylfumarate (BG12), in patients with relapsing-remitting MS (NCT00451451; NCT00420212) demonstrated that this oral compound exhibits an acceptable safety profile and more importantly, that reduces the risk of relapse and disability progression, reduces the number of new/enlarging T2 lesions, gadolinium-positive lesions, and new T1 lesions, and increases the quality of life based on the patient-reported measures of physical and mental functioning. These outstanding results were detected as early as 12 weeks of treatment and maintained over the course (2 years) of both studies (Fox et al., 2012; Gold et al., 2012; Havrdova et al., 2013). Stimulation of mitochondrial biogenesis through pharmacological or metabolic modulation of the peroxisome proliferator-activated receptors (PPAR)/peroxisome proliferatoractivated receptor gamma coactivator 1 alpha (PGC-1a) pathway promises to be an effective therapeutic approach to mitochondrial disorders. Indeed, knockout animals for PGC-1a have deficient postnatal myelination evidencing the strong link between mitochondrial biogenesis and white matter (Xiang et al., 2011). Treatment of COX10 deficient mice with bezafibrate (a PPARa agonist) induces mitochondrial biogenesis, stimulates residual respiratory capacity (Wenz et al., 2008), attenuates astrogliosis and decreases the level of inflammatory markers (Noe et al., in press). Manipulation of the nuclear receptor PPARc, a core element in energy metabolism, is also a promising strategy to modulate mitochondrial function. Similarly, administration of the PPARc ligand pioglitazone arrests axonal degeneration while promoting mitochondria function in an X-ALD mouse model (Morato et al., 2013). Finally, activation of SIRT1, a deacetylase that regulates PGC1a activity and oxidative stress, is showing therapeutic potential. To illustrate, activation of SIRT1 in a mouse model of MS maintains axonal density, prevents neuronal loss, and improves neuronal dysfunction (Shindler et al., 2010). Nevertheless, to reach their full potential, these mitochondrial therapies and the accurate monitoring of its biologi12

cal effects must improve. The current methodology is too limited to address the question of whether the treatment outcome is mediated by mitochondrial modulation, or whether mitochondrial function is regulated without impact on the clinical outcome. The development of proper biomarkers and measurements of mitochondrial function in vivo, in a timelapse manner, will be required to help to solve these questions (Jeppesen et al., 2007; Zhou et al., 2011b). Exploring Gene Therapy Gene therapy is approaching the clinic at rapid pace, and opens new therapeutic options for primary mitochondrial disorders, including mtDNA- and nDNA-related genetic diseases. For nDNA-related mitochondrial diseases, the use of adenoassociated viral vectors has yielded successful results in two animal models: the Ant1 mutant mouse, a mouse model of mitochondrial myopathy (Flierl et al., 2005) and in a mouse model of ethylmalonic encephalomyopathy (Di Meo et al., 2012). Regarding mtDNA, several strategies have been attempted such as replacing mutated mtDNA with reconstructed DNA, selective degradation of mutated mtDNA, heteroplasmic shifting by introducing wild-type mtDNA, or the use of restriction endonucleases to eliminate specific mutations in the mtDNA (Kyriakouli et al., 2008; Tanaka et al., 2002). Treatment of LHON and Leigh syndrome cells with healthy mtDNA increased mitochondrial replication and the transcription and translation of key respiratory genes and proteins (Iyer et al., 2012). A recent study investigated the use of mitochondria-targeted restriction endonuclease, delivered in mice harboring two mtDNA haplotypes. A single injection of endonuclease, markedly changed the mtDNA heteroplasmy in all muscles analyzed, suggesting that this approach could have clinical applications for mitochondrial myopathies (Bacman et al., 2012). Future Directions: Nuclear Transfer Unfortunately, for many devastating mtDNA-related diseases, prenatal or preimplantation diagnosis is not yet reliable, as cells taken for genetic analysis may not reflect the level of heteroplasmy in the embryo or fetus. In these cases, recently developed in vitro fertilization techniques such as maternal spindle transfer and pronuclear transfer, are emerging as superb alternatives, although technically challenging, to prevent transmission of mtDNA (Craven et al., 2011; Craven et al., 2010; Tachibana et al., 2009).The goal is to transplant the nuclear genome from the oocyte or embryo of an affected woman to those from a healthy donor, thus enabling the birth of a healthy, genetically related child without transmitting mutated mtDNA.

Conclusion In this review, we emphasize the notion of mitochondrial dysfunction as the central culprit in degenerative or Volume 00, No. 00

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developmental diseases of brain white matter, in a similar way as it is described in the most common neurodegenerative diseases. Regardless of etiology, both primary and secondary diseases present common pathogenic features involving axonal damage; thus, clinical severity and progression is directly linked with mitochondrial function. Diagnosis remains a challenging issue, but MRI allows the identification of unique patterns of brain damage that can be attributed to specific disease presentations. In combination with next generation sequencing, these methods are expected to yield important advances in the speed and accuracy of disease diagnosis. The pathogenesis of mitochondrial disorders is far from clear. However, it is to be expected that reliable animal models will provide further advances in the understanding of the molecular bases of these disorders; these models will be instrumental in finding therapeutic options for these devastating diseases (Cao et al., 2005; Kruse et al., 2008; Lopez et al., 2009; Quintana et al., 2010). Drugs designed to act on the core features of mitochondrial dysfunction are arising as promising therapeutic strategies for both primary and secondary mitochondrial disorders. However, hope of a definitive solution for these devastating diseases relies on the implementation of novel methodologies such as gene therapy and nuclear transfer for women carrying mtDNA mutations.

Acknowledgment Grant sponsor: European Commission; Grant number: FP7– 241622; Grant sponsor: Spanish Institute for Health Carlos III; Grant number: FIS PI11/01043; Grant sponsor: Autonomous Government of Catalonia; Grant number: 2009SGR85; Grant sponsor: European Leukodystrophy Association; Grant number: ELA2012-044PS5; Grant sponsor: Spanish Ministry of Education; Grant number: FPU program: AP2008-03728. The CIBER on Rare Diseases (CIBERER) and the CIBER on Neurodegenerative Diseases (CIBERNED) are initiatives of the ISCIII. Authors state that they do not have any financial interest related to the work described in the manuscript. All co-authors have seen and agree with the contents of the manuscript. This paper is not being considered for publication elsewhere.

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