Mitochondria and Neurodegeneration

8/7/2019 Mitochondria and Neurodegeneration

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O R I G I N A L P A P E R

Mitochondria and Neurodegeneration

Lucia Petrozzi Giulia Ricci Noemi J. Giglioli Gabriele Siciliano

Michelangelo Mancuso

Published online: 8 May 2007 The Biochemical Society 2007

Abstract Many lines of evidence suggest that mitochondria have a central role inageing-related neurodegenerative diseases. However, despite the evidence of morpho-logical, biochemical and molecular abnormalities in mitochondria in various tissues ofpatients with neurodegenerative disorders, the question is mitochondrial dysfunction anecessary step in neurodegeneration? is still unanswered. In this review, we highlightsome of the major neurodegenerative disorders (Alzheimers disease, Parkinsonsdisease, Amyotrophic lateral sclerosis and Huntingtons disease) and discuss the role ofthe mitochondria in the pathogenetic cascade leading to neurodegeneration.

Keywords Mitochondria mtDNA Alzheimers disease Parkinsons disease Amyotrophic lateral sclerosis Huntingtons disease Neurodegeneration

Introduction

Mitochondria are key regulators of cell survival and death and a dysfunction ofmitochondrial energy metabolism leads to reduced ATP production, impaired calciumbuffering, and increased generation of reactive oxygen species (ROS) (Beal 2005).

Increased production of ROS damages cell membranes through lipid peroxidation andfurther accelerates the high mutation rate of mitochondrial DNA (mtDNA). Accumu-lation of mtDNA mutations enhances normal aging, leads to oxidative damage, causesenergy failure and increased production of ROS, in a vicious cycle. The brain isespecially vulnerable to oxidative damage because of its high content of easily

L. Petrozzi G. Ricci N. J. Giglioli G. Siciliano M. Mancuso (&)Department of Neuroscience, University of Pisa, Via Roma 67, Pisa 56126, Italye-mail: [email protected]

Biosci Rep (2007) 27:87104DOI 10.1007/s10540-007-9038-z

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peroxidizable unsaturated fatty acids, high oxygen consumption rate, and relativepaucity of antioxidant enzymes compared with other organs (Nunomura et al. 2006).Oxidative free radical damage is generally viewed as an etiological factor in braindegeneration and ROS damage within specific brain regions in many neurodegenerativeconditions has been reported (Perry et al. 2002).

Further, conditions of excessive oxidative stress and mitochondrial calcium overloadcan favour mitochondrial permeability transition (MPT) state in which the proton-motive force is disrupted (Crompton 2004). The ultimate result of the activation of theMPT pore is the release of cytochrome c and the induction of caspase-mediatedapoptosis (Stavrovskaya and Kristal 2005).

The mtDNA is particularly susceptible to oxidative damage. Because of its vicinitywith ROS source (electron transport chain) and because it is not protected by histonesand is inefficiently repaired, mtDNA shows a high mutation rate. In the last decades, itwas hypothesized that somatic mtDNA mutations acquired during ageing contribute tothe physiological decline that occurs with ageing and ageing-related neurodegeneration(Lin and Beal 2006).

Beside somatic mutations, mtDNA is characterized also by genetic polymorphisms. Ithas been speculated that polymorphisms in mtDNA may cause subtle differences in theencoded proteins and, thus, minimum changes in oxidative phosphorylation (OXPHOS)activity and free radical overproduction. This could predispose an individual, or apopulation sharing the same mtDNA genotype, to an earlier onset of apoptoticprocesses, such as accumulation of somatic mtDNA mutations and OXPHOSimpairment. The opposite could be true for different polymorphism(s), which couldbe beneficial increasing OXPHOS activity and/or reducing ROS production. Thecommon mtDNA polymorphisms define a variety of mitochondrial continent-specificgenotypes, called haplogroups. In Europe, nine different mitochondrial haplogroupshave been identified (H, I, J, K, T, U, V, W, X).

A series of experimental evidence have been published suggesting that some mtDNAhaplogroups are associated with longevity (Tanaka et al. 1998; De Benedictis et al.1999; Ross et al. 2001; Niemi et al. 2003), as well as with mitochondrial diseases(Torroni et al. 1997; Reynier et al. 1999), and complex diseases (Wallace 2005). Inparticular, in northern Italians, Irish and Finnish, haplogroup J is over-represented inlong-living people and centenarians (De Benedictis 1999; Ross et al. 2001; Niemi et al.2003), suggesting a role for this mtDNA variant in longevity (Santoro et al. 2006).

However, the mechanism by which these haplogroups can impinge upon longevityand diseases is far from being clear (Santoro et al. 2006). To investigate if specificgenetic polymorphisms within the mitochondrial genome could act as susceptibilityfactors and contribute to the clinical phenotype, mtDNA variants have been studied in

neurodegenerative diseases (van der Walt et al. 2004, 2003; Mancuso et al. 2004a;Giacchetti et al. 2004), but contrasting data are reported.

Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases (Lin and Beal 2006) but it is still largely debatedwhether oxidative stress and mitochondrial impairment are involved in the onset andprogression of these disorders or are merely a consequence of neurodegeneration.

This article focuses on the role of mitochondria in neurodegeneration, and reviewssome of the recent relevant data.

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Mitochondrial Involvement in Alzheimers Disease

Alzheimers disease (AD) is a late-onset, progressive, age-dependent neurodegenera-tive disorder that results in the irreversible loss of neurons, particularly in the cortex andhippocampus.

AD is clinically characterized by impairment of cognitive functions and changes inbehaviour and personality. A definitive diagnosis can be made only at autopsy: thepathological hallmarks are neuronal loss, extracellular senile plaques containing thepeptide b-amyloid (Ab) and neurofibrillary tangles, composed of a hyperphosphorylat-ed form of the microtubular protein tau (Selkoe 2001). While the majority of cases arelate-onset and sporadic, approximately 23% of AD cases are early onset and familial,with autosomal dominant inheritance. Familial AD can be caused by mutations in theamyloid precursor protein (APP), which is leaved sequentially by b- and c-secretases,and presenilins 1 and 2 (PS1 and PS2), one or other of which is a component of eachc-secretases complex. Most forms of sporadic late-onset AD have probably a complexaetiology due to environmental and genetic factors which taken alone are not sufficient

to develop the disease. Presently the major risk factor in sporadic AD is recognized inthe allele e4 of apolipoprotein E (ApoE4). However in the majority of late-onset ADpatients, the casual factors are still unknown and genetics factor probably interact withenvironmental factors or with other pathologic or physiologic conditions to exert thepathogenic effect.

Oxidative damage and mitochondrial dysfunction has been widely implicated in thepathogenesis of AD. Oxidative damage occurs early in the AD brain, before the onsetof significant plaque pathology, and seem also to precede the Ab deposition in animalmodels (Pratico and Delanty 2000). There is substantial evidence of morphological,biochemical and molecular abnormalities in mitochondria in various tissues of patientsaffected by AD.

Impaired energy metabolism and abnormalities of mitochondrial respiration are afeature of autopsied brain tissue affected by neurodegeneration, but also of peripheralcells (platelets and fibroblasts) of AD patients. Furthermore, the reduction in brainmetabolism appears directly to relate to the clinical disabilities of the disease and canalso precede the clinical symptoms by decades (Small et al. 1995). Some of the mostdirect pieces of evidence of brain metabolism abnormalities associated with AD comefrom in vivo positron emission tomography (PET). In particular, reduced cerebralmetabolism has been shown in the temporo-parietal cortices of AD patients, and thesechanges precede both neuropsychological impairment and atrophy found with neuroi-maging (Blass et al. 2000). In the last years several studies aimed to define theunderlying basis for the decline in brain metabolism of AD and to test the correlation of

the decreases in mitochondrial enzyme activities with premorbid cognitive status andwith plaque counts (Bubber et al. 2005).

Biochemical analysis in post-mortem AD brains has yielded evidence for impairedactivities of three key enzymes of the tricarboxylic acid (TCA) cycle (the Krebs cycle),which take place in the mitochondria: the pyruvate dehydrogenase complex (PDHC),the a-ketoglutarate dehydrogenase complex (KGDHC) (Gibson et al. 2000; Sorbi et al.1983; Bubber et al. 2005) and the isocitrate dehydrogenase (Bubber et al. 2005).Further, all the changes observed in TCA cycle activities correlated with clinical state,suggesting that their imbalance in AD could lead to diminished brain metabolismresulting in the decline in brain function.

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The most consistent defect in mitochondrial enzymes activity reported in AD hasbeen the electron transport chain (ETC) carrier cytochrome c oxidase (COX, complexIV) (Castellani et al. 2002). Deficient COX activity has been reported by severalauthors in different brain regions (Bosetti et al. 2002; Kish et al. 1992; Maurer et al.2000; Mutisya et al. 1994; Simonian and Hyman 1994; Wong-Riley et al. 1997), but also

in platelets (Parker et al. 1990b) and fibroblasts of sporadic AD patients. Involvementof other mitochondrial ETC complexes is more controversial. Cardoso et al. (2004a) didnot find differences between AD patients and controls in NADH-ubiquinone oxido-reductase (complex I) or succinate dehydrogenase-cytochrome c reductase (complex II/III) activities of mitochondria isolated from platelets. Our group have reported adecrease of COX but not of F1F0ATPase activity in hyppocampus and platelets ofsporadic AD patients (Bosetti et al. 2002; Mancuso et al. 2003).

The ETC impairment limits the ATP production and increases ROS production.Consequently, chronic exposure can also result in oxidative damage to mitochondrialand cellular proteins, lipids and nucleic acids, in a vicious circle (Reddy and Beal 2005).Mitochondria play a critical role in the initiation of apoptosis and the disruption of ETC

has been recognised as an early step of apoptotic cells death (Green and Kroemer 2004;Green and Reed 1998). To date, of the origin of these metabolic abnormalities is stillunclear. It could results from an environmental toxin or from acquired or inheritednuclear DNA (nDNA) and mtDNA mutation(s).

The involvement of non-neuronal tissues, as platelets and fibroblasts, suggests thatthe COX defect is not simply a local consequence of the disease state, but may begenetically determined (Ojaimi et al. 1999). COXs subunits are encoded by bothnDNA and mtDNA, so a low COX activity may result from changes in nDNA, inmtDNA or in the recognition or the import of proteins through the mitochondrialmembrane. To elucidate the origin of the bioenergetic deficits in AD, the cybrid modelshave been developed. In the cytoplasmic hybrid (cybrid) technique, first described in

the 1989 (King and Attardi 1989), cells lacking their own mtDNA are repopulated withexogenous mtDNA from AD patients and controls. Phenotypic differences amongcybrid lines therefore derive from the amplification of donor mtDNA and not fromnuclear or environmental factors. Studies using cybrid cells showed that the enzymaticdefects can be transferred to mtDNA-deficient cells implicating mtDNA mutations.Particularly, sporadic AD platelets mitochondrial genes expressed in cybrids reduceCOX activity (while the citrate synthase activity remained unchanged), reduced ATPlevels and increase oxidative stress (Swerdlow et al. 1997) and in long-term culture,sporadic AD cybrids develop populations of abnormal and damaged mitochondria(Trimmer et al. 2004). Sporadic AD cybrids also overproduce the major amyloidogenicAb peptides (140, 142) in a caspase-dependent manner (Khan et al. 2000) and also

accumulate Congo red amyloid deposits (Khan et al. 2000), mimicking the amyloidplaques observed in AD brain. Cardoso et al. (2004b) have documented that thealterations in AD cybrid oxidative status renders these cells vulnerable to Ab 140 celldeath because these cells manifest an excessive decrease in the mitochondrialmembrane potential (W), excessive mitochondrial release of citochrome c and caspaseenzyme activation. Continuous culture of AD cybrids, with a lowers W relative tocontrols, showed a worsening of the bioenergetic impairment and simultaneously anincreased AD mtDNA replication, that produce mitochondria abnormalities in advance(Trimmer et al. 2004). Thiffault and Bennett (2005) have studied the spontaneous Wfluctuations of mitochondrial hyperpolarized with cyclosporine A. The authors foundthat W flickering, which represent coupling between electron flow, ATP synthesis (F

0F1

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ATP-synthase) and mitochondrial calcium extrusion, was much less. This evidencesuggest that expression of AD mtDNA produces a more complex bioenergeticimpairment beyond simple reduction in complex IV catalytic activity and may resultin impaired ATP synthesis and mitochondrial calcium extrusion.

Moreover, Trimmer and Borland (2005) observed that the mitochondria in AD

cybrid neurites are elongate (whereas in were short and more punctate), and that themean velocity of mitochondrial and lysosomal movement, as well as the percentage ofmoving mitochondria, is significantly reduced in AD cybrids.

Finally, all these studies demonstrate that sporadic AD cybrid cell lines express themorphological and biochemical phenotype observed in vivo and in the cerebral tissue insporadic AD and reinforce the evidence that primary mtDNA changes could beresponsible for the mitochondrial impairment of sporadic AD. On the other hand, otherstudies are controversial and not replicate these results (Ito et al. 1999; Onyango et al.2005).

Also studies attempting to identify mtDNA mutations in AD had limited success.While it is clear that mtDNA mutations accumulate with aging in the human brain (Li

et al. 2002), studies in AD provide somehow conflicting evidences, and more workremains to be done to further ascertain the contribution of mtDNA mutations. Coskunet al. (2004) studied AD cerebral tissue for the sequence of the mtDNA control regionfor potential disease-producing (or pathogen) mutations. They found that 65% of theAD brains harboured the T414G mutation and that this mutation was not present inbrains from controls. Moreover, cloning and sequencing of the mtDNA control regiondetected that all AD brains had an average 63% increase in mutations of theheteroplasmic mtDNA control region and that the brains from AD patients who were80 and more years old had a 130% increase in heteroplasmic control-region mutations.It is also important to note that these mutations were found by authors mainly in theknown mtDNA regulatory elements. Certain AD brains harboured the disease-specific,

control-region mutations T414C and T477C, and several brains from AD patients from74 years to 83 years of age harboured the control-region mutations T477C, T146C, andT195C, at levels up to 7080% in heteroplasmy. AD brains also showed an average 50%reduction in the mtDNA L-strand NADH-dehydrogenase subunit 6 (ND6) transcriptand in the mtDNA/nDNA ratio. Reduced ND6 mRNA and mtDNA copy numbersreduce brain oxidative phosphorylation: for this reason it was speculated that thecontrol-region mutations T477C, T146C, and T195C could be responsible for some ofthe mitochondrial abnormalities observed in AD patients (Coskun et al. 2004). Thesegenetic studies suggest that somatic mutations in the control region, mitochondrial-encoded genes, tRNA and rRNA may have a role in the pathogenesis of sporadic ADpatients (Reddy and Beal 2005). However, in a previous study that involved a larger

number of tissue samples, Chinnery et al. (2001) did not detect the T414C mutation inbrains from normal individuals, AD patients or those with dementia and Lewy bodies.Further, they did not observe the heteroplasmic point mutations in the control regionsegment spanning nucleotide positions 100570 (Chinnery et al. 2001).

As far as the mtDNA coding region, Elson et al. (2006) sequenced the completecoding regions of 145 autoptic AD brain samples and 128 normal controls. Theyobserved that for both synonymous and non-silent changes the overall numbers ofnucleotide substitutions were the same for the AD and control sequences.

Moreover mtDNA polymorphisms has been supposed to have a role in thepathogenesis of AD but at present contrasting data are reported.

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Chagnon et al. (1999) reported that haplogroup T is under-represented in ADpatients, while haplogroup J seems to be over-represented. Another report regarding apossible link between AD and mtDNA genotypes (Van der walt et al. 2004) showedthat males classified as haplogroup U had a significant increase in risk of AD, whilefemales demonstrated a significant decrease in risk with the same U haplogroup. The

authors suggested that inheritance of haplogroup U may have negative effect on agingin Caucasian males. However, this association was not confirmed recently by acollaborative study (Elson et al. 2006), which showed no statistically significantassociation between haplogroup and disease status. The same negative results wereobtained in our laboratory, as we did not find any evidence for an etiological role ofhaplogroup-associated polymorphisms.

In conclusion, the exact role of haplogroups and/or mtDNA point mutations remainto be clarified. Although these evidence of the involvement of mitochondria in AD, itremains unclear whether it plays a causative role or if mitochondrial dysfunction occursonly as a secondary event of another unknown primary process.

The mitochondrial cascade hypothesis could explain many of the biochemical,

genetic and pathological features of sporadic AD: somatic mutations in mtDNA couldcause energy failure, increased production of ROS and accumulation of Ab, which in avicious cycle reinforces the mtDNA damage and the oxidative stress. A similarhypothesis has a strong link with the amyloid cascade hypothesis. In fact several studieshave suggested that the adverse consequences of a primary mitochondrial respiratorychain defect and Ab peptide can be synergistic. Interestingly, the activities of thoseenzymes, which are reduced in the brains from AD patients, such as COX, KGDHC,were inhibited by Ab. Increased intracellular Ab levels can further exacerbate thegenetically driven COX defect in sporadic AD and may facilitate MPT opening, thatinitiate cell death in the apoptosis (Eckert et al. 2003).

Recent evidences has shown that Ab binding alcohol dehydrogenase (ABAD), which

is localized to the mitochondrial matrix, may be a direct molecular link from Ab andmitochondrial toxicity (Lustbader et al. 2004). Ab bound to ABAD was found in ADbrain mitochondria, and blocking this interaction in vitro suppresses Ab inducedapoptosis and free radical generation in neurons (Lustbader et al. 2004). Another studyalso showed that Ab is present in mitochondria, and that in the presence of copper itinhibits COX (Crouch et al. 2005). There is also evidence that c-secretase is present inmitochondria (Hansson at al. 2004) and that APP is associated with the outermitochondrial membrane (Anandatheerthavarada et al. 2003).

On the other hand, mitochondrial dysfunction and oxidative stress may alter APPprocessing leading to intracellular accumulation of Ab (Gabuzda et al. 1994; Ohyagiet al. 2000). In addition, a previous study proved that oxidative stress may increase the

activity of the b-secretase, the enzyme responsible for N-terminal cleavage of Ab fromthe APP (Drake et al. 2003). But the question of what induces mitochondrial geneticabnormalities such as mutations in the coding region remains to be answered.

Mitochondrial Involvement in Parkinsons Disease

Parkinsons disease (PD) is a common neurodegenerative movement disorder charac-terized by the loss of dopaminergic neurons in the substantia nigra (SN) pars compactaand the accumulation of intraneuronal inclusions usually positive for ubiquitin and

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a-synuclein, known as Lewy bodies. Although the mechanisms responsible forneurodegeneration in PD are largely unknown, they result in damage and subsequentloss of dopaminergic neurons (Maguire-Zeiss and Federoff2003); there is a large bodyof evidence suggesting that oxidative stress, mitochondrial dysfunction, excitotoxicityand aberrant proteolitic degradation may be relevant to the pathogenesis (Dawson and

Dawson 2003).Mitochondrial involvement in the pathogenesis of PD is supported by post-mortembiochemical studies; a disease specific and drug independent defect of the mitochondrialrespiratory complex I, that is inhibited by 2530%, was found in samples of SN frompatients who suffered from idiopathic PD (Hattori et al. 1991; Shapira et al. 1990;Schapira 2006). Complex I is inhibited in dopamine-containing neurons by systemicadministration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which caninduce parkinsonism in animal models and in humans (Beal 2003).

This meperidine analogue is metabolised to 1-methyl-phenylpyridinium (MPP+) bythe monoamine oxidase B (MAO-B) in glial cells. MPP+ is subsequently selectivelytaken up by dopaminergic terminals and concentrated in neuronal mitochondria, where

MPP+ binds and inhibits complex I of the respiratory chain, leading to an inhibition ofATP synthesis and the generation of free radicals (Langston et al. 1999). It has alsobeen shown that chronic infusions of the pesticide rotenone, another complex Iinhibitor, produce an animal model of PD in rats (Betarbet et al 2000) and causeoxidative damage to DJ-1 protein, accumulation ofa-synuclein, and proteasomalimpairment (Betarbet et al. 2005).

The defect appeared to be restricted both to complex I and the SN, with other brainareas showing normal activity of the ETC (Cooper et al. 1995; Schapira et al. 1990).However, other researches revealed additional defects in complexes II and III anddefect KGDHC (Migliore et al. 2005a; b). In skeletal muscle of PD patients, reducedcomplex I activity was observed by some groups (Bindoff et al. 1989), but denied by

others (Mann et al. 1992). The studies on platelets show more consistent and univocalresults, with a complex I defect either alone or in combination with a mild defect inother complexes (Schapira 1994).

As mentioned above, the inhibition of complex I observed in PD has an aetiologicimpact. The question then arises as to the origin of the complex I-deficiency in PD. Itcould result from an environmental toxin or an acquired or inherited mtDNAmutation(s). To define the origin of OXPHOS deficit in PD, cybrid PD models havebeen developed. PD platelet mitochondrial genes expressed in cybrids produce reducedcomplex I activity (Gu et al. 1998), suggesting that the complex I deficiency wasdetermined by the mtDNA derived from PD platelets.

Although the role of mitochondrial dysfunction and mtDNA mutations in the

pathogenesis of PD remains controversial, parkinsonism has been associated withseveral mtDNA mutations, including large-scale rearrangements (Casali et al. 2001;Chalmers et al. 1996; Siciliano et al. 2001) and point mutations or microdeletions (DeCoo et al. 1999, Thyagarajan et al. 2000).

A patient with parkinsonism associated with mitochondrial myopathy with raggedred fibers and harbouring the A8344G MERRF mutation in the tRNALys gene wasrecently reported (Horvath et al. 2007); no other clinical signs typical of MERRF werenoted.

Mutations in the nuclear-encoded mtDNA polymerase-c (POLG) gene impairmtDNA replication and result in multiple mtDNA deletions, typically causing chronicprogressive external ophthalmoplegia and myopathy. In such families, POLG mutations

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also cosegregate with parkinsonism (Davidzon et al. 2006; Luoma et al. 2004; Mancusoet al. 2004b). However, a recent study in a large group of PD patients do not supports arole for common POLG genetic variants in PD, indicating that dominant POLGmutations are a rare cause of parkinsonism in the general population (Tiangyou et al.2006). Further, a large proportion of individual pigmented neurons containing high

levels of mtDNA deletions has been recently documented in both aged and PD humanSN (Bender et al. 2006; Kraytsberg et al. 2006). MtDNA mutations are somatic, withdifferent clonally expanded deletions in individual cells, and high levels of thesemutations correlate with COX deficiency on a cell-by-cell basis in the SN.

These results suggest that mtDNA deletions may be directly responsible for impairedcellular respiration and important in the selective neuronal loss observed in aging brainand in PD.

Moreover, many of the genes associated with PD also implicate mitochondria in thedisease pathogenesis. At least nine named nuclear genes have been identified ascausing PD or affecting PD risk. Of the nuclear genes, a-synuclein, parkin, DJ-1,tensin homologue (PTEN)-induced kinase 1 (PINK1), leucine-rich-repeat kinase 2

(LRRK2) and HTRA2 directly or indirectly involve mitochondria (Beal 2005; Lin andBeal 2006).

In transgenic mice, a-synuclein overexpression impairs mitochondrial function,increases oxidative stress and enhances the toxicity of MPTP (Song et al. 2004). Parkinis an ubiquitin E3 ligase that can associate with the outer mitochondrial membrane andprotects against cytochrome c release and caspase activation (Darios et al. 2003); it mayalso associate with mitochondrial-transcription factor A (TFAM) and enhancemitochondrial biogenesis (Kuroda et al. 2006). When oxidized, DJ-1 translocates tomitochondria (intermembrane space and matrix), downregulates the PTEN-tumoursuppressor protein, and protects the cell from oxidative-stress-induced cell death (Kimet al. 2005). PINK-1 is a nuclear-encoded kinase localized to the mitochondrial matrix

(Silvestri et al. 2005) that seems to protect against apoptosis, an effect that is reduced byPD-related mutations or kinase inactivation (Petit et al. 2005). About 10% of the kinaseLRRK2 is localized to mitochondria, and PD-related mutations augment its kinaseactivity (West et al. 2005). HTRA2, a serine protease localized to the mitochondrialintermembrane space, degrades denatured proteins within mitochondria and, if releasedinto the cytosol, promotes programmed cell death by binding inhibitor of apoptosisproteins (Strauss et al. 2005; Suzuki et al. 2001).

The role of the mtDNA variants in PD has been extensively studied. Haplotype J,determined by a single nucleotide polymorphism (SNP) at 10398G and haplotype K inthe control region of mtDNA, reduced the incidence of PD by 50% in Europeansubjects (van der Walt et al. 2003). Further, a SNP at 9055A of ATP6 reduced the risk in

women, and SNP 13708A within the ND5 was protective in individuals older than 70-yrs(van der Walt et al. 2003). Consistent with the previous study, the haplotype clusterUKJT produced a 22% decrease in the risk of getting PD (Pyle et al. 2005). In Finland,the supercluster JTIWX increased the risk of both PD and PD with dementia (Autereet al. 2004). The JTIWX cluster was associated with a twofold increase in nonsynon-ymous substitutions in the mtDNA genes encoding complex I subunits (Autere et al.2004). Another group confirmed that the 10398G polymorphism is protective againstPD in an Italian population (Ghezzi et al. 2005), but this association was not laterconfirmed in Spanish PD patients (Huerta et al. 2005).

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Mitochondrial Involvement in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by theselective degeneration of the anterior horn cells of the spinal cord and cortical motorneurons. Approximately 90% of cases are sporadic (sALS) and 10% are familial

(fALS). About 20% of familial cases result from mutations in the gene encoding for theCu/Zn-superoxide dismutase (SOD1) (Rosen et al. 1993).The aetiology and pathogenesis of the sporadic form of the disease are poorly

understood. It has been hypothesized that the mitochondrial function as well as thebalance between production and detoxication of ROS is disturbed in ALS.

Several studies have reported morphological and metabolic alterations of mitochon-dria in ALS patients and in a variety of experimental models of SOD1-linked fALS.

The first evidence for involvement of mitochondria in ALS came from electronmicroscopy studies in the late 60s (Afifi et al. 1966), which showed abnormalmitochondrial morphology in skeletal muscle. Mitochondrial abnormalities were alsodetected in intramuscular nerves (Atsumi 1981), in proximal axons (Hirano et al. 1984)

and in the anterior horns of the spinal cord of sALS patients (Sasaki and Iwata 1996).Abnormal mitochondrial function in ALS was first shown directly in 1993 when

Bowling and coworkers found an increase in complex I activity in the frontal cortex ofpatients with SOD1 mutations, which was not seen in sALS cases (Bowling et al. 1993).The activities of the other complexes were normal.

Other studies did not replicate this finding. Moreover, deficits in the activities ofmitochondrial respiratory chain complex I (Wiedemann et al. 1998) and complex IV(Vielhaber et al. 2000) have been identified in the skeletal muscle and in the spinal cordof sALS patients (Borthwick et al. 1999; Wiedemann et al. 2002). Recently, data fromEchaniz-Laguna and colleagues indicate that the activity of complex IV in skeletalmuscle of sALS patients is progressively altered as the disease develops, despite an

increase in maximal oxidative phosphorylation capacity of muscular mitochondria(Echaniz-Laguna et al. 2006). In cybrid model, Swerdlow et al. (1998) showed that ALScybrids have impaired respiratory chain function, increased free radical production andaltered calcium homeostasis, suggesting the presence of a primary mtDNA defect.However, these data were not confirmed later (Gajewski et al. 2003).

Two patients with ALS and primary pathogenic mtDNA mutations have beenreported: an out-of-frame mutation of mtDNA encoding for subunit I of COX in onecase (Comi et al. 1998), and a point mutation in the tRNAIle (4274T>C) in the othercase (Borthwick et al 2006).

Further, increased levels of mtDNA common deletion and multiple deletions havebeen detected in brain (Dhaliwal and Grewal 2000) and skeletal muscle (Ro et al. 2003)

of patients with sALS.Finally, Italian individuals classified as haplogroup I demonstrated a significant

decrease in the risk of ALS versus individuals carrying the most common haplogroup H(Mancuso et al. 2004a). However this finding was not confirmed recently by Chinneryet al. (2007), that did not find evidence that mtDNA haplogroups contribute to the riskof developing ALS, studying a large UK cohort of ALS patients and controls.

The availability of mutant SOD1 (mutSOD1) transgenic mice provide excellentmodel to investigate deeply the role of mitochondria in ALS. Thus, research has focusedon expression of mutSOD1 in animal and cellular models of the disease.

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Mitochondrial abnormalities have also been identified in motor neurons fromtransgenic mice expressing G93A or G37R mutSOD1 which accumulate large,membrane-bound vacuoles derived from degenerating mitochondria (Dal Canto andGurney 1994; Dal Canto 1995; Wong et al. 1995; Higgins et al. 2003). It has also beenshown that in G93A SOD1 mice there is a transient explosive increase in vacuolar

mitochondrial degeneration just preceding motor neuron death (Kong and Xu 1998),suggesting that mitochondrial abnormalities trigger the onset of ALS. It has beenproposed that vacuole formation is due to expansion of the mitochondrial intermem-brane space and consequent distension of mitochondrial membranes (Higgins et al.2003).

Several studies in animal and cellular models indicate that expression of mutSOD1 isassociated also with mitochondrial dysfunction but the mechanisms by which mutantprotein might affect cell survival remain to be fully understood. MutSOD1 has beenproposed to affect mitochondrial function in several ways.

SOD1 has traditionally been thought to be a cytoplasmic protein, but a small fractionof cellular SOD1 associates with various mitochondria compartments both in vitro and

in vivo in the brain and spinal cord of transgenic mice expressing either wild-type SOD1(wtSOD1) or mutSOD1 (Vijayvergiya et al. 2005; Mattiazzi et al. 2002; Pasinelli et al.2004) and in human spinal cord (Liu et al. 2004). SOD1 may modulate mitochondrialfunction through localization to the mitochondria. The localization of SOD1 tomitochondria has been reported to occur only in affected tissues and to occurpreferentially for mutSOD1 (Liu et al. 2004).

MutSOD1 may interfere with the elements of the ETC, thereby disrupting ATP-generating oxidative phosphorylation. G93A mutSOD1 transgenic mice causesimpaired mitochondrial energy metabolism in the brain and spinal cord in the earlystages of the disease (Mattiazzi et al. 2002). Complex I activity in G93A-SOD1 mice hasbeen reported as reduced (Jung et al. 2002; Kirkinezos et al. 2005). Complex IV activity

is reported to be reduced, but only at very late disease stages (Kirkinezos et al. 2005;Mattiazzi et al. 2002). ATP levels are depleted in presymptomatic mice (Browne et al.2006). Nonetheless, complex I activity and ATP synthesis has been reported asunchanged in aged G85R SOD1 mice (Damiano et al. 2006).

MutSOD1 has been proposed to generate toxic ROS via aberrant superoxidechemistry (Estevez et al. 1999) and to promote oxidative damage to mitochondrialproteins and lipids (Mattiazzi et al. 2002).

MutSOD1 may also disrupt mechanisms by which mitochondria buffer cytosoliccalcium levels. Long before the onset of motor weakness and massive neuronal deaththere is a decrease in the calcium-loading capacity in mitochondria from the brain andspinal cord, but not the liver, of mice expressing G93A or G85R mutSOD1 (Damiano

et al. 2006).MutSOD1 accumulates and aggregates in the outer mitochondrial membrane and

may indirectly affect similar pathways linked to mitochondria by physically blocking theprotein import machines, TOM and TIM (Liu et al. 2004).

MutSOD1 aggregates may interfere with components of mitochondrial-dependentapoptotic machinery. It has been shown that mitochondrial targeting of mutSOD1caused cytochrome c release and apoptosis, whereas targeting to the endoplasmicreticulum or nucleus did not cause cell death (Takeuchi et al. 2002). Mutant, but notwild-type, SOD1 species bind and sequester mitochondrial Bcl-2, rendering themunavailable for anti-apoptotic functions (Pasinelli et al. 2004). Finally, Ferri et al. (2006)suggest that the mechanism underlying the mutSOD1 accumulation in the

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mitochondrial fraction is mediated by modification of cysteine residues. They havedemonstrate that mutSOD1 proteins accumulate in a oxidized aggregate state formingcross-linked oligomers and their presence causes a shift in the mitochondrial redox stateand impairment of respiratory complexes.

All these mechanisms of mitochondrial involvement are not mutually exclusive and

may interact and cooperate in establishing a vicious cycle, ultimately resulting inmitochondrial dysfunction and cell death (Manfredi and Xu 2005).

Mitochondrial Involvement in Huntingtons Disease

Huntingtons disease (HD) is a genetic autosomic disease characterized clinically bypsychiatric disturbances, progressive cognitive impairment and choreiform movements,and pathologically by selective degeneration of medium spiny GABAergic neurons inthe striatum, resulting in a progressive atrophy of the caudate nucleus, putamen andglobus pallidus (Davies and Ramsden 2001).

The HD mutation is an expansion of CAG repeats within exon 1 of the gene thatcodes for huntingtin (Gusella et al. 1983), a cytoplasmic protein of unknown function.Because the CAG triplet codes for glutamine, when mutated, the protein presents apolyglutamine tract at the N-terminus resulting from more than 38/3955 CAG repeats(in adult-onset HD), while expansion of 70 repeats or more occur in juvenile cases, incontrast with normal individuals containing less than 35 CAG repeats (Rego andOliviera 2003). It has been hypothesised that the expanded polyglutamine segmentconfers a dominant gain of function to the protein, ultimately leading to neurodegen-eration (Gusella and McDonald 1995). There is considerable evidence that one of theconsequences of the gene expansion may be a mitochondrial metabolic defect resultingin impaired energy metabolism (Browne et al. 1997), which in turn can lead to an

increased oxidative damage.Various lines of evidence demonstrate the involvement of mitochondrial dysfunction

in the pathogenesis of HD. Magnetic resonance imaging spectroscopy showed increasedproduction of lactate in the cerebral cortex and basal ganglia in HD patients (Jenkinset al. 1993; Koroshetz et al. 1997). Biochemical studies of brain tissue from HD patientshave demonstrated multiple defects in the caudate: decreased complex II activity(Butterworth et al. 1985) and decreased complex II-III activity and no alteration ofcomplex I or IV activities (Mann et al. 1990). In platelets, one study reported decreasedcomplex I activity and no change in the activities of complexes II-III and IV (Parkeret al. 1990a). Also ultrastructural abnormalities in mitochondria have been described inHD cortical tissue (Goebel et al. 1978; Gardian and Vecsei 2004).

Conclusions

In the past 1015 years, research has been directed at clarifying the involvement ofmitochondria and defects in mitochondrial oxidative phosphorylation in late-onsetneurodegenerative disorders. A critical role for mitochondrial dysfunction and oxidativedamage in neurodegenerative diseases has been greatly strengthened by recent findings(recently revised in Mancuso et al. 2006). Mitochondrial metabolic abnormalities, DNAmutations and oxidative stress contribute to ageing, the greatest risk factor forneurodegenerative diseases. Further, mitochondrial abnormalities occur early in most of

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the neurodegenerative diseases, and the evidences of specific interactions of disease-related proteins with mitochondria represent ultimate proof of mitochondrial involve-ment in neurodegeneration. The question of what induces mitochondrial geneticabnormalities remains to be answered. Further studies examining the importance of themitochondrial pathophysiology in neurodegeneration may provide a target for

additional treatments with agents that improve mitochondrial function, target theMPT, or that exert antioxidant activity.

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