Biosci Rep (2007) 27:87–104 DOI 10.1007/s10540-007-9038-z ORIGINAL PAPER
Mitochondria and Neurodegeneration Lucia Petrozzi Æ Giulia Ricci Æ Noemi J. Giglioli Æ Gabriele Siciliano Æ Michelangelo Mancuso
Published online: 8 May 2007 Ó The Biochemical Society 2007
Abstract Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. However, despite the evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients with neurodegenerative disorders, the question ‘‘is mitochondrial dysfunction a necessary step in neurodegeneration?’’ is still unanswered. In this review, we highlight some of the major neurodegenerative disorders (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis and Huntington’s disease) and discuss the role of the mitochondria in the pathogenetic cascade leading to neurodegeneration.
Keywords Mitochondria mtDNA Alzheimer’s disease Parkinson’s disease Amyotrophic lateral sclerosis Huntington’s disease Neurodegeneration
Introduction Mitochondria are key regulators of cell survival and death and a dysfunction of mitochondrial energy metabolism leads to reduced ATP production, impaired calcium buffering, and increased generation of reactive oxygen species (ROS) (Beal 2005). Increased production of ROS damages cell membranes through lipid peroxidation and further accelerates the high mutation rate of mitochondrial DNA (mtDNA). Accumulation of mtDNA mutations enhances normal aging, leads to oxidative damage, causes energy failure and increased production of ROS, in a vicious cycle. The brain is especially 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, Italy e-mail:
[email protected]
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peroxidizable unsaturated fatty acids, high oxygen consumption rate, and relative paucity of antioxidant enzymes compared with other organs (Nunomura et al. 2006). Oxidative ‘‘free radical’’ damage is generally viewed as an etiological factor in brain degeneration and ROS damage within specific brain regions in many neurodegenerative conditions has been reported (Perry et al. 2002). Further, conditions of excessive oxidative stress and mitochondrial calcium overload can favour mitochondrial permeability transition (MPT) state in which the protonmotive force is disrupted (Crompton 2004). The ultimate result of the activation of the MPT pore is the release of cytochrome c and the induction of caspase-mediated apoptosis (Stavrovskaya and Kristal 2005). The mtDNA is particularly susceptible to oxidative damage. Because of its vicinity with ROS source (electron transport chain) and because it is not protected by histones and is inefficiently repaired, mtDNA shows a high mutation rate. In the last decades, it was hypothesized that somatic mtDNA mutations acquired during ageing contribute to the physiological decline that occurs with ageing and ageing-related neurodegeneration (Lin and Beal 2006). Beside somatic mutations, mtDNA is characterized also by genetic polymorphisms. It has been speculated that polymorphisms in mtDNA may cause subtle differences in the encoded proteins and, thus, minimum changes in oxidative phosphorylation (OXPHOS) activity and free radical overproduction. This could predispose an individual, or a population sharing the same mtDNA genotype, to an earlier onset of apoptotic processes, such as accumulation of somatic mtDNA mutations and OXPHOS impairment. The opposite could be true for different polymorphism(s), which could be beneficial increasing OXPHOS activity and/or reducing ROS production. The common mtDNA polymorphisms define a variety of mitochondrial continent-specific genotypes, called haplogroups. In Europe, nine different mitochondrial haplogroups have been identified (H, I, J, K, T, U, V, W, X). A series of experimental evidence have been published suggesting that some mtDNA haplogroups 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). In particular, in northern Italians, Irish and Finnish, haplogroup J is over-represented in long-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 longevity and diseases is far from being clear (Santoro et al. 2006). To investigate if specific genetic polymorphisms within the mitochondrial genome could act as susceptibility factors 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 ageingrelated neurodegenerative diseases (Lin and Beal 2006) but it is still largely debated whether oxidative stress and mitochondrial impairment are involved in the onset and progression of these disorders or are merely a consequence of neurodegeneration. This article focuses on the role of mitochondria in neurodegeneration, and reviews some of the recent relevant data.
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Mitochondrial Involvement in Alzheimer’s Disease Alzheimer’s disease (AD) is a late-onset, progressive, age-dependent neurodegenerative disorder that results in the irreversible loss of neurons, particularly in the cortex and hippocampus. AD is clinically characterized by impairment of cognitive functions and changes in behaviour and personality. A definitive diagnosis can be made only at autopsy: the pathological hallmarks are neuronal loss, extracellular senile plaques containing the peptide b-amyloid (Ab) and neurofibrillary tangles, composed of a hyperphosphorylated form of the microtubular protein tau (Selkoe 2001). While the majority of cases are late-onset and sporadic, approximately 2–3% of AD cases are early onset and familial, with autosomal dominant inheritance. Familial AD can be caused by mutations in the amyloid 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 each c-secretases complex. Most forms of sporadic late-onset AD have probably a complex aetiology 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 in the allele e4 of apolipoprotein E (ApoE4). However in the majority of late-onset AD patients, the casual factors are still unknown and genetics factor probably interact with environmental factors or with other pathologic or physiologic conditions to exert the pathogenic effect. Oxidative damage and mitochondrial dysfunction has been widely implicated in the pathogenesis of AD. Oxidative damage occurs early in the AD brain, before the onset of significant plaque pathology, and seem also to precede the Ab deposition in animal models (Pratico` and Delanty 2000). There is substantial evidence of morphological, biochemical and molecular abnormalities in mitochondria in various tissues of patients affected by AD. Impaired energy metabolism and abnormalities of mitochondrial respiration are a feature of autopsied brain tissue affected by neurodegeneration, but also of peripheral cells (platelets and fibroblasts) of AD patients. Furthermore, the reduction in brain metabolism appears directly to relate to the clinical disabilities of the disease and can also precede the clinical symptoms by decades (Small et al. 1995). Some of the most direct pieces of evidence of brain metabolism abnormalities associated with AD come from in vivo positron emission tomography (PET). In particular, reduced cerebral metabolism has been shown in the temporo-parietal cortices of AD patients, and these changes precede both neuropsychological impairment and atrophy found with neuroimaging (Blass et al. 2000). In the last years several studies aimed to define the underlying 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 and with plaque counts (Bubber et al. 2005). Biochemical analysis in post-mortem AD brains has yielded evidence for impaired activities 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 metabolism resulting in the decline in brain function.
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The most consistent defect in mitochondrial enzymes activity reported in AD has been the electron transport chain (ETC) carrier cytochrome c oxidase (COX, complex IV) (Castellani et al. 2002). Deficient COX activity has been reported by several authors 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. Involvement of other mitochondrial ETC complexes is more controversial. Cardoso et al. (2004a) did not find differences between AD patients and controls in NADH-ubiquinone oxidoreductase (complex I) or succinate dehydrogenase-cytochrome c reductase (complex II/ III) activities of mitochondria isolated from platelets. Our group have reported a decrease of COX but not of F1F0–ATPase activity in hyppocampus and platelets of sporadic 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 mitochondrial and 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 still unclear. It could results from an environmental toxin or from acquired or inherited nuclear DNA (nDNA) and mtDNA mutation(s). The involvement of non-neuronal tissues, as platelets and fibroblasts, suggests that the COX defect is not simply a local consequence of the disease state, but may be genetically determined (Ojaimi et al. 1999). COX’s subunits are encoded by both nDNA and mtDNA, so a low COX activity may result from changes in nDNA, in mtDNA or in the recognition or the import of proteins through the mitochondrial membrane. To elucidate the origin of the bioenergetic deficits in AD, the cybrid models have been developed. In the cytoplasmic hybrid (‘‘cybrid’’) technique, first described in the 1989 (King and Attardi 1989), cells lacking their own mtDNA are repopulated with exogenous mtDNA from AD patients and controls. Phenotypic differences among cybrid lines therefore derive from the amplification of donor mtDNA and not from nuclear or environmental factors. Studies using cybrid cells showed that the enzymatic defects can be transferred to mtDNA-deficient cells implicating mtDNA mutations. Particularly, sporadic AD platelets mitochondrial genes expressed in cybrids reduce COX activity (while the citrate synthase activity remained unchanged), reduced ATP levels 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 amyloidogenic Ab peptides (1–40, 1–42) in a caspase-dependent manner (Khan et al. 2000) and also accumulate Congo red amyloid deposits (Khan et al. 2000), mimicking the amyloid plaques observed in AD brain. Cardoso et al. (2004b) have documented that the alterations in AD cybrid oxidative status renders these cells vulnerable to Ab 1–40 cell death because these cells manifest an excessive decrease in the mitochondrial membrane potential (W), excessive mitochondrial release of citochrome c and caspase enzyme activation. Continuous culture of AD cybrids, with a lowers W relative to controls, showed a worsening of the bioenergetic impairment and simultaneously an increased AD mtDNA replication, that produce mitochondria abnormalities in advance (Trimmer et al. 2004). Thiffault and Bennett (2005) have studied the spontaneous W fluctuations of mitochondrial hyperpolarized with cyclosporine A. The authors found that W flickering, which represent coupling between electron flow, ATP synthesis (F0F1
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ATP-synthase) and mitochondrial calcium extrusion, was much less. This evidence suggest that expression of AD mtDNA produces a more complex bioenergetic impairment beyond simple reduction in complex IV catalytic activity and may result in 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 the mean velocity of mitochondrial and lysosomal movement, as well as the percentage of moving mitochondria, is significantly reduced in AD cybrids. Finally, all these studies demonstrate that sporadic AD cybrid cell lines express the morphological and biochemical phenotype observed in vivo and in the cerebral tissue in sporadic AD and reinforce the evidence that primary mtDNA changes could be responsible for the mitochondrial impairment of sporadic AD. On the other hand, other studies 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 work remains to be done to further ascertain the contribution of mtDNA mutations. Coskun et al. (2004) studied AD cerebral tissue for the sequence of the mtDNA control region for potential disease-producing (or pathogen) mutations. They found that 65% of the AD brains harboured the T414G mutation and that this mutation was not present in brains from controls. Moreover, cloning and sequencing of the mtDNA control region detected that all AD brains had an average 63% increase in mutations of the heteroplasmic mtDNA control region and that the brains from AD patients who were 80 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 the known mtDNA regulatory elements. Certain AD brains harboured the disease-specific, control-region mutations T414C and T477C, and several brains from AD patients from 74 years to 83 years of age harboured the control-region mutations T477C, T146C, and T195C, at levels up to 70–80% in heteroplasmy. AD brains also showed an average 50% reduction in the mtDNA L-strand NADH-dehydrogenase subunit 6 (ND6) transcript and in the mtDNA/nDNA ratio. Reduced ND6 mRNA and mtDNA copy numbers reduce brain oxidative phosphorylation: for this reason it was speculated that the control-region mutations T477C, T146C, and T195C could be responsible for some of the mitochondrial abnormalities observed in AD patients (Coskun et al. 2004). These genetic studies suggest that somatic mutations in the control region, mitochondrialencoded genes, tRNA and rRNA may have a role in the pathogenesis of sporadic AD patients (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 in brains from normal individuals, AD patients or those with dementia and Lewy bodies. Further, they did not observe the heteroplasmic point mutations in the control region segment spanning nucleotide positions 100–570 (Chinnery et al. 2001). As far as the mtDNA coding region, Elson et al. (2006) sequenced the complete coding regions of 145 autoptic AD brain samples and 128 normal controls. They observed that for both synonymous and non-silent changes the overall numbers of nucleotide substitutions were the same for the AD and control sequences. Moreover mtDNA polymorphisms has been supposed to have a role in the pathogenesis 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 AD patients, while haplogroup J seems to be over-represented. Another report regarding a possible link between AD and mtDNA genotypes (Van der walt et al. 2004) showed that males classified as haplogroup U had a significant increase in risk of AD, while females demonstrated a significant decrease in risk with the same U haplogroup. The authors suggested that inheritance of haplogroup U may have negative effect on aging in Caucasian males. However, this association was not confirmed recently by a collaborative study (Elson et al. 2006), which showed no statistically significant association between haplogroup and disease status. The same negative results were obtained in our laboratory, as we did not find any evidence for an etiological role of haplogroup-associated polymorphisms. In conclusion, the exact role of haplogroups and/or mtDNA point mutations remain to be clarified. Although these evidence of the involvement of mitochondria in AD, it remains unclear whether it plays a causative role or if mitochondrial dysfunction occurs only 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 could cause energy failure, increased production of ROS and accumulation of Ab, which in a vicious cycle reinforces the mtDNA damage and the oxidative stress. A similar hypothesis has a strong link with the amyloid cascade hypothesis. In fact several studies have suggested that the adverse consequences of a primary mitochondrial respiratory chain defect and Ab peptide can be synergistic. Interestingly, the activities of those enzymes, which are reduced in the brains from AD patients, such as COX, KGDHC, were inhibited by Ab. Increased intracellular Ab levels can further exacerbate the genetically driven COX defect in sporadic AD and may facilitate MPT opening, that initiate 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 and mitochondrial toxicity (Lustbader et al. 2004). Ab bound to ABAD was found in AD brain mitochondria, and blocking this interaction in vitro suppresses Ab –induced apoptosis and free radical generation in neurons (Lustbader et al. 2004). Another study also showed that Ab is present in mitochondria, and that in the presence of copper it inhibits COX (Crouch et al. 2005). There is also evidence that c-secretase is present in mitochondria (Hansson at al. 2004) and that APP is associated with the outer mitochondrial membrane (Anandatheerthavarada et al. 2003). On the other hand, mitochondrial dysfunction and oxidative stress may alter APP processing leading to intracellular accumulation of Ab (Gabuzda et al. 1994; Ohyagi et 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 from the APP (Drake et al. 2003). But the question of what induces mitochondrial genetic abnormalities such as mutations in the coding region remains to be answered.
Mitochondrial Involvement in Parkinson’s Disease Parkinson’s disease (PD) is a common neurodegenerative movement disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN) pars compacta and the accumulation of intraneuronal inclusions usually positive for ubiquitin and
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a-synuclein, known as Lewy bodies. Although the mechanisms responsible for neurodegeneration in PD are largely unknown, they result in damage and subsequent loss of dopaminergic neurons (Maguire-Zeiss and Federoff 2003); there is a large body of evidence suggesting that oxidative stress, mitochondrial dysfunction, excitotoxicity and aberrant proteolitic degradation may be relevant to the pathogenesis (Dawson and Dawson 2003). Mitochondrial involvement in the pathogenesis of PD is supported by post-mortem biochemical studies; a disease specific and drug independent defect of the mitochondrial respiratory complex I, that is inhibited by 25–30%, was found in samples of SN from patients who suffered from idiopathic PD (Hattori et al. 1991; Shapira et al. 1990; Schapira 2006). Complex I is inhibited in dopamine-containing neurons by systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which can induce parkinsonism in animal models and in humans (Beal 2003). This meperidine analogue is metabolised to 1-methyl-phenylpyridinium (MPP+) by the monoamine oxidase B (MAO-B) in glial cells. MPP+ is subsequently selectively taken up by dopaminergic terminals and concentrated in neuronal mitochondria, where MPP+ binds and inhibits complex I of the respiratory chain, leading to an inhibition of ATP synthesis and the generation of free radicals (Langston et al. 1999). It has also been shown that chronic infusions of the pesticide rotenone, another complex I inhibitor, produce an animal model of PD in rats (Betarbet et al 2000) and cause oxidative damage to DJ-1 protein, accumulation of a-synuclein, and proteasomal impairment (Betarbet et al. 2005). The defect appeared to be restricted both to complex I and the SN, with other brain areas 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 and defect KGDHC (Migliore et al. 2005a; b). In skeletal muscle of PD patients, reduced complex 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 univocal results, with a complex I defect either alone or in combination with a mild defect in other complexes (Schapira 1994). As mentioned above, the inhibition of complex I observed in PD has an aetiologic impact. The question then arises as to the origin of the complex I-deficiency in PD. It could result from an environmental toxin or an acquired or inherited mtDNA mutation(s). To define the origin of OXPHOS deficit in PD, cybrid PD models have been developed. PD platelet mitochondrial genes expressed in cybrids produce reduced complex I activity (Gu et al. 1998), suggesting that the complex I deficiency was determined 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 with several mtDNA mutations, including large-scale rearrangements (Casali et al. 2001; Chalmers et al. 1996; Siciliano et al. 2001) and point mutations or microdeletions (De Coo et al. 1999, Thyagarajan et al. 2000). A patient with parkinsonism associated with mitochondrial myopathy with ragged red fibers and harbouring the A8344G MERRF mutation in the tRNALys gene was recently reported (Horvath et al. 2007); no other clinical signs typical of MERRF were noted. Mutations in the nuclear-encoded mtDNA polymerase-c (POLG) gene impair mtDNA replication and result in multiple mtDNA deletions, typically causing chronic progressive 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; Mancuso et al. 2004b). However, a recent study in a large group of PD patients do not supports a role for common POLG genetic variants in PD, indicating that dominant POLG mutations 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 human SN (Bender et al. 2006; Kraytsberg et al. 2006). MtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations correlate with COX deficiency on a cell-by-cell basis in the SN. These results suggest that mtDNA deletions may be directly responsible for impaired cellular respiration and important in the selective neuronal loss observed in aging brain and in PD. Moreover, many of the genes associated with PD also implicate mitochondria in the disease pathogenesis. At least nine named nuclear genes have been identified as causing 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 and Beal 2006). In transgenic mice, a-synuclein overexpression impairs mitochondrial function, increases oxidative stress and enhances the toxicity of MPTP (Song et al. 2004). Parkin is an ubiquitin E3 ligase that can associate with the outer mitochondrial membrane and protects against cytochrome c release and caspase activation (Darios et al. 2003); it may also associate with mitochondrial-transcription factor A (TFAM) and enhance mitochondrial biogenesis (Kuroda et al. 2006). When oxidized, DJ-1 translocates to mitochondria (intermembrane space and matrix), downregulates the PTEN-tumour suppressor protein, and protects the cell from oxidative-stress-induced cell death (Kim et 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 by PD-related mutations or kinase inactivation (Petit et al. 2005). About 10% of the kinase LRRK2 is localized to mitochondria, and PD-related mutations augment its kinase activity (West et al. 2005). HTRA2, a serine protease localized to the mitochondrial intermembrane space, degrades denatured proteins within mitochondria and, if released into the cytosol, promotes programmed cell death by binding inhibitor of apoptosis proteins (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 in the control region of mtDNA, reduced the incidence of PD by 50% in European subjects (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 cluster UKJT 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 (Autere et al. 2004). The JTIWX cluster was associated with a twofold increase in nonsynonymous substitutions in the mtDNA genes encoding complex I subunits (Autere et al. 2004). Another group confirmed that the 10398G polymorphism is protective against PD in an Italian population (Ghezzi et al. 2005), but this association was not later confirmed 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 the selective degeneration of the anterior horn cells of the spinal cord and cortical motor neurons. 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 the Cu/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 the balance between production and detoxication of ROS is disturbed in ALS. Several studies have reported morphological and metabolic alterations of mitochondria 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 electron microscopy studies in the late 60s (Afifi et al. 1966), which showed abnormal mitochondrial morphology in skeletal muscle. Mitochondrial abnormalities were also detected 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 of patients 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 of mitochondrial 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 cord of sALS patients (Borthwick et al. 1999; Wiedemann et al. 2002). Recently, data from Echaniz-Laguna and colleagues indicate that the activity of complex IV in skeletal muscle 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 ALS cybrids have impaired respiratory chain function, increased free radical production and altered 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 been reported: an out-of-frame mutation of mtDNA encoding for subunit I of COX in one case (Comi et al. 1998), and a point mutation in the tRNAIle (4274T>C) in the other case (Borthwick et al 2006). Further, increased levels of mtDNA ‘‘common deletion’’ and multiple deletions have been 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 Chinnery et al. (2007), that did not find evidence that mtDNA haplogroups contribute to the risk of developing ALS, studying a large UK cohort of ALS patients and controls. The availability of mutant SOD1 (mutSOD1) transgenic mice provide excellent model to investigate deeply the role of mitochondria in ALS. Thus, research has focused on expression of mutSOD1 in animal and cellular models of the disease.
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Mitochondrial abnormalities have also been identified in motor neurons from transgenic mice expressing G93A or G37R mutSOD1 which accumulate large, membrane-bound vacuoles derived from degenerating mitochondria (Dal Canto and Gurney 1994; Dal Canto 1995; Wong et al. 1995; Higgins et al. 2003). It has also been shown 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 been proposed that vacuole formation is due to expansion of the mitochondrial intermembrane space and consequent distension of mitochondrial membranes (Higgins et al. 2003). Several studies in animal and cellular models indicate that expression of mutSOD1 is associated also with mitochondrial dysfunction but the mechanisms by which mutant protein might affect cell survival remain to be fully understood. MutSOD1 has been proposed to affect mitochondrial function in several ways. SOD1 has traditionally been thought to be a cytoplasmic protein, but a small fraction of 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 mitochondrial function through localization to the mitochondria. The localization of SOD1 to mitochondria has been reported to occur only in affected tissues and to occur preferentially for mutSOD1 (Liu et al. 2004). MutSOD1 may interfere with the elements of the ETC, thereby disrupting ATPgenerating oxidative phosphorylation. G93A mutSOD1 transgenic mice causes impaired mitochondrial energy metabolism in the brain and spinal cord in the early stages of the disease (Mattiazzi et al. 2002). Complex I activity in G93A-SOD1 mice has been 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 as unchanged in aged G85R SOD1 mice (Damiano et al. 2006). MutSOD1 has been proposed to generate toxic ROS via aberrant superoxide chemistry (Estevez et al. 1999) and to promote oxidative damage to mitochondrial proteins and lipids (Mattiazzi et al. 2002). MutSOD1 may also disrupt mechanisms by which mitochondria buffer cytosolic calcium levels. Long before the onset of motor weakness and massive neuronal death there is a decrease in the calcium-loading capacity in mitochondria from the brain and spinal 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 the protein import machines, TOM and TIM (Liu et al. 2004). MutSOD1 aggregates may interfere with components of mitochondrial-dependent apoptotic machinery. It has been shown that mitochondrial targeting of mutSOD1 caused cytochrome c release and apoptosis, whereas targeting to the endoplasmic reticulum or nucleus did not cause cell death (Takeuchi et al. 2002). Mutant, but not wild-type, SOD1 species bind and sequester mitochondrial Bcl-2, rendering them unavailable 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 have demonstrate that mutSOD1 proteins accumulate in a oxidized aggregate state forming cross-linked oligomers and their presence causes a shift in the mitochondrial redox state and 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 in mitochondrial dysfunction and cell death (Manfredi and Xu 2005).
Mitochondrial Involvement in Huntington’s Disease Huntington’s disease (HD) is a genetic autosomic disease characterized clinically by psychiatric disturbances, progressive cognitive impairment and choreiform movements, and pathologically by selective degeneration of medium spiny GABAergic neurons in the striatum, resulting in a progressive atrophy of the caudate nucleus, putamen and globus pallidus (Davies and Ramsden 2001). The HD mutation is an expansion of CAG repeats within exon 1 of the gene that codes for huntingtin (Gusella et al. 1983), a cytoplasmic protein of unknown function. Because the CAG triplet codes for glutamine, when mutated, the protein presents a polyglutamine tract at the N-terminus resulting from more than 38/39–55 CAG repeats (in adult-onset HD), while expansion of 70 repeats or more occur in juvenile cases, in contrast with normal individuals containing less than 35 CAG repeats (Rego and Oliviera 2003). It has been hypothesised that the expanded polyglutamine segment confers a dominant ‘gain of function’ to the protein, ultimately leading to neurodegeneration (Gusella and McDonald 1995). There is considerable evidence that one of the consequences of the gene expansion may be a mitochondrial metabolic defect resulting in 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 increased production of lactate in the cerebral cortex and basal ganglia in HD patients (Jenkins et al. 1993; Koroshetz et al. 1997). Biochemical studies of brain tissue from HD patients have demonstrated multiple defects in the caudate: decreased complex II activity (Butterworth et al. 1985) and decreased complex II-III activity and no alteration of complex I or IV activities (Mann et al. 1990). In platelets, one study reported decreased complex I activity and no change in the activities of complexes II-III and IV (Parker et al. 1990a). Also ultrastructural abnormalities in mitochondria have been described in HD cortical tissue (Goebel et al. 1978; Gardian and Vecsei 2004).
Conclusions In the past 10–15 years, research has been directed at clarifying the involvement of mitochondria and defects in mitochondrial oxidative phosphorylation in late-onset neurodegenerative disorders. A critical role for mitochondrial dysfunction and oxidative damage in neurodegenerative diseases has been greatly strengthened by recent findings (recently revised in Mancuso et al. 2006). Mitochondrial metabolic abnormalities, DNA mutations and oxidative stress contribute to ageing, the greatest risk factor for neurodegenerative diseases. Further, mitochondrial abnormalities occur early in most of
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the neurodegenerative diseases, and the evidences of specific interactions of diseaserelated proteins with mitochondria represent ultimate proof of mitochondrial involvement in neurodegeneration. The question of what induces mitochondrial genetic abnormalities remains to be answered. Further studies examining the importance of the mitochondrial pathophysiology in neurodegeneration may provide a target for additional treatments with agents that improve mitochondrial function, target the MPT, or that exert antioxidant activity.
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