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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 morpho-
logical, 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). Accumu-
lation 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: mmancuso@inwind.it
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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 proton-
motive 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 ageing-
related 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 neurodegenera-


tive 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 hyperphosphorylat-
ed 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 (Praticò 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 neuroi-
maging (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 oxido-
reductase (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, mitochondrial-
encoded 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 charac-


terized 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 nonsynon-
ymous 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 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 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 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 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 ATP-
generating 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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Biosci Rep (2007) 27:87–104 97

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 neurodegen-
eration (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 disease-


related proteins with mitochondria represent ultimate proof of mitochondrial involve-
ment 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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