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DOI 10.1007/s10540-007-9038-z
ORIGINAL PAPER
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.
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
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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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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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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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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