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Biochemical Society Transactions (2007) Volume 35, part 5
Mitochondrial dysfunction in neurodegenerative
disorders
M. Baron, A.P. Kudin and W.S. Kunz1
Department of Epileptology and Life&Brain Center, University Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany
Abstract
There is compelling evidence for the direct involvement of mitochondria in certain neurodegenerative
disorders, such as Morbus Parkinson, FRDA (Friedreich’s ataxia), ALS (amyotrophic lateral sclerosis), and
temporal lobe epilepsy with Ammon’s horn sclerosis. This evidence includes the direct genetic evidence of
pathogenic mutations in mitochondrial proteins in inherited Parkinsonism {such as PARK6, with mutations
in the mitochondrial PINK1 [PTEN (phosphatase and tensin homologue deleted on chromosome 10)-induced
kinase 1]} and in FRDA (with mutations in the mitochondrial protein frataxin). Moreover, there is functional
evidence of impairment of the respiratory chain in sporadic forms of Parkinsonism, ALS, and temporal lobe
epilepsy with Ammon’s horn sclerosis. In the sporadic forms of the above-mentioned neurodegenerative
disorders, increased oxidative stress appears to be the crucial initiating event that affects respiratory chain
function and starts a vicious cycle finally leading to neuronal cell death. We suggest that the critical factor
that determines the survival of neurons in neurodegenerative disorders is the degree of mitochondrial DNA
damage and the maintenance of an appropriate mitochondrial DNA copy number. Evidence for a depletion
of intact copies of the mitochondrial genome has been provided in all above-mentioned neurodegenerative
disorders including ALS and temporal lobe epilepsy with Ammon’s horn sclerosis. In the present study, we
critically review the available data.
Introduction
This review summarizes recent functional and genetic
findings reporting a mitochondrial impairment in certain
neurodegenerative diseases, such as Morbus Parkinson,
FRDA (Friedreich’s ataxia), ALS (amyotrophic lateral
sclerosis) and temporal lobe epilepsy.
Morbus Parkinson
Morbus Parkinson [PD (Parkinson’s disease)] is a
neurodegenerative disorder affecting dopaminergic neurons
in substantia nigra. Mitochondrial respiratory complex I
deficiency and oxidative stress have been reported to occur
in these neurons, and cytoplasmic aggregates (‘Lewy bodies’)
of α-synuclein and other proteins have been observed in the
affected neurons [1].
Among the different mitochondrial abnormalities that
have been described in human neurodegenerative diseases,
the respiratory complex I deficit appears to be relatively
PD-specific. For PD, this deficit has been documented
by reduced immunoreactivity for complex I not only in
autopsies of the degenerated substantia nigra [2], but also
Key words: amyotrophic lateral sclerosis (ALS), Friedreich’s ataxia, mitochondrion, Morbus
Parkinson, neurodegenerative disorder.
Abbreviations used: ALS, amyotrophic lateral sclerosis; fALS, familiar ALS; FRDA, Friedreich’s
ataxia; FXN, frataxin; mtDNA, mitochondrial DNA; PD, Parkinson’s disease; PTEN, phosphatase
and tensin homologue deleted on chromosome 10; PINK1, PTEN-induced kinase 1; ROS, reactive
oxygen species; sALS, sporadic ALS; SOD, superoxide dismutase.
1
To whom correspondence should be addressed, at Division of Neurochemistry,
NeuroCognition, Life&Brain Center, University Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn,
Germany (email [email protected]).
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Authors Journal compilation by enzyme activity measurements in apparently unaffected
peripheral cells such as fibroblasts [3], platelets and skeletalmuscle fibres [4–6]. In spite of controversies about PD
pathology in peripheral cells [7], it has been shown that
mitochondria from thrombocytes of PD patients transferred
to rho-zero cells, which lack mitochondrial DNA, induce a
complex I defect [8]. The observation that the degeneration
of dopaminergic neurons can be modelled with inhibitors of
the mitochondrial respiratory chain such as rotenone [9] or
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) [10],
which both inhibit complex I, corroborates an involvement
of mitochondrial dysfunction in the pathogenesis of PD.
Disorders with monogenetic inheritance resembling the
clinical picture of PD while displaying early onset are rare
but highly relevant, since they allowed the identification
of the respective disease genes: mutations in α-synuclein
(PARK1), parkin (PARK2), UCH-L1 (ubiquitin C-terminal
esterase L1) (PARK5) and DJ-1 (PARK7) were shown
to result in protein misfolding, ubiquitin–proteasome
deficits and oxidative stress [11,12]. The first genetic link to
mitochondrial dysfunction came from PARK6, where the
mitochondrial protein kinase PINK1 [PTEN (phosphatase
and tensin homologue deleted on chromosome 10)-induced
kinase 1] was found mutated [13] by a W437OPA truncation
mutation, a G309D missense mutation with postulated loss
of ATP binding [14], or several other nonsense mutations,
indicating a loss of PINK1 function within mitochondria as
the cause of pathogenesis [15].
A common feature of sporadic and inherited forms of PD
is increased oxidative stress in dopaminergic neurons. Since
Central Nervous System
mitochondrial respiratory chain complex I appears to be the
main source of ROS (reactive oxygen species) in neurons [16],
an important contribution of mitochondria in the neurodegenerative process is very likely. Additional ROS generation
by the cytosolic tyrosine hydroxylase and monoamine
oxidases might underlie the preferential degeneration of
neurons with dopaminergic neurotransmission in PD.
The molecular mechanism explaining the persistent mitochondrial dysfunction in dopaminergic neurons is suggested
to be related to clonal accumulation of deleted mtDNA
(mitochondrial DNA) molecules at the single-cell level
[17,18]. This in turn diminishes the residual amount of wildtype mtDNA, thus leading to mitochondrial dysfunction by
reduced expression of mitochondrially encoded proteins.
FRDA
Human FXN (frataxin) is a ∼17 kDa protein whose deficiency causes FRDA, a neurodegenerative disorder characterized by degeneration of the Purkinje neurons of the
cerebellum that causes limb ataxia, loss of proprioception,
dysarthria, skeletal abnormalities, hypertrophic cardiomyopathy and increased incidence of diabetes. In the vast majority
of patients (96–98%), the defective expression of FXN is
due to a homozygous GAA triplet repeat expansion within
the first intron of the FXN gene, located on chromosome
9q13 [19]. The hyperexpansion of GAA repeats determines
the formation of a triple helix non-B DNA structure,
resulting in an inhibition of FXN mRNA transcription
[20]. Moreover, missense mutations are present in FRDA
compound heterozygotes, representing 2–4% of patients,
which carry an intronic GAA expansion on one FXN
allele and an exonic point mutation, mainly located at the
C-terminal region of FXN, on the other allele [21]. FXN is
involved in several aspects of intracellular iron metabolism,
such as biogenesis of haem [22] and iron–sulfur clusters [23],
iron binding/storage [24] and iron chaperone activity [25].
Consequently, FXN-defective organisms, from unicellular
yeast to humans, exhibit a plethora of metabolic disturbances
caused by intramitochondrial iron accumulation, such as the
loss of iron–sulfur cluster-dependent enzymes [26], reduced
oxidative phosphorylation [27] and altered antioxidant
defences [28]. In this context, it has to be mentioned that
the molecular cause for reduced mitochondrial oxidative
phosphorylation is a severe decrease in copy number of
mtDNA as a result of increased oxidative stress [26].
ALS
ALS is a devastating motoric disease (incidence 2:100 000)
caused by a progressive degeneration of the anterior horn cells
of the spinal cord and cortical motor neurons. The primary
cause of the neuronal cell death in ALS so far remains unclear.
Some early concepts relate the neurodegenerative process to
glutamate-induced excitotoxicity [29]. There is compelling
evidence for increased oxygen radical damage in brain
tissue of patients with ALS [30]. In line with this concept,
it was demonstrated that some patients with autosomaldominant fALS (familiar ALS) have point mutations in the
Cu2+ /Zn2+ SOD1 (superoxide dismutase 1) gene [31]. While
the aetiology of sALS (sporadic ALS) has remained unknown,
20% of fALS cases are associated with a dominantly inherited
mutation in this particular gene. Till now, more than 100
different mutations in SOD1 have been described [32]. Surprisingly, most of these mutant SODs retain full enzymatic
activity, and therefore a ‘toxic gain of function’ as cause for
the disease has been postulated. Nevertheless, it remained
unclear how the mutated SOD1 causes the selective loss of
motor neurons. Mouse models, which carry these mutations,
develop severe motor neuron disease [33,34], and the most
prominent ultrastructural abnormality is the presence of
vacuoles in axons and dendrites, which appear to be derived
from degenerating mitochondria [33]. Similarly, in anterior
horn neurons of patients with sALS, conglomerations of
dark abnormal mitochondria were detected [35]. These
findings strongly suggest an involvement of mitochondria
in the process of degeneration of motor neurons. Abnormal
mitochondria also have been observed by COX (cytochrome
c oxidase)/SDH (succinate dehydrogenase) double staining
of motor neurons [36] in early stages of the disease.
Additionally, impaired mitochondrial function has been
detected in peripheral tissues of patients with ALS, such as
in skeletal-muscle biopsies [37,38] and in cybrids made from
thrombocytes of ALS patients fused to rho-zero cells [39]. In
addition to certain rare mtDNA mutations being suggested to
play a role in the pathogenesis of the disease [40], an important
mechanism explaining at least the mitochondrial dysfunction
seems to be mtDNA depletion [38], which is most probably,
like in the above-mentioned neurodegenerative diseases, also
related to increased oxidative stress. Since mtDNA depletion
has been directly observed in skeletal-muscle biopsies from
sALS patients in early stages of the disease [38], this finding
has been implicated to be relevant for the neurodegenerative
process [41].
Temporal lobe epilepsy
Epilepsy is one of the most common neurological disorders,
affecting approx. 0.5–0.7% of the human population worldwide. The hallmarks of epilepsy are recurrent seizures, which
on a cellular level consist of synchronized discharges of large
groups of neurons that interrupt normal function. One of the
most frequent and devastating forms of epilepsy involves
the development of an epileptic focus in temporal lobe
structures. Prolonged seizures (status epilepticus), induced in
experimental models by kainic acid or pilocarpine, are known
to activate neuronal cell death mechanisms in temporal lobe
structures similar to other neurodegenerative disorders. This
neuronal cell death is also observed in human temporal lobe
epilepsy and is one of the most important aspects of epileptogenesis. Specifically in the hippocampus, the loss of CA1 and
CA3 pyramidal neurons, with relative sparing of the granular
neurons of the dentate gyrus and some types of interneurons,
is the histopathological hallmark of Ammon’s horn sclerosis.
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Biochemical Society Transactions (2007) Volume 35, part 5
Figure 1 Citrate synthase and mtDNA copy numbers in human
hippocampal subfields
(A) Distribution of the mitochondrial marker enzyme citrate synthase in
hippocampal subfields of patients with temporal lobe epilepsy. Closed
bars, lesion patients (n = 7); open bars, patients with Ammon’s horn
sclerosis (n = 19). For experimental details, see [44]. (B) Mitochondrial
DNA copy numbers in hippocampal subfields of patients with temporal
lobe epilepsy. Closed bars, lesion patients (n = 7); open bars, patients
with Ammon’s horn sclerosis (n = 19). The copy numbers were
determined by real-time PCR using the nuclear Kir 4.1 gene as single copy
reference. (A, B) The PCRs were performed on an iCyclerTM (Bio-Rad).
The PCR conditions were as follows: 3 min at 95◦ C, 45 cycles with 15 s
at 95◦ C as first segment and 1 min at 60◦ C as second segment, 1 min at
95◦ C, 1 min at 55◦ C, 80 cycles with increasing temperature 0.5◦ C each
10 s from 55 to 95◦ C (melting curve), and infinite hold at 16◦ C. The
cycle number values were determined from fits of experimental data
to a sigmoidal curve by using the equation: y = y0 + a(1 − e−bx )c . The
inflection point equals the cycle number value used in the copy number
calculations. Triplicate experiments were performed and arithmetic
means and standard deviations were calculated. The primer efficiency
was calculated from serial dilutions. The copy number values were
verified by using a calibration with counted fibroblasts and dilution
series of mitochondrial PCR fragments. *P < 0.05; **P < 0.01. DG, dentate
gyrus; PH, parahippocampal gyrus.
Since neurons contain the highest amounts of mitochondria,
the most affected subfield CA1 showed a 50% decreased
activity, while the less severely affected CA3 subfield had an
approx. 30% diminished activity. The underlying mechanism
of this regional selectivity of neuronal cell death remains
to be elucidated yet. Probably the most important factor,
preceding neuronal cell death after status epilepticus, is
the increased level of ROS observed in various models
of experimental epilepsy, such as after kainate-induced
hippocampal damage, after pilocarpine treatment or in low
Mg2+ -induced epileptiform activity of brain slices and slice
cultures (cf. [43]). Mitochondrial respiratory chain complex I
is very likely to be the most important source of production
of these ROS [16]. Moreover, increased production of ROS
is a feature of partially respiratory chain complex I-inhibited
mitochondria [16], and it is noteworthy to mention in this
context that a severe impairment of respiratory chain complex
I activity is present in the focus of epileptic activity: the CA3
neurons of the hippocampus from patients with Ammon’s
horn sclerosis and in the parahippocampal gyrus of patients
with parahippocampal lesions [42]. Similar observations
were made in the vulnerable CA1 and CA3 hippocampal
subfields of pilocarpine-treated chronic epileptic rats [44]. As
a potential cause of the detected impairment of mitochondrial
respiratory chain in the rat model, a decrease in the
mtDNA copy number was delineated [44]. As shown in
Figure 1(B), similar results can be obtained by determinations
of mitochondrial DNA copy number in human hippocampal
subfields from patients with temporal lobe epilepsy and
Ammon’s horn sclerosis (open bars) in comparison with
lesion patients (filled bars). In analogy to the rat study [44],
reduced mtDNA copy numbers are detectable for both the
CA1 and the CA3 regions. Whereas for the CA1 region a
considerable decrease in the content of mitochondria is very
likely to be responsible for this observation (cf. Figure 1A),
the 2-fold lower mtDNA copy numbers in the CA3 region
cannot be explained by a lowered mitochondrial content.
Thus, as observed in the pilocarpine model of temporal lobe
epilepsy [44], mtDNA depletion is a feature of CA3 neurons
in Ammon’s horn sclerosis. Since oxygen radicals are known
to create mtDNA strand breaks, which facilitate mtDNA
breakdown, this finding implies a role of oxygen radicals in
causing neuronal mtDNA damage occurring selectively
in brain areas generating epileptic activity.
Mitochondrial DNA depletion is a frequent
cause of bioenergetic defects in human
neurological disease
This profile of hippocampal neuronal cell death is visible in
the activity distribution of the mitochondrial marker enzyme,
citrate synthase, shown in Figure 1(A) (for details see [42]).
C The
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Authors Journal compilation In addition to neurodegenerative diseases, which show the
feature of mtDNA depletion in postmitotic cells, there also
exists a broad spectrum of genetic syndromes presenting with
neurological phenotypes, which are associated with reduced
mtDNA copy numbers due to mutations in various nuclear
genes involved in mtDNA maintenance. These include genes
for deoxyguanosine kinase [45], thymidine kinase [46],
the muscle-, brain- and heart-specific isoforms of adenine
Central Nervous System
nucleotide translocase [47], the mitochondrial helicase
Twinkle [48] and the mitochondrial polymerase γ [49,50].
This clearly underlines that the maintenance of the correct
mtDNA copy number is a critical factor for proper neuronal
functioning.
In summary, the reduction of intact mtDNA copies
by oxidative stress-related mutagenesis appears to be the
molecular cause of the observed mitochondrial dysfunction
in the above-mentioned neurodegenerative diseases. Interestingly, comparable clinical phenotypes, associated with
epilepsy, ataxia and various forms of encephalopathy, are
also found in genetic disorders caused by mutations in genes
affecting the mtDNA maintenance.
This study was supported by the Deutsche Forschungsgemeinschaft
(KU-911/15-1 and SCHR-562/4-3) and the BMBF (Bundesministerium für Bildung und Forschung) (01GZ0704).
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Received 8 June 2007
doi:10.1042/BST0351228
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