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Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses.

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Does Impairment of Energy Metabolism
Result in Excitotoxic Neuronal Death in
Neurodegenerative Illnesses?
M. Flint Beal, MD
The etiology of nerve cell death in neuronal degenerative diseases is unknown, but it has been hypothesized that
excitotoxic mechanisms may play a role. Such mechanisms may play a role in diseases such as Huntington’s disease,
Parkinson’s disease, amyotrophic lateral sclerosis, and Alzheimer’s disease. In these illnesses, the slowly evolving neuronal death is unlikely to be due to a sudden release of glutamate, such as occurs in ischemia. One possibility, however,
is that a defect in mitochondrial energy metabolism could secondarily lead to slow excitotoxic neuronal death, by
making neurons more vulnerable to endogenous glutamate. With reduced oxidative metabolism and partial cell membrane depolarization, voltage-dependent N-methyl-D-aspartate (NMDA) receptor ion channels would be more easily
activated. In addition, several other processes involved in buffering intracellular calcium may be impaired. Recent
studies in experimental animals showed that mitochondrial toxins can result in a pattern of neuronal degeneration
closely resembling that seen in Huntington’s disease, which can be blocked with NMDA antagonists. NMDA antagonists also block neuronal degeneration induced by l-methyl-4-phenylpyridium,
which has been implicated in experimental models of Parkinson’s disease. The delayed onset of neurodegenerative illnesses could be related to the progressive impairment of mitochondrial oxidative phosphorylation, which accompanies normal aging. If defective
mitochondrial energy metabolism plays a role in cell death in neurodegenerative disorders, potential therapeutic
strategies would be to use excitatory amino acid antagonists or agents to bypass bioenergetic defects.
Beal MF. Does impairment of energy metabolism result in excitotoxic neuronal death in
neurodegenerative illnesses? Ann Neurol 1992;31:119- 130
A large number of studies now suggest that excitatory
amino acids play a role in the mechanism of neuronal
death in several diseases. Experimental studies in both
ischemia and hypoglycemia have shown that neuronal
death can be blocked by excitatory amino acid antagonists 111. In these circumstances, there is a dramatic
increase in extracellular glutamate, reflecting both increased release and impaired uptake. The role of excitotoxic mechanisms in neurodegenerative illnesses,
however, is more speculative. These illnesses result in
gradually evolving, relentless neuronal death, unaccompanied by any intense tissue reaction or cellular
response. The loss of neurons and fibers frequently is
accompanied by gliosis. The onset is often subtle and
progression is insidious. There is frequently selective
involvement of circumscribed systems of neurons,
which may be related either anatomically or physiologically. These diseases are exemplified by illnesses such
as Alzheimer’s disease, Huntington’s disease (HD),
Parkinson’s disease, and cerebellar degenerations. The
present review addresses the possibility that defects
in mitochondrial energy metabolism could secondarily
result in excitotoxic neuronal degeneration in neurodegenerative diseases.
From the Neurology Service, Massachusetts General Hospital and
Harvard Medical School, Boston, MA.
Address correspondence to Dr Bed, Neurology Research 4, Massachusetts General Hospital, Boston, MA 02 114.
Structure and Function of Mitochondria
Mitochondria in differing cell types vary widely in size,
shape, and number 12, 31. Each mitochondrion has an
outer membrane that is freely permeable to large molecules and surrounds the mitochondrion, and an inner
membrane that is relatively impermeable and contains
the electron transport enzyme complexes. The inner
compartment of the mitochondrion, enclosed by the
inner membrane, is the matrix in which the Krebs cycle takes place. N A D H and FADH, generated from
the Krebs cycle donate electrons, which are carried
through the series of transport enzymes of the inner
mitochondrial membrane to ATP synthase, the last enzyme complex of the electron transport chain (Fig).
Concomitantly, ejection of protons across the inner
mitochondrial membrane results in an electrochemical
proton gradient, which stores potential energy. Oxida-
Received Jul 1, 1991, and in revised form Aug 19 and Sep 13
Accepted for publication Sep 13, 1991.
Copyright 0 1992 by the American Neurological Association 119
+ L
- .
Cytochrorne c
NADH Ubiquinone
Succinate Ubiquinol Ubiquinol Cytochrorne c
The electron transport chain consists of five major complexes,
each of whiih is made up of numerouj subunits. A proton gradient generated by complexes I , 111, and 1V is uJed by complex V
to generate ATP from ADP.
tive phosphorylation is the coupling of the transfer of
reducing equivalents (electrons) to oxygen with the
synthesis of ATP.
The electron transport chain consists of a complex
array of enzymes 12, 31. Complex I ( N A D H ubiquinone oxidoreductase), the main entranc'e to the electron transport chain, is composed of 26 subunits, 7 of
which are encoded by mitochondrial D N A . Complex
I1 (succinate ubiquinol oxidoreductasei, another entrance to the electron transport unit, consists of 5 subunits that are nuclear encoded. Complex I11 (ubiquinol
cytochrome c oxidoreductase) has 1 1 subunits, with 1
(cytochrome 6) encoded by mitochondrial DNA. Complex IV (cytochrome c oxidase) is composed of 13 subunits, with 3 encoded by mitochondrial D N A , and
complex 'J (ATP synthase) is composed of 12 subunits,
with 2 mitochondrially encoded subunits.
Nuclear D N A encodes the vast maiority of mitochondria] proteins, including numerous components of
the electron transport chain; proteins involved in mitochondrial D N A replication, transcription, and translation; and all matrix, inner, and outer membrane proteins, which are transported to specific mitochondrial
compartments by means of signal peptides C41.Disruption of the electron transport chain could therefore
occur by mutations in either mitochontirial or nuclear
DNA. As yet most documented defects have occurred
in mitochondria1 DNA; however, much less information is available regarding nuclear encoded subunits
of the electron transport chain. Recent evidence has
associated human diseases with nuclear encoded de-
120 Annals of Neurology
Vol 31
No 2 February 1992
fects [ S , 61.If mitochondrial defects are involved in
autosomal dominant disorders such as HD, then, they
would have to be encoded by nuclear D N A , since mitochondria] D N A is maternally transmitted. There has
been speculation that mitochondrial D N A might play
a role in the preponderance of juvenile-onset HD in
patients having inherited the genetic defect from their
fathers. Recent evidence, however, argues againijt this
[ 7 ] ,and favors genomic imprinting, which depends on
the degree of methylation of chromosomes of pa.terna1
and maternal origin [ 8 ] .
Evidence for Impaired Metabolism i n
Neurodegenerative Diseases
The largest body of evidence suggesting an impairment
of energy metabolism has come from studies of glucose
metabolism using positron emission tomography. The
major difficulty with these studies is that it is difficult
to determine whether changes play a role in the disease
process or are merely secondary to neuronal loss. In
HD, there is decreased glucose metabolism in the basal
ganglia, and some but not all studies have shown abnormalities in at-risk patients [9-14). A recent study
showed reduced glucose metabolism in HI) cerebral
cortex, as compared with normal control cortex [l5].
Biochemical studies have shown reduced pyruvate
dehydrogenase activity in the basal ganglia and hippocampus in H D , but not in other brain regions 116, 17).
A recent report noted decreased complex II/III activity
in the caudate but not in the putamen or cortex [I$).
In platelets a decrease in complex I activity was reported in patients with HI), but not in family members
at risk for H D [19]. In the caudate nucleus, significant
reductions in cytochrome oxidase activity and cytochrome adi were found, whereas cytochromes b and
ccI were normal {201. Low levels of cytochrome aa,
or reduced cytochrome oxidase activity are sometimes
observed in patients with complex I defects ~ 2 1 ) .
A further piece of evidence implicating a metabolic
defect in HD is the progressive weight loss exhibited
by these patients despite high caloric intakes. The falloff in weight is greatest in patients with early onset and
with dystonia, rather than chorea, suggesting that it
may not be solely due to motor dysfunction C22). The
increased metabolism is also not associated with any
thyroid abnormalities. It is of interest that cases of nonthyroidal hypermetabolism (Luft’s disease) are associated with abnormal mitochondria and defective respiratory control C23, 241.
In Alzheimer’s disease a consistent pattern of reduced temporoparietal glucose metabolism has been
reported, and it precedes nonmemory congnitive deficits early in the disease [25, 261. In frontal cortex,
pyruvate dehydrogenase activity is reduced, consistent
with neuronal loss, yet succinate dehydrogenase activity is normal {27). In cerebral biopsy specimens, some
evidence has been found for an uncoupling of mitochondrial energy metabolism C28). In platelets, reduced cytochrome oxidase activity has been observed
In Parkinson’s disease, an increasing body of evidence has implicated a defect in complex I of mitochondrial energy metabolism in the pathogenesis of the
illness. The toxic metabolite of 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine(MPTP), 1-methyl-4-phenylpyridium (MPP+), has been shown to be a specific
inhibitor of mitochondrial complex I C30-32f. Postmortem studies of complex I activity in Parkinson’s
disease have shown reduced activity in the substantia
nigra, but not in other brain regions {33, 341. A complex I deficiency has also been found in platelets of
patients with Parkinson’s disease C351 and in muscle
biopsy specimens [36]. A 10-fold increase in mitochondrial DNA with deletions has been found in parkinsonian striatum as compared with normal controls
137-391; however, similar observations have been
made in normal aging C40, 41).
In cerebellar degenerations, studies with positron
emission tomography have documented reduced glucose metabolism in olivopontocerebellar degeneration
and increased metabolism in Friedrich‘s ataxia [42,431.
Several of the patients with olivopontocerebellar degeneration showed significant hypometabolism with
minor degrees of atrophy 142). An abnormality in pyruvate metabolism has been noted in Friedrich‘s ataxia
{ZS], while some patients with olivopontocerebellar atrophy have a deficiency of glutamate dehydrogenase
activity [44f. In motor neuron disease, there are widespread decreases in cerebral glucose metabolism in the
cortex, despite the localized neuronal degeneration
c45, 461.
Effects of Inhibitors of Mitochondrial Energy
Metabolism in Experimental Animals
and in Humans
Hurst examined the effects of several different metabolic toxins on the central nervous system in monkeys
C471. He noted that repeated doses of potassium cyanide would produce severe bilateral lesions in the basal
ganglia as well as areas of necrosis in the white matter.
Sodium azide was also found to produce bilateral necrotic lesions in the basal ganglia, with the caudate and
putamen affected more than the globus pallidus. Miyoshi produced symmetrical basal ganglia lesions in rats
with repeated injections of sodium azide [48). Bilateral
striatal lesions in rats were produced by both cyanide
and sodium azide by Hicks [49].
Hurst noted that the administration of azide to monkeys resulted in “attacks” of abnormal movements
r47). This was subsequently investigated further by
Mettler {SOj. He found that intramuscular injections of
sodium azide for 8 to 10 weeks to monkeys produced
episodic variable dyskinesia. This dyskinesia was characterized as choreoathetosis. Histologically there were
symmetrical lesions in the putamen and retrograde
changes in the substantia nigra.
A particularly interesting compound is the plant
toxin 3-nitropropionic acid. This compound causes a
variety of motor disturbances in livestock. It has also
caused putaminal necrosis and delayed dystonia in children in China, where it has been a fungal contaminant
of sugar cane E5l). It is an irreversible inhibitor of
succinate dehydrogenase, and therefore will interfere
with the tricarboxylic acid cycle, as well as with complex I1 of mitochondrial respiration. In mice and rats,
large doses have been shown to produce a symmetrical
striatal degeneration C52, 5 31. The neuronal degeneration was characterized by swollen cell processes and
neurons, similar to changes observed with excitotoxins.
In vitro studies have shown that 3-nitropropionic acid
toxicity is blockable with kynurenic acid or N-methylD-aspartate (NMDA) antagonists { 5 11.
In humans, cyanide toxicity led to delayed development of a parkinsonian syndrome, with prominent bradykinesia, but no tremor C54, 5 5). The neuropathological findings in one patient showed degeneration in the
globus pallidus and putamen, but sparing of the dopaminergic neurons of the substantia nigra [551. Inhibitors of mitochondrial energy metabolism can therefore
cause selective neuronal degeneration and neurological
symptoms in both experimental animals and humans.
Neurological Deficits Accompanying
Known Disorders of Mitochondrial
Energy Metabolism
A number of diseases in recent years have been documented to involve defects in mitochondrial energy.
Most of these diseases are myopathies but a few show
Neurological Progress: Bed: Energy Impairment in Neurodegenerative Illnesses
12 I
involvement of the central nervous system. Harding
recently reviewed this subject [56}.In one report, clinically significant central nervous system involvement
was found in 29 crf 85 patients with mitochondrial myopathy C57). Nine patients had movement disorders
that included dystonia, chorea, parkinsonism, and myoclonus. One patient developed ataxia, dementia, and
parkinsonism followed by dystonia, starting at age 6 1.
There was a defect in complex I in muscle. Neuropathological findings 5 years after the onset showed the
features of olivopontocerebellar atrophy as well as neuronal loss in the putamen and substantia nigra. Other
mitochondrial diseases include Leber’s optic atrophy,
mitochondrial encephalomyopathy with lactic acidosis
and stroke-like episodes (MELAS), and myoclonus epilepsy with ragged red fibers (MERRF) [58-631. These
diseases show maternal inheritance, consistent with defects in mitochondria1 D N A which is inherited from
the mother.
Perhaps the most interesting of the mitochondria1
encephalopathies is MERRF, which was first defined
by Fukuhara and colleagues in 1980 [64].The typical
clinical features are myoclonus, ataxia, and weakness
[65, 661. Generalized seizures, dementia, hearing loss,
and optic atrophy are frequent. The age of onset varies
from childhood to the 60s. The neuropathological features are those of a system degeneration with selective
neuronal loss affecting particularly the dentate riucleus
and inferior olive, with tract degeneration in the superior cerebellar piiduncles and posterior columns, and
widespread gliosis in the brainstem and cerebellum
165, 66}. Some patients have also shown involvement
of the globus pallidus, substantia nigra, locus ceruleus,
cerebellar cortex, and gracile and cuneate nuclei [67,
681. Positron emission tomographic studies show decreased cortical metabolic rates for glucose and oxygen
utilization C651, while magnetic resonance spectroscopy findings for brain phosphate metabolites and p H
are normal C6‘)).
Mitochondria1 encephalopathies, therefore, share a
number of clinical features with neurodegenerative diseases. These include decreased glucose utilization, delayed and variable onset of neurological symptoms
(often in adulthood), slow progression, and neur-opathological findings of loss of circumscribed groups of
Tissue Specificity of t h e Respiratory Chain
Neurodegenerative diseases are characterized by selective involvement of circumscribed systems of neurons.
How can one account for the specificity of both organ
and neuronal involvement with a defect in mitochondrial enerby metabolism! O n e possibility is the fmding
of tissue-specific isoenzyme forms of the respiratory
chain complexes. The occurrence of tissue-specific iso-
Annals of Neurology
Vol 31
No 2
February 1992
forms of mammalian cytochrome c oxidase was shown
by Kuhn-Nentwig and Kadenbach 1701. They used
quantitative immunoassays to show that more than
three different isoenzymes are present for many subunits of cytochrome oxidase, and that these isoenzymes
show tissue-specific distributions. More recently, tissue-specific distribution of different isoenzymes has
been shown in humans [7 1, 72). Tissue-specific distribution of the adenine nucleotide translocator has also
been reported [73, 741. In a human lethal mitochondrial disease with a nuclear mutation affecting respiratory complexes I and IV, skeletal muscle, the heart,
and the liver were affected, but not the kidney or brain
[6]. Tissue-specific decreases in mitochondrial DNA
have also recently been reported 1751.
Recent findings in Leber’s disease are also of interest. A defect in complex I activity has been found in
this illness. The mitochondrially encoded subunits of
complex I are encoded by N D ( N A D H dehydrogenase) genes. About half the families have a mutation
in the ND4 gene as originally reported by Wallace and
coworkers [SS]. A large Queensland family has a form
of Leber’s disease in which family members, in addition
to optic neuropathy, also frequently display neurological complications including dysarthria, ataxia, tremors,
and posterior column signs. An infantile encephalopathy occurs in members of the family. This family has
been shown to have a mutation in the ND1 gene [76).
These findings show that mutations in differing subunits of complex I can show differing phenotypic expression.
Selective involvement of neuronal systems in neurodegenerative diseases may therefore be a consequence
of tissue- or neuronal system-specific expression of
the defect. A second factor to consider is the metabolic
demands of various neuronal systems, which could interact with a defect in energy metabolism.
Excitotoxic Mechanisms i n
Neurodegenerative Diseases
Olney coined the term “excitotoxic” to describe the
neurotoxic effects of excitatory amino acids, which destroyed neurons in the area of injection, while sparing
fibers of passage and afferent terminals [77). The initial
observation suggesting that excitotoxicity may play a
role in HD was made by Coyle and Schwarcz and by
the McGeers in 1076 C78, 791. They observed that
intrastriatal injections of the rigid glutamate analogue
kainic acid resulted in striatal lesions that were similar
to HD in many respects. In particular, the lesions resulted in a loss of markers for intrinsic striatal neurons,
yet a preservation of striatal afferents such as dopamine. Nonneuronal elements such as glia were spared.
The parallels extended to subtle aspects of the neuropathology, such as the sparing of large striatal neurons.
Table 1. Similarities of Huntington’s Disease and Striatal Excitotoxin Lesions
Huntington’s Disease
Excitotoxin Lesions
Decreased striatal glucose metabolism
Onset in middle age
Preserved NADPH-diaphorase neurons
Preserved parvalbumin neurons
Preserved acetylcholinesterase (large) neurons
Decreased enkephalin and substance P neurons
Decreased GABA
Decreased substance P
Decreased enkephalin
Decreased choline acetyltransferase
Increased somatostatin
Increased neuropeptide Y
Increased neurotensin
Preserved dopamine
Increased serotonin
Decreased NMDA receptors
Decreased opiate receptors
Decreased muscarinic receptors
Decreased GABA, benzodiazepine receptors
Decreased serotonin receptors
Decreased dopamine D, receptors
Dopamine-inducible chorea in primates
Learning deficits
Decreased striatal glucose metabolism
Resistance of immature animals
Preserved NADPH-diaphorase neurons”
Preserved parvalbumin neurons”
Preserved acetylcholinesterase (large) neurons
Decreased enkephalin and substance P neurons
Decreased GABA
Decreased substance P
Decreased enkephalin
Decreased choline acetyltransferase
Increased somatostatin”
Increased neuropeptide Y”
Increased neurotensin
Preserved dopamine
lncreased serotonin
NMDA receptors
opitate receptors
muscirinic receptors
GABA, benzodiazepine receptors
serotonin receptors
doparnine D, receptors
“Seen with N-methyl-o-aspartate agonists only.
gamma aminobutyric acid; NMDA = N-methyl-D-aspartate
We and others later found that some neuronal populations in H D were spared [80-82]. In particular, the
medium-size aspiny neurons containing somatostatin
and neuropeptide Y and staining with the histochemical marker NADPH-diaphorase are spared [SO, 811.
In addition, the large cholinergic aspiny neurons are
also spared [82]. W e found that NADPH-diaphorase-staining neurons are preferentially vulnerable to
kainic acid 1831, but that lesions with the NMDA agonist quinolinic acid [841 produce relative sparing of
these neurons [85, 861. This finding was contested C87,
881 but was confirmed in studies of both striatal cell
cultures and organotypic striatal cultures [89-9 I}. W e
subsequently showed that other N M D A agonists such
as L-homocysteic acid or N-methyl-D-aspartate also
produce relative sparing of NADPH-diaphorasestaining neurons [86, 92). We also confirmed the sparing of NADPH-diaphorase-staining neurons following quinolinic acid induction of lesions in primates
{93]. The relative sparing is seen much more dramatically with chronic striatal lesions in rats, in which there
is marked striatal shrinkage [94]. A second population
of aspiny neurons, which stain with parvalbumin and
gamma-aminobutyric acid (GABA), is also relatively
spared by NMDA agonists but is preferentially vulner-
able to kainic acid 1951. These parvalbumin aspiny neurons are also spared in HD striatum 1961.
Lesions with N M D A agonists, such as quinolinic
acid, provide a neurochemical model that closely mimics the alterations observed in HD striatum [84-86,
941. Not only is there a depletion of markers of spiny
neurons (GABA and substance P), but there are significant increases in neurochemical markers of aspiny
neurons (somatostatin and neuropeptide Y ) and a depletion of choline acetyltransferase activity 194). There
are increases in serotonin with preserved dopamine
concentrations. Quinolinic acid-induced lesions result
in increases in neurotensin irnmunoreactivity similar
to changes seen in HD [973. Quinolinic acid-induced
lesions also result in preferential depletion of NMDA
receptors, similar to observations in HD [98]. Depletions of GABA, benzodiazepine, opiate, dopaminergic,
and muscarinic receptors are also seen [99-1041. In
rats, motor hyperactivity, learning deficits, and reductions in striatal glucose metabolism are seen 11051091. In primates, excitotoxin lesions result in chorea
inducible by dopaminergic agonists [93, 110, 1111.
These similarities between HD and excitotoxin lesions
are summarized in Table 1.
If an NMDA excitotoxic process does play a role in
Neurological Progress: Beak Energy Impairment in Neurodegenerative Illnesses 123
neuronal degeneration in H D , one would expect the
neurons containing high densities of these receptors to
be prefertintially vulnerable, resulting in a depletion
of NMDA receptors. Young and colleagues recently
showed that this is indeed the case. They found a
depletion of NMDA and kainate receptors in HD putamen ll 12, 113). Furthermore, in studying the brain
of an asymptomatic at-risk patient, they found a 50%
depletion of NMDA receptors, suggesting that this is
an early phenomenon in the disease process {l 141.
The role of glutamate in amyotrophic lateral sclerosis is an area of great interest. The unusual amino acid
beta-N-methylamino-L-alanine(BMAA) has been implicated in the pathogenesis of parkinsonism-amyotrophic lateral sclerosis dementia of Guam { 1151. More
recent studies showed abnormalities in glutamate in
both brain tissue and spinal fluid of patients with amyotrophic lateral sclerosis { 1 16- 119). When administered to primates, BMAA causes degenerative changes
in anterior horn cells [115}.
Recent interest in Alzheimer's disease has focused
on the role of amyloid. Amyloid produces dosedependent cell loss and degenerative changes in neurons both in vitro and in vivo C120, 121). The distribution of pathology in Alzheimer's disease, however, is
difficult to explain solely on the basis of the distribution of arnyloid. It is, therefore, possible that excitotoxic mechanisms play a secondary role. In cell culture,
amyloid enhances glutamate neurotoxic ity C122). In
addition, in Alzheimer's disease glutamatergic neurons
are prone to develop neurofibrillary tangles E123). The
numbers of neurofibrillary tangles increase, with progression from primary sensory areas to second- and
third-order association areas [124, 1251. 'These corticocortical pathways are known to use glutamate as a neurotransmitter. A loss of NMDA receptors has also
been observed in cerebral cortex and hippocampus affected by Alzheimer's disease l126, 127). It is, therefore, possible that neurotoxic effects of amyloid could
make neurons more susceptible to glutamate neurotoxicity, which could then contribute to neuronal degeneration.
Effects of A g i n g o n Mitochondrial
Energy Metabolism
Decreasing mitochondrial function with aging may
help to explain the delayed onset of neurodegenerative illnesses. The expression of human mitochondrial
DNA is needed for maintenance of the mitochondrial
respiratory and oxidative phosphorylation system. Mitochondrial D N A encodes 13 protein-coding genes
specifying hydrophobic subunits of the rnitochondrial
respiratory enzyme complex. It has been estimated that
rnitochondrial D N A mutates at 10 times the frequency
of nuclear DNA, due to oxidative damage and the lack
of a mitochondrial D N A repair system l128). Since
124 Annals of Neurology Vol 31 No 2
February 1992
the mitochondrial D N A is very tightly packed, with
no noncoding intervening sequences, mutations in the
mitochondrial D N A are likely to have functional sequelae. Continuous accumulation of mitochoindrial
mutations, which has been postulated to occur in aging,
may be reflected by a deterioration in capacity for oxidative metabolism { 1291. This hypothesis was recently
verified in skeletal muscle biopsy specimens from subjects aged 16 to 92 years l130). There was a significant
negative correlation between age and respiration rate,
measured with three different substrates. There were
also decreases in succinate-cytochrome c reductase and
cytochrome oxidase activities with age. An age-related
mitochondrial D N A deletion was recently identified
138, 41).
If a neurodegenerative disease, therefore, resulted
in a partial impairment of mitochondrial oxidativl: metabolism, it is possible that a further loss of oxidative
metabolism during aging would lead to delayed onset
of neuronal degeneration.
Role of Mitochondrial Dysfunction in
Producing Excitotoxin Lesions I n Vivo
Mitochondria are essential to the cell for maintaining
the normal voltage gradient across the cell mem'brane
as well as a number of processes controlling intracellular calcium. An impairment of energy metabolism with
reduced ATP levels leads to several consequences
1131-1331. An interference with sodium-potassium
adenosine triphosphatase function depolarizes cell
membranes, which permits the intracellular accumulation of sodium. This can relieve the voltage-dependent
M g f i block of N M D A channels, cause the opening
of voltage-dependent calcium channels, and reverse the
sodium-calcium antiport system, such that calcium enters the cell as sodium is extruded. Impaired energy
also prevents ATP-dependent extrusion of calcium and
the storage of excess intracellular calcium in the endoplasmic reticulum by ATP-dependent mechanisms.
The mitochondria also contain a high-capacity uniporc
mechanism for calcium uptake, which relies on thle potential across the inner mitochondrial membrane t o
electrophoretically transport calcium internally. The intramitochondrial calcium levels can be regulated by an
antiport system exchanging two sodium ions for one
calcium ion. ATP is also necessary for high-affinity reuptake of glutamate by glial cells.
In cultured neurons, inhibitors of oxidative phosphorylation or of the sodium-potassium pump allow
NMDA or glutamate to become neurotoxic { 1341.
This is presumably due to a reduction in resting Inembrane potential (above -60 to - 3 0 mV), which is
then insufficient to maintain the voltage-dependent
Mg+ block of N M D A receptors, leading to persistent
receptor activation. Consistent with this notion, (3lney
and colleagues found that depolarization of chick retina
with potassium produced a lesion that histologically
resembled an excitotoxic lesion 11351, and potassium
channel activators can prevent excitotoxicity in vitro
1.136). Recent work in chicken retina showed that both
chemically induced hypoglycemia and blockers of electron transport (potassium cyanide) resulted in excitotoxic lesions blockable with NMDA antagonists, which
were not accompanied by increases in glutamate release f1371. Graded titration of membrane potential
with potassium mimicked the toxicity produced with
graded metabolic inhibition [ 138). These results indicate that ambient glutamate can result in excitotoxic
damage if intracellular energy metabolism is compromised. Electrophysiological studies in both hippocampus and neocortex show that there is sufficient ambient
glutamate to tonically activate NMDA receptors 1139,
We recently obtained evidence in vivo that several
inhibitors of mitochondrial energy metabolism result in
excitotoxic neuronal degeneration. We initially studied
aminooxyacetic acid, a nonspecific inhibitor of transaminases, which inhibits kynurenine transaminase, the
synthetic enzyme for kynurenic acid 1141, 1421, an
endogenous inhibitor of excitatory amino acid receptors. Aminooxyacetic acid, however, had little effect
o n kynurenic acid concentrations, but did result in
depletions of ATP and increases in lactate, consistent
with a defect in mitochondrial energy metabolism
[143, 1441. Aminooxyacetic acid is a potent inhibitor
of aspartate transaminase, which is an essential component of the malate-aspartate shunt across mitochondrial
membranes 1145, 1461. It is now generally accepted
that oxidation of N A D H from the cytoplasm is accomplished by the transport of reducing equivalents from
the cytoplasm to the mitochondria f 1441. The malateaspartate shunt is the predominant shuttle in the brain.
A block of aspartate aminotransferase in both brain
slices and synaptosomes results in decreased oxygen
consumption, decreased glucose and pyruvate oxidation, and an increase in N A D H / N A D in the cytosol
t147-1491. We found that the aminooxyacetic acid
produces excitotoxin lesions in vivo, which can be
blocked by NMDA antagonists or prior decortication,
removing the striatal glutamate input 11431. Similar
observations were initially reported by Urbanska and
associates f 1501. Electrophysiological studies showed
that aminooxyacetic acid does not directly activate
ligand-gated ion channels in cultured cortical or striatal neurons C1431. Lesions with aminooxyacetic acid
produced marked sparing of NADPH-diaphorasestaining and large neurons, which was more striking
than that we have seen with NMDA agonists, closely
resembling HD. Aminooxyacetic acid, therefore, appears to cause excitotoxic lesions in vivo by impairing
mitochondrial metabolism.
The MPTP model of Parkinson's disease has stimu-
lated much recent research [151). Administration of
this compound to both men and primates results in a
clinical syndrome closely resembling Parkinson's disease, accompanied by damage to the dopaminergic
neurons of the substantia nigra. Metabolism of MPTP
by the enzyme monoamine oxidase to MPP+, and the
subsequent uptake of this toxic metabolite into dopamine terminals, have been established as crucial steps
leading to the toxicity of MPTP 130, 31, 152). The
final step in MPTP-induced toxicity is thought to involve interference with mitochondrial energy metabolism 130, 31). MPP+ and its analogues have been
shown to block electron flow from N A D H dehydrogenase to coenzyme Q by binding at or near the same
site that binds rotenone and piericidin 1321, two wellcharacterized inhibitors of complex I. This results in
decreased ATP formation [153] and possibly the generation of cytotoxic free radicals. The means by which
decreased ATP formation leads to cell death, however,
has not been clear. A recent study showed that MPP+
toxicity in the substantia nigra can be blocked by either
local or systemic administration of NMDA antagonists
C1541. We confirmed this observation in studies of
MPP+ toxicity in rat striatum, and showed that MPP'
results in marked impairment of energy metabolism in
vivo [144, 155). Impaired ATP formation induced by
MPP+ may result in excitotoxic neuronal death due
to partial membrane depolarization and relief of the
Mg' + block on the NMDA receptor, resulting in receptor activation.
Another illness in which energy depletion may lead
to excitotoxic neuronal degeneration is thiamine deficiency, which causes Wernicke's encephalopathy. Thiamine deficiency results in reduced cerebral glucose
utilization, and impaired mitochondrial energy metabolism f156, 157). The resulting lesions resemble those
occurring during anoxia and can be blocked with
NMDA antagonists ClSB].
Mitochondrial energy toxins result in histotoxic hypoxia. It is, therefore, of interest that lesions with mitochondrial toxins and ischemic brain damage share several attributes. Ischemic brain damage is ameliorated
by excitatory amino acid antagonists [l] and is attenuated by pentobarbital f l 5 9 , 1601, as is aminooxyacetic
acid (A0AA)-induced striatal damage 1143) and damage induced by MPP+ to dopaminergic neurons in culture 11611. One further similarity is that ischemic brain
damage in both the cerebral cortex and the striatum
spares NADPH-diaphorase interneurons [ 162- 1641,
which are also spared by AOAA and MPP' striatal
lesions 1143, 1551.
Possible Therapeutic Approaches
If a bioenergetic defect results in neuronal degeneration by an excitotoxic mechanism, then two therapeutic
approaches can be envisioned. The first is to attempt
Neurological Progress: Beal: Energy Impairment in Neurodegenerative Illnesses
to ameliorate or bypass the bioenergetic defect and
thereby prevent secondary excitotoxic damage. The
approaches used most frequently are: (1) to administer
vitamins that are coenzymes of respiratory enzymes,
such as thiamine, biotin, or riboflavin; or (2) to administer vitamin C, vitamin K, (menadione), or coenzyme
Qloeither to brid,ge a defect in the electron transport
or to substitute for coenzyme Qluas an electron acceptor and donor [165}. These approaches have met
with variable success. Some patients with MELAS have
shown improvement with coenzyme Q, whereas others
have not [166-168). Responses to coenzyme Q.,menadione, or riboflavin with carnitine have been observed
in a small number of patients with mitochondrid myopathies [169-17 1).
The second approach would be to use excitatory
amino acid antagonists to prevent neuronal death.
These strategies were recently reviewed E1721. The
use of competitive and noncompetitive NMDA antagonists is clearly effective in blocking neuronal death
both in vitro and in vivo. These compounds, however,
have untoward behavioral effects and impair learning
and memory E173). It is, therefore, unclear whether
they will be suitable for chronic administration in humans. One approach may be to use compounds that
block the glycine allosteric site on the NMDA receptor
complex. Antagonists at this site have neuroprouxtive
effects in vivo and may produce less behavioral toxicity
than other agents {173, 174).
The mechanisms of neuronal death in neurodegenerative diseases remain one of the great challenges of
neurological investigation. Diseases of mitochondrial
energy metabolism share several features with neurodegenerative diseases, including delayed onset and circumscribed neuronal degeneration. Animal models
have yielded important clues as to the etiology of neurodegenerative illnesses. The MPTP model of Parkinson’s disease appears to involve a defect in mitochondrial energy metabolism induced by its metabolite
MPP’. Improved models of HD can be produced by
compounds such as aminooxyacetic acid, which produce defects in oxidative phosphorylation. Both these
models appear to involve excitotoxic mechanisms as a
final common pathway of cell death, since the cell
death can be prevented with NMDA antagonists. Progressive deficits in mitochondrial energy metabolism
may, therefore, result in slow excitotoxic neuronal
death. If similar mechanisms occur in human neurodegenerative disorders, then they may be amenable to
therapy with either excitatory amino acid antagonists
or compounds that ameliorate bioenergetic defects.
This work was supported by National Institute of Neurological Disorder and Stroke grants 16367 and NS10828
126 Annals of Nrurology
Vol 31
No 2
February 1992
The secretarial assisrance of Sharon Melanson is gratefully acknowledged.
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