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Cortical metabolism in pyruvate dehydrogenase deficiency revealed by ex vivo multiplet (13)C NMR of the adult mouse brain.
[pyruvate dehydrogenase deficiency]
The
pyruvate
dehydrogenase
complex
(
PDC
)
,
required
for
complete
glucose
oxidation
,
is
essential
for
brain
development
.
Although
PDC
deficiency
is
associated
with
a
severe
clinical
syndrome
,
little
is
known
about
its
effects
on
either
substrate
oxidation
or
synthesis
of
key
metabolites
such
as
glutamate
and
glutamine
.
Computational
simulations
of
brain
metabolism
indicated
that
a
25
%
reduction
in
flux
through
PDC
and
a
corresponding
increase
in
flux
from
an
alternative
source
of
acetyl-
CoA
would
substantially
alter
the
(
13
)
C
NMR
spectrum
obtained
from
brain
tissue
.
Therefore
,
we
evaluated
metabolism
of
[
1
,
6
-
(
13
)
C
(
2
)
]
glucose
(
oxidized
by
both
neurons
and
glia
)
and
[
1
,
2
-
(
13
)
C
(
2
)
]
acetate
(
an
energy
source
that
bypasses
PDC
)
in
the
cerebral
cortex
of
adult
mice
mildly
and
selectively
deficient
in
brain
PDC
activity
,
a
viable
model
that
recapitulates
the
human
disorder
.
Intravenous
infusions
were
performed
in
conscious
mice
and
extracts
of
brain
tissue
were
studied
by
(
13
)
C
NMR
.
We
hypothesized
that
mice
deficient
in
PDC
must
increase
the
proportion
of
energy
derived
from
acetate
metabolism
in
the
brain
.
Unexpectedly
,
the
distribution
of
(
13
)
C
in
glutamate
and
glutamine
,
a
measure
of
the
relative
flux
of
acetate
and
glucose
into
the
citric
acid
cycle
,
was
not
altered
.
The
(
13
)
C
labeling
pattern
in
glutamate
differed
significantly
from
glutamine
,
indicating
preferential
oxidation
of
[
1
,
2
-
(
13
)
C
]
acetate
relative
to
[
1
,
6
-
(
13
)
C
]
glucose
by
a
readily
discernible
metabolic
domain
of
the
brain
of
both
normal
and
mutant
mice
,
presumably
glia
.
These
findings
illustrate
that
metabolic
compartmentation
is
preserved
in
the
PDC
-
deficient
cerebral
cortex
,
probably
reflecting
intact
neuron-glia
metabolic
interactions
,
and
that
a
reduction
in
brain
PDC
activity
sufficient
to
induce
cerebral
dysgenesis
during
development
does
not
appreciably
disrupt
energy
metabolism
in
the
mature
brain
.
Diseases
Validation
Diseases presenting
"brain tissue"
symptom
22q11.2 deletion syndrome
alexander disease
cadasil
classical phenylketonuria
congenital toxoplasmosis
gm1 gangliosidosis
hereditary cerebral hemorrhage with amyloidosis
homocystinuria without methylmalonic aciduria
hydrocephalus with stenosis of the aqueduct of sylvius
phenylketonuria
pyruvate dehydrogenase deficiency
sneddon syndrome
wolf-hirschhorn syndrome
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