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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
"cerebral dysgenesis"
symptom
pyruvate dehydrogenase deficiency
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