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LETM1-dependent mitochondrial Ca2+ flux modulates cellular bioenergetics and proliferation.
[wolf-hirschhorn syndrome]
Dysregulation
of
mitochondrial
Ca
(
2
+
)
-
dependent
bioenergetics
has
been
implicated
in
various
pathophysiological
settings
,
including
neurodegeneration
and
myocardial
infarction
.
Although
mitochondrial
Ca
(
2
+
)
transport
has
been
characterized
,
and
several
molecules
,
including
LETM
1
,
have
been
identified
,
the
functional
role
of
LETM
1
-
mediated
Ca
(
2
+
)
transport
remains
unresolved
.
This
study
examines
LETM
1
-
mediated
mitochondrial
Ca
(
2
+
)
transport
and
bioenergetics
in
multiple
cell
types
,
including
fibroblasts
derived
from
patients
with
Wolf-
Hirschhorn
syndrome
(
WHS
)
.
The
results
show
that
both
mitochondrial
Ca
(
2
+
)
influx
and
efflux
rates
are
impaired
in
LETM
1
knockdown
,
and
similar
phenotypes
were
observed
in
ΔEF
hand
,
(
D
676
A
D
688
K
)
LETM
1
mutant-overexpressed
cells
,
and
in
cells
derived
from
patients
with
WHS
.
Although
LETM
1
levels
were
lower
in
WHS-derived
fibroblasts
,
the
mitochondrial
Ca
(
2
+
)
uniporter
components
MCU
,
MCUR
1
,
and
MICU
1
remain
unaltered
.
In
addition
,
the
MCU
mitoplast
patch-clamp
current
(
IMCU
)
was
largely
unaffected
in
LETM
1
-
knockdown
cells
.
Silencing
of
LETM
1
also
impaired
basal
mitochondrial
oxygen
consumption
,
possibly
via
complex
IV
inactivation
and
ATP
production
.
Remarkably
,
LETM
1
knockdown
also
resulted
in
increased
reactive
oxygen
species
production
.
Further
,
LETM
1
silencing
promoted
AMPK
activation
,
autophagy
,
and
cell
cycle
arrest
.
Reconstitution
of
LETM
1
or
antioxidant
overexpression
rescued
mitochondrial
Ca
(
2
+
)
transport
and
bioenergetics
.
These
findings
reveal
the
role
of
LETM
1
-
dependent
mitochondrial
Ca
(
2
+
)
flux
in
shaping
cellular
bioenergetics
.
-
Doonan
,
P
J
.
,
Chandramoorthy
,
H
.
C
.
,
Hoffman
,
N
.
E
.
,
Zhang
,
X
.
,
Cárdenas
,
C
.
,
Shanmughapriya
,
S
.
,
Rajan
,
S
.
,
Vallem
,
S
.
,
Chen
,
X
.
,
Foskett
,
J
.
K
.
,
Cheung
,
J
.
Y
.
,
Houser
,
S
.
R
.
,
Madesh
,
M
.
LETM
1
-
dependent
mitochondrial
Ca
(
2
+
)
flux
modulates
cellular
bioenergetics
and
proliferation
.
Diseases
Validation
Diseases presenting
"impaired basal mitochondrial oxygen consumption"
symptom
wolf-hirschhorn syndrome
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