Molecular Neurobiology,
Journal Year:
2024,
Volume and Issue:
61(11), P. 9529 - 9538
Published: April 23, 2024
Abstract
Epilepsy
is
one
of
the
most
common
neurological
disorders
in
world.
Common
epileptic
drugs
generally
affect
ion
channels
or
neurotransmitters
and
prevent
emergence
seizures.
However,
up
to
a
third
patients
suffer
from
drug-resistant
epilepsy,
there
an
urgent
need
develop
new
therapeutic
strategies
that
go
beyond
acute
antiepileptic
(antiseizure)
therapies
towards
therapeutics
also
might
have
effects
on
chronic
epilepsy
comorbidities
such
as
cognitive
decline
depression.
The
mitochondrial
calcium
uniporter
(MCU)
mediates
rapid
Ca
2+
transport
through
inner
membrane.
influx
essential
for
functions,
but
longer
elevations
intracellular
levels
are
closely
associated
with
seizure-induced
neuronal
damage,
which
underlying
mechanisms
Using
neuronal-specific
MCU
knockout
mice
(MCU
−/−ΔN
),
we
demonstrate
deficiency
reduced
hippocampal
excitability
vivo.
Furthermore,
vitro
analyses
glioneuronal
cells
reveal
no
change
total
differences
handling.
reduces
ROS
production,
declines
metabolic
fluxes,
consequently
prevents
cell
death.
This
effect
was
observed
under
pathological
conditions,
low
magnesium
culture
model
seizure-like
activity
excitotoxic
glutamate
stimulation,
whereby
suppresses
overload
seen
WT
cells.
study
highlights
importance
at
interface
handling
metabolism
mediator
stress-related
dysfunction,
indicates
modulation
potential
target
future
antiepileptogenic
therapy.
Communications Biology,
Journal Year:
2023,
Volume and Issue:
6(1)
Published: Jan. 12, 2023
Abstract
Patients
with
primary
mitochondrial
oxidative
phosphorylation
(OxPhos)
defects
present
fatigue
and
multi-system
disorders,
are
often
lean,
die
prematurely,
but
the
mechanistic
basis
for
this
clinical
picture
remains
unclear.
By
integrating
data
from
17
cohorts
of
patients
diseases
(
n
=
690)
we
find
evidence
that
these
disorders
increase
resting
energy
expenditure,
a
state
termed
hypermetabolism
.
We
examine
phenomenon
longitudinally
in
patient-derived
fibroblasts
multiple
donors.
Genetically
or
pharmacologically
disrupting
OxPhos
approximately
doubles
cellular
expenditure.
This
cell-autonomous
occurs
despite
near-normal
coupling
efficiency,
excluding
uncoupling
as
general
mechanism.
Instead,
is
associated
DNA
instability,
activation
integrated
stress
response
(ISR),
increased
extracellular
secretion
age-related
cytokines
metabokines
including
GDF15.
In
parallel,
accelerate
telomere
erosion
epigenetic
aging
per
cell
division,
consistent
excess
expenditure
accelerates
biological
aging.
To
explore
potential
mechanisms
effects,
generate
longitudinal
RNASeq
methylation
resource
dataset,
which
reveals
conserved,
energetically
demanding,
genome-wide
recalibrations.
Taken
together,
findings
highlight
need
to
understand
how
influence
energetic
cost
living,
link
between
cells
diseases.
Gut,
Journal Year:
2022,
Volume and Issue:
71(12), P. 2551 - 2560
Published: Feb. 16, 2022
Objective
Patients
with
increased
PD-L1
+
host
cells
in
tumours
are
more
potent
to
benefit
from
antiprogrammed
death-1/programmed
death
ligand-1
(PD-L1)
treatment,
but
the
underlying
mechanism
is
still
unclear.
We
aim
elucidate
nature,
regulation
and
functional
relevance
of
hepatocellular
carcinoma
(HCC).
Design
A
total
untreated
184
HCC
patients
was
enrolled
randomly.
C57BL/6
mice
given
injection
Hepa1-6
form
autologous
hepatoma.
ELISpot,
flow
cytometry
real-time
PCR
applied
analyse
phenotypic
characteristics
isolated
directly
specimens
paired
blood
samples
or
generated
ex
vivo
vitro
culture
systems.
Immunofluorescence
immunohistochemistry
performed
detect
presence
immune
on
paraffin-embedded
formalin-fixed
samples.
The
regulatory
mechanisms
metabolic
switching
assessed
by
both
studies.
Results
demonstrate
that
macrophages,
which
constructively
represent
major
cellular
source
tumours,
display
an
HLA-DR
high
CD86
glycolytic
phenotype,
significantly
produce
antitumourigenic
IL-12p70
polarised
intrinsic
metabolism.
Mechanistically,
a
key
enzyme
PKM2
triggered
hepatoma
cell
derived
fibronectin
1,
via
HIF-1α-dependent
manner,
concurrently
controls
properties
inflammation-mediated
expression
macrophages.
Importantly,
although
macrophages
predict
poor
prognosis
patients,
blocking
these
eliminates
PD-L1-dominant
immunosuppression
liberates
properties.
Conclusions
Selectively
modulating
‘context’
might
restore
their
provide
precise
strategy
for
anticancer
therapy.
Nature,
Journal Year:
2024,
Volume and Issue:
634(8036), P. 1150 - 1159
Published: Oct. 2, 2024
Ageing
impairs
the
ability
of
neural
stem
cells
(NSCs)
to
transition
from
quiescence
proliferation
in
adult
mammalian
brain.
Functional
decline
NSCs
results
decreased
production
new
neurons
and
defective
regeneration
following
injury
during
ageing
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: July 14, 2023
Abstract
Resistance
to
endocrine
treatments
and
CDK4/6
inhibitors
is
considered
a
near-inevitability
in
most
patients
with
estrogen
receptor
positive
breast
cancers
(ER
+
BC).
By
genomic
metabolomics
analyses
of
patients’
tumours,
metastasis-derived
patient-derived
xenografts
(PDX)
isogenic
cell
lines
we
demonstrate
that
fraction
metastatic
ER
BC
highly
reliant
on
oxidative
phosphorylation
(OXPHOS).
Treatment
by
the
OXPHOS
inhibitor
IACS-010759
strongly
inhibits
tumour
growth
multiple
palbociclib
resistant
PDX.
Mutations
PIK3CA
/
AKT1
genes
are
significantly
associated
response
IACS-010759.
At
metabolic
level,
vivo
decreased
levels
metabolites
glutathione,
glycogen
pentose
phosphate
pathways
treated
tumours.
In
vitro,
cells
show
increased
dependency
ROS
upon
treatment.
Finally,
patients,
high
expression
predict
poor
prognosis.
conclusion,
these
results
identify
as
promising
target
for
treatment
patients.
Stem Cell Research & Therapy,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: Jan. 2, 2024
Beyond
the
observed
alterations
in
cellular
structure
and
mitochondria,
mechanisms
linking
rare
genetic
mutations
to
development
of
heart
failure
patients
affected
by
desmin
remain
unclear
due
part,
lack
relevant
human
cardiomyocyte
models.
Journal of Translational Genetics and Genomics,
Journal Year:
2025,
Volume and Issue:
9(1), P. 1 - 10
Published: Jan. 15, 2025
Adenosine
triphosphate
(ATP)
is
the
energy
currency
within
all
living
cells
and
involved
in
many
vital
biochemical
reactions,
including
cell
viability,
metabolic
status,
death,
intracellular
signaling,
DNA
RNA
synthesis,
purinergic
synaptic
active
transport,
muscle
contraction.
Consequently,
altered
ATP
production
frequently
viewed
as
a
contributor
to
both
disease
pathogenesis
subsequent
progression
of
organ
failure.
Barth
syndrome
(BTHS)
an
X-linked
mitochondrial
characterized
by
fatigue,
skeletal
weakness,
cardiomyopathy,
neutropenia,
growth
delay
due
inherited
TAFAZZIN
enzyme
mutations.
BTHS
widely
hypothesized
literature
be
model
defective
leading
deficits.
Prior
patient
data
have
linked
impaired
reduced
phosphocreatine
ratios
(PCr/ATP)
children
adult
hearts
muscles,
suggesting
primary
role
for
perturbed
energetics.
Moreover,
although
only
limited
direct
measurements
content
ADP/ATP
ratio
(an
indicator
available
from
hydrolysis)
so
far
been
carried
out,
analysis
divergent
animal
models,
cultured
types,
diverse
organs
has
failed
uncover
unifying
understanding
molecular
mechanisms
linking
deficiency
This
review
mainly
focuses
on
energetics
striated
mitochondriopathy.