bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 13, 2024
Abstract
Cardiovascular
diseases
are
often
associated
with
impairment
in
mitochondrial
function
detected
by
reduced
oxygen
consumption
using
high-resolution
respirometry.
However,
existing
respirometry
protocols
limited
the
necessity
for
fresh
tissue
samples.
This
study
developed
a
method
tailored
substrate-inhibitor
titration
(TSIT)
of
electron
transport
complexes
(ETC)
to
measure
frozen
cardiac
samples
Briefly,
acetyl-CoA
was
added
fuel
tricarboxylic
acid
(TCA)
cycle
NADH
production,
enabling
complex
I
(CI)-linked
respiratory
assessment.
then
maximum
CI-linked
capacity,
followed
rotenone
and
succinate
assess
II
(CII)-linked
capacity.
TSIT
functional
differences
between
atrial
ventricular
tissue,
comparable
results
as
measured
It
also
dysfunction
across
various
(patho)physiological
mouse
models
(including
aging,
ischemia
reperfusion,
obesity,
CI
deficiency)
well
human
donor
samples,
highlighting
its
clinical
potential.
Furthermore,
we
showed
first
evidence
supercomplexes
(SCs)
formation
ETC-SCs
TCA
metabolon,
underpinning
feasibility.
In
conclusion,
established
novel,
robust,
sensitive
translational
assessing
(dys)function
from
species,
flexible
analysis
both
laboratory
settings.
Nature Communications,
Год журнала:
2025,
Номер
16(1)
Опубликована: Янв. 2, 2025
Abstract
Glucose
deprivation,
a
hallmark
of
the
tumor
microenvironment,
compels
cells
to
seek
alternative
energy
sources
for
survival
and
growth.
Here,
we
show
that
glucose
deprivation
upregulates
expression
mitochondrial-cytochrome
c
oxidase
II
(MT-CO2),
subunit
essential
respiratory
chain
complex
IV,
in
facilitating
glutaminolysis
sustaining
cell
survival.
Mechanistically,
activates
Ras
signaling
enhance
MT-CO2
transcription
inhibits
IGF2BP3,
an
RNA-binding
protein,
stabilize
mRNA.
Elevated
increases
flavin
adenosine
dinucleotide
(FAD)
levels
activating
lysine-specific
demethylase
1
(LSD1)
epigenetically
upregulate
JUN
transcription,
consequently
promoting
glutaminase-1
(GLS1)
Furthermore,
is
indispensable
oncogenic
Ras-induced
growth,
elevated
associated
with
poor
prognosis
lung
cancer
patients.
Together,
these
findings
reveal
role
adapting
metabolic
stress
highlight
as
putative
therapeutic
target
Ras-driven
cancers.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Март 1, 2025
The
de
novo
purine
synthesis
pathway
is
fundamental
for
nucleic
acid
production
and
cellular
energetics,
yet
the
role
of
mitochondrial
metabolism
in
modulating
this
process
remains
underexplored.
In
many
cancers,
metabolic
reprogramming
supports
rapid
proliferation
survival,
but
specific
contributions
tricarboxylic
(TCA)
cycle
enzymes
to
nucleotide
biosynthesis
are
not
fully
understood.
Here,
we
demonstrate
that
TCA
enzyme
succinate
dehydrogenase
(SDH)
essential
maintaining
optimal
normal
cancer
cells.
Genetic
or
pharmacological
inhibition
SDH
markedly
attenuates
synthesis,
leading
a
significant
reduction
cell
proliferation.
Mechanistically,
causes
an
accumulation
succinate,
which
directly
impairs
biosynthetic
pathway.
response,
cells
compensate
by
upregulating
salvage
pathway,
adaptation
represents
potential
therapeutic
vulnerability.
Notably,
co-inhibition
induces
pronounced
antiproliferative
antitumoral
effects
preclinical
models.
These
findings
only
reveal
signaling
regulating
also
provide
promising
strategy
targeting
dependencies
cancer.
Fats
are
the
human
body’s
most
energy-dense
macronutrients
with
oxidoreductase
reactions
being
fundamental
to
yielding
adenosine
triphosphate
(ATP),
energy
currency
of
our
body.
In
periods
catabolic
stress,
fats
become
vital
generation.
Multiple
acyl-coenzyme
A
dehydrogenase
deficiency
(MADD),
is
a
rare
fatty
acid
oxidation
disorder
that
impairs
metabolism
and
can
lead
life-threatening
complications.
To
understand
pathophysiology
MADD,
it
various
involved
in
at
molecular
level.
This
chapter
will
delve
into
normal
biochemistry
how
reduced
shuttles
nicotinamide
adenine
dinucleotide
(NADH)
flavin
(FADH2)
transfer
their
electrons
mitochondrial
electron
transport
chain
(ETC)
generate
ATP.
The
go
on
explore
an
error
these
biochemical
abnormalities
symptomatology
seen
MADD.
Biomedical Papers,
Год журнала:
2025,
Номер
unknown
Опубликована: Апрель 14, 2025
Mitochondria,
double-membraned
organelles
within
all
eukaryotic
cells,
are
essential
for
the
proper
functioning
of
human
organism.
The
frequently
used
phrase
"powerhouses
cell"
fails
to
adequately
capture
their
multifaceted
roles.
In
addition
producing
energy
in
form
adenosine
triphosphate
through
oxidative
phosphorylation,
mitochondria
also
involved
apoptosis
(programmed
cell
death),
calcium
regulation,
and
signaling
reactive
oxygen
species.
Recent
research
suggests
that
they
can
communicate
with
one
another
influence
cellular
processes.
Impaired
mitochondrial
function
on
hand,
have
widespread
profound
effects
organismal
health,
contributing
various
diseases
age-related
conditions.
Regular
exercise
other
promotes
health
by
enhancing
volume,
density,
functionality.
Although
has
made
significant
progress
last
few
decades,
mainly
use
modern
technologies,
there
is
still
a
need
intensify
efforts
this
field.
Exploring
new
approaches
enhance
could
potentially
impact
longevity.
review,
we
focus
discoveries,
examine
structure
diverse
roles
body,
explore
metabolism
emphasize
importance
maintaining
overall
health.
Biochemical Society Transactions,
Год журнала:
2024,
Номер
52(2), С. 529 - 538
Опубликована: Март 25, 2024
Certain
cancer
cells
within
solid
tumors
experience
hypoxia,
rendering
them
incapable
of
oxidative
phosphorylation
(OXPHOS).
Despite
this
oxygen
deficiency,
these
exhibit
biochemical
pathway
activity
that
relies
on
NAD+.
This
mini-review
scrutinizes
the
persistent,
residual
Complex
I
oxidizes
NADH
in
absence
as
electron
acceptor.
The
resulting
NAD+
assumes
a
pivotal
role
fueling
α-ketoglutarate
dehydrogenase
complex,
critical
component
decarboxylation
branch
glutaminolysis
—
hallmark
oncometabolic
pathway.
proposition
is
through
glutamine
catabolism,
high-energy
phosphate
intermediates
are
produced
via
substrate-level
mitochondrial
matrix
substantiated
by
succinyl-CoA
ligase,
partially
compensating
for
an
OXPHOS
deficiency.
These
insights
provide
rationale
exploring
inhibitors
treatment,
even
when
functionality
already
compromised.
