bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2024,
Номер
unknown
Опубликована: Дек. 17, 2024
Abstract
In
eukaryotes,
oxygen
consumption
is
mainly
driven
by
the
respiratory
activity
of
mitochondria,
which
generates
most
cellular
energy
that
sustains
life.
This
parameter
provides
direct
information
about
mitochondrial
all
aerobic
biological
systems.
Using
Seahorse
analyzer
instrument,
we
show
here
deletion
oca3/emc2
gene
(
oca3Δ
)
encoding
Emc2
subunit
ER
membrane
complex
(EMC),
a
conserved
chaperone/insertase
aids
protein
biogenesis
in
ER,
severely
affects
rates
and
quiescence
survival
Schizosaccharomyces
pombe
yeast
cells.
Remarkably,
defects
mutation
(EMC
dysfunction)
rescued
synergistically
disruption
ergosterol
biosynthesis
erg5Δ)
action
fluidizing
agent
tween
20,
suggesting
role
fluidity
sterols
composition
respiration
fission
yeast.
Physiological Reviews,
Год журнала:
2024,
Номер
104(4), С. 1533 - 1610
Опубликована: Окт. 1, 2024
Coenzyme
Q
(CoQ),
also
known
as
ubiquinone,
comprises
a
benzoquinone
head
group
and
long
isoprenoid
side
chain.
It
is
thus
extremely
hydrophobic
resides
in
membranes.
best
for
its
complex
function
an
electron
transporter
the
mitochondrial
transport
chain
(ETC)
but
required
several
other
crucial
cellular
processes.
In
fact,
CoQ
appears
to
be
central
entire
redox
balance
of
cell.
Remarkably,
structure
therefore
properties
have
not
changed
from
bacteria
vertebrates.
metazoans,
it
synthesized
all
cells
found
most,
maybe
all,
biological
nutritional
supplement,
mostly
because
involvement
with
antioxidant
defenses.
However,
whether
there
any
health
benefit
oral
consumption
well
established.
Here
we
review
redox-active
molecule
ETC
enzymatic
systems,
role
prooxidant
reactive
oxygen
species
generation,
separate
mechanisms.
We
biosynthesis,
which
particularly
extreme
hydrophobicity,
consequences
primary
secondary
deficiency,
including
human
patients.
Primary
deficiency
rare
inborn
condition
due
mutation
biosynthetic
genes.
Secondary
much
more
common,
accompanies
variety
pathological
conditions,
disorders
aging.
this
context,
discuss
importance,
great
difficulty,
alleviating
by
supplementation.
Cell Reports,
Год журнала:
2024,
Номер
43(5), С. 114148 - 114148
Опубликована: Май 1, 2024
pathogenic
variant
induces
cardiac
insufficiency
and
neurodevelopmental
delay
in
mice
d
Consequently,
with
Coq2
mutations
exhibit
perinatal
lethality
4HB
stimulates
mitochondrial
metabolism
human
cells
COQ2
defects
rescues
multisystemic
disease
prevents
the
A252V
model
Coenzyme
Q
(CoQ)
is
an
essential
redox-active
lipid
that
plays
a
major
role
in
the
electron
transport
chain,
driving
mitochondrial
ATP
synthesis.
In
Saccharomyces
cerevisiae
(yeast),
CoQ
biosynthesis
occurs
exclusively
matrix
via
large
protein-lipid
complex,
synthome,
comprised
of
itself,
late-stage
CoQ-intermediates,
and
polypeptides
Coq3-Coq9
Coq11.
Coq11
suggested
to
act
as
negative
modulator
synthome
assembly
synthesis,
its
deletion
enhances
Coq
polypeptide
content,
produces
enlarged
restores
respiration
mutants
lacking
chaperone
polypeptide,
Coq10.
The
resides
specific
niches
within
inner
membrane,
termed
domains,
are
often
located
adjacent
endoplasmic
reticulum-mitochondria
encounter
structure
(ERMES).
Loss
ERMES
destabilizes
renders
less
efficient.
Here
we
show
COQ11
suppresses
respiratory
deficient
phenotype
select
mutants,
results
repair
reorganization
domains.
Given
ER-mitochondrial
contact
sites
coordinate
biosynthesis,
used
Split-MAM
(Mitochondrial
Associated
Membrane)
artificial
tether
consisting
site
reporter,
evaluate
effects
membrane
tethers
on
both
wild-type
mutant
yeast
strains.
Overall,
this
work
identifies
novel
suppressor
phenotypes
associated
with
indicates
ER-mitochondria
influence
content
turnover,
highlighting
regulating
homeostasis.
ABSTRACT
In
eukaryotes,
oxygen
consumption
is
mainly
driven
by
the
respiratory
activity
of
mitochondria,
which
generates
most
cellular
energy
that
sustains
life.
This
parameter
provides
direct
information
about
mitochondrial
all
aerobic
biological
systems.
Using
Seahorse
analyzer
instrument,
we
show
here
deletion
oca3/emc2
gene
(
oca3Δ
)
encoding
Emc2
subunit
ER
membrane
complex
(EMC),
a
conserved
chaperone/insertase
aids
protein
biogenesis
in
ER,
severely
affects
rates
and
quiescence
survival
Schizosaccharomyces
pombe
yeast
cells.
Remarkably,
defect
mutation
(EMC
dysfunction)
rescued
synergistically
disruption
ergosterol
biosynthesis
erg5Δ)
action
fluidizing
agent
tween
20,
suggesting
role
fluidity
sterol
composition
respiration
fission
yeast.
bioRxiv (Cold Spring Harbor Laboratory),
Год журнала:
2025,
Номер
unknown
Опубликована: Май 28, 2025
Abstract
Metabolons
-
transient
assemblies
of
sequential
metabolic
enzymes
facilitate
the
reactions
multi-step
pathways,
yet,
how
they
mechanistically
bolster
flux
remains
unknown.
Here,
we
investigate
molecular
determinants
metabolon
formation
in
coenzyme
Q
(CoQ)
biosynthesis
using
coarse-grained
dynamics
simulations
and
biochemical
experiments.
We
show
that
COQ
forms
at
critical
region
a
phase
transition,
where
both
clustering
exhibit
coordinated
sigmoidal
responses
to
changes
protein-protein
interaction
strength.
These
complete
metabolons
enable
substrate
channeling
between
enzymes,
leading
crucial
enhancement
CoQ
production
efficiency.
Selectively
disrupting
interactions
randomly
shuffling
network
demonstrate
protein-proximity
rather
than
fine
structure
clusters
is
imperative
for
channeling.
Grounded
experiment
simulation,
these
findings
provide
framework
understanding
organization
function
across
diverse
pathways.
Journal of Clinical Medicine,
Год журнала:
2024,
Номер
13(8), С. 2391 - 2391
Опубликована: Апрель 19, 2024
Cerebellar
ataxia
is
a
neurological
syndrome
characterized
by
the
imbalance
(e.g.,
truncal
ataxia,
gait
ataxia)
and
incoordination
of
limbs
while
executing
task
(dysmetria),
caused
dysfunction
cerebellum
or
its
connections.
It
frequently
associated
with
other
signs
cerebellar
dysfunction,
including
abnormal
eye
movements,
dysmetria,
kinetic
tremor,
dysarthria,
and/or
dysphagia.
Among
so-termed
mitochondrial
ataxias,
variants
in
genes
encoding
steps
coenzyme
Q10
biosynthetic
pathway
represent
common
cause
autosomal
recessive
primary
deficiencies
(PCoQD)s.
PCoQD
potentially
treatable
condition;
therefore,
correct
timely
diagnosis
essential.
After
brief
presentation
illustrative
case
an
Italian
woman
this
condition
(due
to
novel
homozygous
nonsense
mutation
Coenzyme
Q
(CoQ)
is
a
lipidic
compound
widely
distributed
in
nature
with
crucial
functions
metabolism,
protection
against
oxidative
damage
and
ferroptosis,
other
processes.
CoQ
biosynthesis
conserved
complex
pathway
involving
several
proteins.
COQ2
member
of
the
UbiA
family
transmembrane
prenyltransferases
that
catalyzes
condensation
head
tail
precursors
CoQ,
key
step
process
because
its
product
first
intermediate
will
be
modified
by
next
component
synthesis
process.
Mutations
this
protein
have
been
linked
to
primary
deficiency
humans,
rare
disease
predominantly
affecting
organs
high
energy
demand.
The
reaction
catalyzed
mechanism
are
still
unknown.
Here
we
aimed
at
clarifying
exploring
possible
substrate
binding
sites
using
strategy
based
on
homology,
comprising
identification
ligand-bound
homologs
solved
structures
available
Protein
Data
Bank
(PDB)
their
subsequent
structural
superposition
AlphaFold
predicted
model
for
COQ2.
results
highlight
some
residues
located
central
cavity
or
matrix
loops
may
involved
interaction,
them
mutated
patients.
Furthermore,
analyze
modifications
introduced
pathogenic
mutations
found
humans.
These
findings
shed
new
light
understanding
function
and,
thus,
pathogenicity
deficiency.
