NAD+ metabolism and its roles in cellular processes during ageing
Nature Reviews Molecular Cell Biology,
Год журнала:
2020,
Номер
22(2), С. 119 - 141
Опубликована: Дек. 22, 2020
Язык: Английский
Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing
Nature Reviews Drug Discovery,
Год журнала:
2020,
Номер
19(9), С. 609 - 633
Опубликована: Июль 24, 2020
Язык: Английский
NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential
Signal Transduction and Targeted Therapy,
Год журнала:
2020,
Номер
5(1)
Опубликована: Окт. 7, 2020
Abstract
Nicotinamide
adenine
dinucleotide
(NAD
+
)
and
its
metabolites
function
as
critical
regulators
to
maintain
physiologic
processes,
enabling
the
plastic
cells
adapt
environmental
changes
including
nutrient
perturbation,
genotoxic
factors,
circadian
disorder,
infection,
inflammation
xenobiotics.
These
effects
are
mainly
achieved
by
driving
effect
of
NAD
on
metabolic
pathways
enzyme
cofactors
transferring
hydrogen
in
oxidation-reduction
reactions.
Besides,
multiple
-dependent
enzymes
involved
physiology
either
post-synthesis
chemical
modification
DNA,
RNA
proteins,
or
releasing
second
messenger
cyclic
ADP-ribose
(cADPR)
NAADP
.
Prolonged
disequilibrium
metabolism
disturbs
physiological
functions,
resulting
diseases
diseases,
cancer,
aging
neurodegeneration
disorder.
In
this
review,
we
summarize
recent
advances
our
understanding
molecular
mechanisms
-regulated
responses
stresses,
contribution
deficiency
various
via
manipulating
cellular
communication
networks
potential
new
avenues
for
therapeutic
intervention.
Язык: Английский
NAD+ in Brain Aging and Neurodegenerative Disorders
Cell Metabolism,
Год журнала:
2019,
Номер
30(4), С. 630 - 655
Опубликована: Окт. 1, 2019
NAD+
is
a
pivotal
metabolite
involved
in
cellular
bioenergetics,
genomic
stability,
mitochondrial
homeostasis,
adaptive
stress
responses,
and
cell
survival.
Multiple
NAD+-dependent
enzymes
are
synaptic
plasticity
neuronal
resistance.
Here,
we
review
emerging
findings
that
reveal
key
roles
for
related
metabolites
the
adaptation
of
neurons
to
wide
range
physiological
stressors
counteracting
processes
neurodegenerative
diseases,
such
as
those
occurring
Alzheimer's,
Parkinson's,
Huntington
amyotrophic
lateral
sclerosis.
Advances
understanding
molecular
mechanisms
NAD+-based
resilience
will
lead
novel
approaches
facilitating
healthy
brain
aging
treatment
neurological
disorders.
Nicotinamide
adenine
dinucleotide
(NAD+)
fundamental
molecule
health
disease,
it
central
several
bioenergetic
functions.
synthesized
via
three
major
pathways,
including
de
novo
biosynthesis,
Preiss-Handler
pathway,
salvage
pathway
(Figure
1).
While
aspartate
most
photosynthetic
eukaryotes,
kynurenine
only
synthetic
mammals.
The
starts
with
catabolism
amino
acid
tryptophan
converted
two
steps
intermediate
kynurenine,
which
can
generate
NAD+,
kynurenic
acid,
or
xanthurenic
(Vécsei
et
al.,
2013Vécsei
L.
Szalárdy
Fülöp
F.
Toldi
J.
Kynurenines
CNS:
recent
advances
new
questions.Nat.
Rev.
Drug
Discov.
2013;
12:
64-82Crossref
PubMed
Scopus
(263)
Google
Scholar).
modulates
functions
synthesis
neurotransmitters
(glutamate
acetylcholine)
well
regulates
N-methyl-D-aspartate
(NMDA)
receptor
activity
free
radical
production
exhibits
"double-edged
sword"
effects
on
both
neuroprotective
(tryptophan,
picolinic
acid)
neurotoxic
intermediates,
3-hydroxykynurenine
(3-HK)
generates
radicals,
3-hydroxyanthranilic
(3-HAA),
quinolinic
(that
induces
glutamate
excitotoxicity)
an
NMDA
antagonist,
agonist
ambient
levels
these
determined
by
different
enzymes,
preferentially
localized
microglia
astrocytes,
suggesting
necessary
glial
cell-neuron
communication
(Schwarcz
Pellicciari,
2002Schwarcz
R.
Pellicciari
Manipulation
kynurenines:
targets,
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Exp.
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2002;
303:
1-10Crossref
(399)
synthesize
from
pyridine
bases.
synthesizes
nicotinic
(NA)
(NAAD).
One
important
step
constitutes
nicotinamide
mononucleotide
adenylyltransferases
(NMNATs),
also
pathways.
Three
mammalian
NMNATs
exist,
NMNAT1–3,
showing
mice
D.
melanogaster
models
(Ali
2013Ali
Y.O.
Li-Kroeger
Bellen
H.J.
Zhai
R.G.
Lu
H.C.
NMNATs,
evolutionarily
conserved
maintenance
factors.Trends
Neurosci.
36:
632-640Abstract
Full
Text
PDF
(0)
NMNAT1
NMNAT3
ubiquitously
expressed,
NMNAT2
enriched
brain,
adequate
seem
be
essential
axon
development
survival
(Gilley
2019Gilley
Mayer
P.R.
Yu
G.
Coleman
M.P.
Low
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(4)
recycling
(NAM)
(NMN)
intracellular
phosphoribosyltransferase
(iNAMPT),
followed
conversion
NMN
into
(Bogan
Brenner,
2008Bogan
K.L.
Brenner
C.
Nicotinic
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Additionally,
riboside
(NR)
integrates
this
NR
kinase
1
(NRK1)
NRK2
(Bieganowski
2004Bieganowski
P.
Discoveries
nutrient
NRK
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establish
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fungi
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Despite
NAMPT
being
relatively
highly
expressed
brown
adipocyte,
liver,
kidney
tissues
compared
tissue
mice,
studies
have
supported
role
iNAMPT
(Stein
Imai,
2014Stein
L.R.
Imai
S.
Specific
ablation
Nampt
adult
neural
stem
cells
recapitulates
their
functional
defects
during
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Dearborn
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Experimental
evidence
suggests
blood
NA
NAM
able
cross
plasma
membrane,
while
cannot
taken
up
directly
but
needs
smaller
uncharged
molecules
enter
(Hara
2007Hara
Yamada
K.
Shibata
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Hashimoto
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Extracellularly,
digested
membrane-bound
CD38
CD157,
further
metabolized
extracellular
(eNAMPT);
however,
CD73
ways
been
proposed.
First,
converts
CD73,
presumptive
nucleoside
transporter
(Fletcher
2017Fletcher
Doig
C.L.
Oakey
L.A.
Callingham
Da
Silva
Xavier
Garten
A.
Elhassan
Y.S.
al.Nicotinamide
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2013Grozio
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Second,
may
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NMN,
not
NR,
NAM,
membrane
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2016Camacho-Pereira
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M.G.
Chini
C.C.S.
Nin
V.
Escande
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Third,
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Yoshino
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Lei
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Sasaki
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newly
transporter,
Slc12a8,
regulated
murine
small
intestine,
Slc12a8
deficiency
abrogates
uptake
vitro
vivo
These
pathways
detailed
Figure
1.
Studies
humans
indicate
supplementation
dramatically
upregulates
NAAD,
unknown
metabolic
possibilities
NAAD
and/or
(NAMN)
(Trammell
2016aTrammell
Schmidt
M.S.
Weidemann
B.J.
Jaksch
Dellinger
R.W.
Z.
Abel
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uniquely
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Thus,
although
intensively
characterized
long
time,
there
remaining
determined.
vital
redox
cofactor
ATP
production,
substrate
at
least
four
families
healthspan
longevity
(Fang
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Lautrup
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al.Declining
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plays
glycolysis
citric
(TCA)
cycle,
its
ability
accept
hydride
equivalents,
forming
NADH
(Krebs,
1970Krebs
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Wallace,
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one
electron
donors
oxidative
phosphorylation
(OXPHOS)
mitochondria,
providing
electrons
transport
chain
(ETC)
ratio
NAD+/NADH
various
reactions
compartments,
increased
influence
homeostasis
changes
(Ying,
2008Ying
NADP+/NADPH
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regulation
biological
consequences.Antioxid.
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functions,
antioxidation
generation
stress,
calcium
death
In
addition
NAD+-consuming
proteins,
catabolize
NAM.
They
class
III
histone
deacetylases
sirtuins
(SIRTs),
poly
(ADP-ribose)
polymerases
(PARPs),
ADP
ribosyl-cyclases
(CD38/CD157),
NADase
sterile
alpha
TIR
motif-containing
(SARM1)
mammals,
seven
SIRTs,
regulate
large
number
survival,
rejuvenation,
cancer,
(Chalkiadaki
Guarente,
2015Chalkiadaki
Guarente
multifaceted
15:
608-624Crossref
(150)
SIRTs
spectrum
disease
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Armstrong
C.M.
Kaeberlein
Transcriptional
silencing
Sir2
NAD-dependent
deacetylase.Nature.
2000;
403:
795-800Crossref
(2280)
For
example,
SIRT1
consumes
glycolysis,
gluconeogenesis,
balance
between
biogenesis
mitophagy
responses
exercise
metabolic/excitatory
challenges
(Bonkowski
Sinclair,
2016Bonkowski
Sinclair
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Slowing
ageing
design:
rise
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compounds.Nat.
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2016Cheng
Yang
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Maharana
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al.Mitochondrial
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Fang,
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Furthermore,
shown
promote
neurite
outgrowth
development,
regulating
dendritic
arborization,
long-term
potentiation
learning,
memory
(Gao
2010Gao
W.Y.
Mao
Y.W.
Gräff
Guan
Pan
Mak
Kim
Su
S.C.
Tsai
L.H.
miR-134.Nature.
466:
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(585)
Among
17
PARPs,
them
capable
adding
multiple
ADP-ribose
units
(poly[ADP-ribosyl]ation)
PARylation;
they
PARP1,
PARP2,
PARP5a
(tankyrase
1),
PARP5b
2)
(Leung,
2017Leung
A.K.L.
PARPs.Curr.
27:
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Rouleau
2010Rouleau
Patel
Hendzel
Kaufmann
S.H.
Poirier
G.G.
PARP
inhibition:
PARP1
beyond.Nat.
293-301Crossref
(813)
supports
transfers
first
moiety
lysine,
arginine,
glutamate,
aspartate,
serine
residues
acceptor
protein,
preceding
ones,
thereby
poly(ADP-ribose)
(PAR)
chains
(Bonfiglio
2017Bonfiglio
Fontana
Q.
Colby
Gibbs-Seymour
Atanassov
Bartlett
Zaja
Ahel
Matic
Serine
ADP-ribosylation
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2014Daniels
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S.E.
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Phosphoproteomic
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majority
PARylation
executed
participates
processes,
DNA
repair,
DNA/RNA
response.
PAR
serving
signaling
scaffolding
element
2016bFang
Scheibye-Knudsen
Chua
Nuclear
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stabilization
repair
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catalytic
single-strand
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bulky
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double-strand
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(DSBs)
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Chaudhuri
Nussenzweig,
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Nussenzweig
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However,
excessive
activation
trigger
death,
termed
parthanatos,
formation
triggers
release
apoptosis-inducing
factor
(AIF)
cytosolic
side
outer
membrane.
AIF
then
translocated
nucleus
activate
macrophage
migration
inhibitory
(MIF,
nuclease),
finally
results
MIF-dependent
chromatinolysis
(Wang
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Notably,
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hexokinase
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Karuppagounder
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24:
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view
detrimental
endogenous
exogenous
excitotoxicity,
ischemia-reperfusion
injury,
inflammation-induced
(Yu
Scholar)
targeting
provide
therapeutic
strategies
diseases.
catalyzes
Ca2+-responsive
messenger
cyclic
(cADPR)
use
immunity,
inflammation,
even
social
behaviors
(Jin
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H.X.
Hirai
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Nagai
Lopatina
O.
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N.A.
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type
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(i.e.,
C-terminal)
(with
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facing
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Lam
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Conformational
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age-dependent
increase
CD38,
contribute
impaired
function
lymphocyte
differentiation
antigen,
(Mizuguchi
1995Mizuguchi
Otsuka
Sato
Ishii
Kon
Nishina
Katada
Ikeda
localization
antigen
brain.Brain
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knockout
show
significant
protection
against
ischemic
(Long
2017Long
J.H.
Klimova
Fowler
Loane
D.J.
Kristian
despite
high
level
poly-ADP-ribosylation.Neurochem.
42:
283-293Crossref
(1)
SARM1
recognized
cleaves
ADPR,
cADPR
domain.
It
non-brain
tissues,
liver
(Essuman
2017Essuman
Summers
D.W.
X.
DiAntonio
Milbrandt
toll/interleukin-1
possesses
intrinsic
cleavage
promotes
pathological
axonal
degeneration.Neuron.
93:
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(18)
An,
2018Pan
Z.G.
X.S.
deletion
restrains
NAFLD
fat
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(HFD)
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498:
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(7)
cyclase
glycohydrolase
activities,
estimated
Michaelis
constant
(Km)
24
μM,
similar
other
known
NAD+-consumers
(PARP1,
50–97
μM;
SIRT1,
94–96
15–25
μM)
(Cantó
2015Cantó
Menzies
K.J.
Auwerx
homeostasis:
balancing
act
nucleus.Cell
22:
31-53Abstract
degeneration
therefore
potential
target
intervention
holds
signal,
clear.
SIRTS,
CD38/CD157,
compete
each
consume
NAD+;
thus,
enzyme
impair
activities
enzymes.
interrelationships
reviewed
recently
equilibrium
synthesis,
consumption,
cytoplasm,
nucleus,
Golgi
apparatus.
Two
expression
subcellular-specific
NAD+-synthetic
transporters
metabolites.
convert
NAD+.
include
Язык: Английский
NAD+ homeostasis in health and disease
Nature Metabolism,
Год журнала:
2020,
Номер
2(1), С. 9 - 31
Опубликована: Янв. 20, 2020
Язык: Английский
Mitochondrial Dysfunction and Mitophagy in Parkinson’s Disease: From Mechanism to Therapy
Trends in Biochemical Sciences,
Год журнала:
2020,
Номер
46(4), С. 329 - 343
Опубликована: Дек. 13, 2020
Язык: Английский
Mitophagy and Neuroprotection
Trends in Molecular Medicine,
Год журнала:
2019,
Номер
26(1), С. 8 - 20
Опубликована: Июль 30, 2019
Язык: Английский
Autophagy in Parkinson's Disease
Journal of Molecular Biology,
Год журнала:
2020,
Номер
432(8), С. 2651 - 2672
Опубликована: Фев. 13, 2020
Impaired
protein
homeostasis
and
accumulation
of
damaged
or
abnormally
modified
are
common
disease
mechanisms
in
many
neurodegenerative
disorders,
including
Parkinson's
(PD).
As
one
the
major
degradation
pathways,
autophagy
plays
a
pivotal
role
maintaining
effective
turnover
proteins
organelles
cells.
Several
decades
research
efforts
led
to
insights
into
potential
contribution
impaired
machinery
α-synuclein
degeneration
dopaminergic
neurons,
two
features
PD
pathology.
In
this
review,
we
summarize
recent
pathological,
genetic,
mechanistic
findings
that
link
defective
with
pathogenesis
human
patients,
animals,
cellular
models
discuss
current
challenges
field.
Язык: Английский
Regulation and Function of Mitochondria–Lysosome Membrane Contact Sites in Cellular Homeostasis
Trends in Cell Biology,
Год журнала:
2019,
Номер
29(6), С. 500 - 513
Опубликована: Март 18, 2019
Язык: Английский
Role of NAD+ in regulating cellular and metabolic signaling pathways
Molecular Metabolism,
Год журнала:
2021,
Номер
49, С. 101195 - 101195
Опубликована: Фев. 18, 2021
Nicotinamide
adenine
dinucleotide
(NAD+),
a
critical
coenzyme
present
in
every
living
cell,
is
involved
myriad
of
metabolic
processes
associated
with
cellular
bioenergetics.
For
this
reason,
NAD+
often
studied
the
context
aging,
cancer,
and
neurodegenerative
disorders.
Cellular
depletion
compromised
adaptive
stress
responses,
impaired
neuronal
plasticity,
DNA
repair,
senescence.
Increasing
evidence
has
shown
efficacy
boosting
levels
using
precursors
various
diseases.
This
review
provides
comprehensive
understanding
into
role
aging
other
pathologies
discusses
potential
therapeutic
targets.
An
alteration
NAD+/NADH
ratio
or
pool
size
can
lead
to
derailment
biological
system
contribute
disorders,
tumorigenesis.
Due
varied
distribution
different
locations
within
cells,
direct
NAD+-dependent
humans
remains
unestablished.
In
regard,
longitudinal
studies
are
needed
quantify
its
related
metabolites.
Future
research
should
focus
on
measuring
fluxes
through
pathways
synthesis
degradation.
Язык: Английский
