Letter in response to 'the role of succinate and ROS in reperfusion injury - A critical appraisal' by Andrienko et al

Autor: Antonio Rodríguez-Sinovas, David Garcia-Dorado, Marisol Ruiz-Meana, Ignasi Barba
Rok vydání: 2017
Předmět:
0301 basic medicine
Succinate
Succinic Acid
Ischemia/reperfusion injury
030204 cardiovascular system & hematology
0302 clinical medicine
MCU
mitochondrial calcium uniporter
Hexokinase
Bcl-xL
B-cell lymphoma-extra large
PCr
phosphocreatine
ANT
adenine nucleotide translocase
Bak
Bcl-2 homologous antagonist/killer
MitoPY1
Mitochondria Peroxy-Yellow 1
CrP
creatine phosphate
Heart
LS
light scattering
Bcl-2
B cell lymphoma 2
Mitochondria
NCLX
Na+/Ca2+ exchanger
Bid
BH3 interacting-domain death agonist
Anesthesia
Reperfusion Injury
BCECF
2′
7′-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein
pmf
proton motive force
VDAC
voltage-dependent anion channel
OMM
outer mitochondrial membrane
Cardiology and Cardiovascular Medicine
CsA
cyclosporine A
IMM
inner mitochondrial membrane
Bax
Bcl-2-like protein 4
medicine.medical_specialty
mPTP
mitochondrial permeability transition pore
Cyp-D
cyclophilin D
Mdivi-1
mitochondrial division inhibitor 1
Article
03 medical and health sciences
ROS
reactive oxygen species
GSK3β
glycogen synthase kinase 3β
PO1
Peroxy-Orange 1
SOD
superoxide dismutase
medicine
Humans
Molecular Biology
Drp1
dynamin-related protein 1
business.industry
IR
ischemia/reperfusion
5-cH2DCFDA
5-carboxy-2′
7′dichlorodihydrofluorescein diacetate
Succinates
IP
ischemic preconditioning
HK
hexokinase
REF
reverse electron flow
medicine.disease
Permeability transition pore
PKCε
protein kinase Cε
Surgery
Critical appraisal
030104 developmental biology
G-6-P
glucose-6-phosphate
Calcium
IF1
ATP synthase inhibitor factor 1
business
Reactive oxygen species
Reperfusion injury
DHE
dihydroethidium
CK
creatine kinase
Bad
Bcl-2-associated death promoter
Zdroj: Journal of Molecular and Cellular Cardiology
ISSN: 1095-8584
Popis: We critically assess the proposal that succinate-fuelled reverse electron flow (REF) drives mitochondrial matrix superoxide production from Complex I early in reperfusion, thus acting as a key mediator of ischemia/reperfusion (IR) injury. Real-time surface fluorescence measurements of NAD(P)H and flavoprotein redox state suggest that conditions are unfavourable for REF during early reperfusion. Furthermore, rapid loss of succinate accumulated during ischemia can be explained by its efflux rather than oxidation. Moreover, succinate accumulation during ischemia is not attenuated by ischemic preconditioning (IP) despite powerful cardioprotection. In addition, measurement of intracellular reactive oxygen species (ROS) during reperfusion using surface fluorescence and mitochondrial aconitase activity detected major increases in ROS only after mitochondrial permeability transition pore (mPTP) opening was first detected. We conclude that mPTP opening is probably triggered initially by factors other than ROS, including increased mitochondrial [Ca2+]. However, IP only attenuates [Ca2+] increases later in reperfusion, again after initial mPTP opening, implying that IP regulates mPTP opening through additional mechanisms. One such is mitochondria-bound hexokinase 2 (HK2) which dissociates from mitochondria during ischemia in control hearts but not those subject to IP. Indeed, there is a strong correlation between the extent of HK2 loss from mitochondria during ischemia and infarct size on subsequent reperfusion. Mechanisms linking HK2 dissociation to mPTP sensitisation remain to be fully established but several related processes have been implicated including VDAC1 oligomerisation, the stability of contact sites between the inner and outer membranes, cristae morphology, Bcl-2 family members and mitochondrial fission proteins such as Drp1.
Graphical abstract Image 1
Highlights • Mitochondrial ROS production during early reperfusion (RPF) occurs after mPTP opening. • Conditions do not favour ROS production by reverse electron flow during early RPF. • Ischemic preconditioning (IP) does not attenuate succinate accumulation in ischemia. • IP reduction of ROS and Ca2+ during RPF is secondary to attenuation of mPTP opening. • IP attenuates mPTP opening by mechanisms independent of ROS and Ca2+ such as HK2.
Databáze: OpenAIRE
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