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Mitochondrial potassium
transport: the role of the
MitoKATP
Mitochondrial potassium
transport: the role of the
MitoKATP
WeiGuo
2005.1.14
WeiGuo
2005.1.14
Mitochondrial potassium cycle Mitochondrial potassium cycle
• Mitochondria are structurally complex. The inner
membrane contains the essential components of
the electron transport proteins and all of the
exchange carriers
• Mitochondria are structurally complex. The inner
membrane contains the essential components of
the electron transport proteins and all of the
exchange carriers
Mitochondrial potassium cycleMitochondrial potassium cycle
• The mitochondrial K+ cycle consists of influx and
efflux pathways for K+, H+, and anions
• These ions are exchanged between the matrix and
the intermembrane space ( IMS ); however, the
outer membrane (OM) does not present a barrier
to further exchange of small ions with the cytosol
• The mitochondrial K+ cycle consists of influx and
efflux pathways for K+, H+, and anions
• These ions are exchanged between the matrix and
the intermembrane space ( IMS ); however, the
outer membrane (OM) does not present a barrier
to further exchange of small ions with the cytosol
Influx pathway for potassiumInflux pathway for potassium
IMS
matrix
MitoKAT
P
K+
leak
K+ K+
H+
ETS
∆Ψ
Matrix alkalinizatio
n
Pi-
OH-
Pi-H+ symporte
r
Electron transport system (ETS) generates membrane potential (∆Ψ). ∆Ψ can drive K+ influx by diffusion (‘‘K+ leak’’) and via the mitoKATP. This K+ for H+ exchange will alkalinize the matrix, causing phosphate to enter via the Pi-H+ symporter.
Efflux pathway for potassiumEfflux pathway for potassium
• Net uptake of K+ salts will be accompanied by
osmotically obligated water, resulting in matrix
swelling. Excess matrix K+ is then ejected by the
K+/H+ antiporter
• Net uptake of K+ salts will be accompanied by
osmotically obligated water, resulting in matrix
swelling. Excess matrix K+ is then ejected by the
K+/H+ antiporter
K+-H+
antiporter
Early work on the potassium cycleEarly work on the potassium cycle
• Diffusive K+ influx would be sufficient to cause
matrix water content to increase, with eventual
lysis. This would be avoided by the K+/H+
antiporter
• Diffusive K+ influx would be sufficient to cause
matrix water content to increase, with eventual
lysis. This would be avoided by the K+/H+
antiporter
synthesizing ATP at very high rates
∆Ψ decreases matrix contraction
mito-KATP
Maintain matrix volume
MitoKATP meets a different need in
volume regulation
MitoKATP on matrix and IMS volumes MitoKATP on matrix and IMS volumes
• MitoKATP opening was shown to regulate matrix
volume during ischemia and state 3 respiration
• MitoKATP opening was shown to regulate matrix
volume during ischemia and state 3 respiration
Addition of antimycin A to simulate ischemia
DE
depolarization and decrease in
diffusive K+ influxaddition of ADP to trigger state 3 respiration
10–15% contraction in matrix volume
matrix volume return to original state
5-HD
MitoKATP on matrix and IMS volumesMitoKATP on matrix and IMS volumes
• Changes in IMS could be estimated by means of
membrane surface areas (SA)
• Studies shown that mitoKATP opening decreases
IMS volume
• Physiological changes in matrix volume may have
important effects on IMS structure–function
• Changes in IMS could be estimated by means of
membrane surface areas (SA)
• Studies shown that mitoKATP opening decreases
IMS volume
• Physiological changes in matrix volume may have
important effects on IMS structure–function
Two distinct consequences of opening mitoKATP Two distinct consequences of opening mitoKATP
• When ∆Ψ is high → opening mitoKATP → matrix
alkalinization → production of reactive oxygen
species (ROS) ↑
• When ∆Ψ is depressed → opening mitoKATP →
prevent contraction of the matrix and expansion of
the IMS
• When ∆Ψ is high → opening mitoKATP → matrix
alkalinization → production of reactive oxygen
species (ROS) ↑
• When ∆Ψ is depressed → opening mitoKATP →
prevent contraction of the matrix and expansion of
the IMS
Is mitoKATP involved in all modes of cardioprotection ?Is mitoKATP involved in all modes of cardioprotection ?
• Ischemic preconditioning √
• Calcium preconditioning √
• KCO preconditioning √
• Delayed preconditioning √
• Adaptive preconditioning √
• Na+/H+ exchange inhibition √
• Ischemic post-conditioning ?
• Ischemic preconditioning √
• Calcium preconditioning √
• KCO preconditioning √
• Delayed preconditioning √
• Adaptive preconditioning √
• Na+/H+ exchange inhibition √
• Ischemic post-conditioning ?
During which phase is mitoKATP opening crucial for cardioprotection?
During which phase is mitoKATP opening crucial for cardioprotection?
• MitoKATP is proposed to play distinct roles in
each phase of ischemia– reperfusion
• MitoKATP is proposed to play distinct roles in
each phase of ischemia– reperfusion
Preconditioning
phase
Ischemic
phase
Reperfusion
phase
As a end-effector
of cardioprotection
As a end-effector
of cardioprotection
As a trigger of
cardioprotection
During the preconditioning phaseDuring the preconditioning phase
• The role of mitoKATP opening is to increase
production of ROS
• Moderate increases in ROS play an important
second messenger role in a variety of signaling
pathways
• The role of mitoKATP opening is to increase
production of ROS
• Moderate increases in ROS play an important
second messenger role in a variety of signaling
pathways
A proposed mechanism for increased ROSA proposed mechanism for increased ROS
ROS↑
IMS
Matrix
Matrix alkalinizatio
n
OH-
Pi-H+ symporte
r Pi-K+ K+
MitoKATP K+
leak
Pi- uptake will be less than K+ uptake
K+ uptake creating a gradient for uptake of Pi on the Pi–H+ symporter, Pi uptake will be less than K+ uptake, because Pi is present in much lower concentrations than K+. For this reason, matrix pH always increases when matrix volume increases due to uptake of K+ and Pi.
During the ischemic phaseDuring the ischemic phase
• mitochondrial permeability transition (MPT)
• The primary role of matrix Ca2 + is to stimulate ROS
production upon reperfusion
• Ca2 + cannot open MPT unless ROS are present
• Cytosolic Ca2 + may play an additional role in
promoting ROS oxidation of adenine nucleotide
translocase (ANT)
• mitochondrial permeability transition (MPT)
• The primary role of matrix Ca2 + is to stimulate ROS
production upon reperfusion
• Ca2 + cannot open MPT unless ROS are present
• Cytosolic Ca2 + may play an additional role in
promoting ROS oxidation of adenine nucleotide
translocase (ANT)
The mechanism by which mitoKATP
protects the heart during ischemia phase
The mechanism by which mitoKATP
protects the heart during ischemia phase
• The opening of mitoKATP preserves the structure–
function of the IMS and maintains the low
permeability of the outer membrane to adenine
nucleotides, thereby preserving ADP for
phosphorylation upon reperfusion
• The opening of mitoKATP preserves the structure–
function of the IMS and maintains the low
permeability of the outer membrane to adenine
nucleotides, thereby preserving ADP for
phosphorylation upon reperfusion
Outer mitochondrial membrane permeability to
ADP and ATP was controlled by voltage-dependent
anion channel (VDAC)
• In heart, VDAC is normally in a low-conductance state that is poorly permeable to nucleotides, and energy transfers are mediated instead by creatine and creatine phosphate.
matrix
IMS
Outer Mem
Inner Mem
ATP
ADP
ANT
VDAC
CKCr / PCr
•During ischemia, ∆Ψ will decrease, resulting in reduced uptake of K+,contraction of the matrix, and expansion of the IMS
MitoKATP regulation of VDAC permeability to
nucleotides during ischemia
•This means that all of cellular ATP is available for hydrolysis, and, ultimately, unavailability of ADP for rephosphorylation upon reperfusion
•IMS expansion will cause Mi-CK to dissociate from VDAC, leading to a high outer membrane conductance to ATP and ADP
During the reperfusion phase During the reperfusion phase
• The opening of mitoKATP facilitates rapid energy
conversion to phosphocreatine (PCr) . Under
these conditions, mitochondria will not produce a
burst of ROS upon reperfusion, and the
irreversible opening of the MPT will not occur
• The opening of mitoKATP facilitates rapid energy
conversion to phosphocreatine (PCr) . Under
these conditions, mitochondria will not produce a
burst of ROS upon reperfusion, and the
irreversible opening of the MPT will not occur
Outer Mem
Inner Mem
ATP / ADP
ANT
VDAC
CK
Energy transfer from mitochondria to myofibrils is
mediated by two parallel
pathways—creatine/creatine phosphate (Cr/CrP)
and ATP/ADP
• In the Cr/CrP system, myofibrillar creatine kinase converts ADP to creatine. Mi-CK bridge the IMS between outer membrane VDAC and inner membrane ANT.
Cr / PCr
• Cr/CrP is more efficient
•About 67% of the energy production in heart has been found to arise from the CK system
• During reperfusion, expansion of the IMS will cause Mi-CK to dissociate from VDAC, leading to a high outer membrane conductance to ATP and ADP
MitoKATP facilitates rapid energy conversion to
phosphocreatine (PCr) during the reperfusion
phase
• If mitoKATP is open, the outer membrane will retain its low permeability to nucleotides, and the mitochondria can restore energy levels using the more efficient metabolic channeling via Mi-CK
SummarySummary
• Mitochondria potassium cycle
• Two distinct consequences of Opening mitoKATP
• mitoKATP plays cardio-protective effect during all
three phases of the ischemia–reperfusion injury
• Mitochondria potassium cycle
• Two distinct consequences of Opening mitoKATP
• mitoKATP plays cardio-protective effect during all
three phases of the ischemia–reperfusion injury
Thank you !