Mitochondrial potassium transport: the role of the MitoKATP

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Mitochondrial potassium transport the role of
the MitoKATP

• WeiGuo 2005.1.14

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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

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Mitochondrial 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

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Influx pathway for potassium

• Electron transport system (ETS) generates
  membrane potential (??).
• ?? 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.

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Efflux 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

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Early 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

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MitoKATP meets a different need in volume
regulation
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MitoKATP on matrix and IMS volumes

• MitoKATP opening was shown to regulate matrix
  volume during ischemia and state 3 respiration

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MitoKATP 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 structurefunction

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Two distinct consequences of opening mitoKATP

• When ?? is high ? opening mitoKATP ? matrix
  alkalinization ? production of reactive oxygen
  species (ROS) ?
• When ?? is depressed ? opening mitoKATP ? prevent
  contraction of the matrix and expansion of the IMS

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Is mitoKATP involved in all modes of
cardioprotection ?

• Ischemic preconditioning v
• Calcium preconditioning v
• KCO preconditioning v
• Delayed preconditioning v
• Adaptive preconditioning v
• Na/H exchange inhibition v
• Ischemic post-conditioning ?

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During which phase is mitoKATP opening crucial
for cardioprotection?

• MitoKATP is proposed to play distinct roles in
• each phase of ischemia reperfusion

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During 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

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A proposed mechanism for increased ROS

• K uptake creating a gradient for uptake of Pi
  on the PiH 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.

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During 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)

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The mechanism by which mitoKATP protects the
heart during ischemia phase

• The opening of mitoKATP preserves the
  structurefunction of the IMS and maintains the
  low permeability of the outer membrane to adenine
  nucleotides, thereby preserving ADP for
  phosphorylation upon reperfusion

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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.

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MitoKATP regulation of VDAC permeability to
nucleotides during ischemia

• During ischemia, ?? will decrease, resulting in
  reduced uptake of K,
• contraction of the matrix, and expansion of the
  IMS

• IMS expansion will cause Mi-CK to dissociate from
  VDAC, leading to a high outer membrane
  conductance to ATP and ADP

• This means that all of cellular ATP is available
  for hydrolysis, and, ultimately, unavailability
  of ADP for rephosphorylation upon reperfusion

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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

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Energy transfer from mitochondria to myofibrils
is mediated by two parallel pathwayscreatine/crea
tine phosphate (Cr/CrP) and ATP/ADP
Outer Mem
VDAC

• Cr/CrP is more efficient
• About 67 of the energy production in heart has
  been found to arise from the CK system

CK
Cr / PCr
ANT
Inner Mem
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.

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MitoKATP facilitates rapid energy conversion to
phosphocreatine (PCr) during the reperfusion phase

• 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

• 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

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Summary

• Mitochondria potassium cycle
• Two distinct consequences of Opening mitoKATP
• mitoKATP plays cardio-protective effect during
  all three phases of the ischemiareperfusion
  injury

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Thank you !