Temporary Sequestration of Potassium by Mitochondria in Astrocytes

Kozoriz, Michael G.; Church, John A.; Ozog, Mark A.; Naus, Christian C.; Krebs, Claudia

doi:10.1074/jbc.m109.082073

Cited by 41 publications

(26 citation statements)

References 78 publications

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“…Matrix K + (mK + ) was measured in HL-1 cells using the K + -sensitive fluorescent indicator PBFI; PBFI was loaded to favor mitochondrial localization as described previously [39]. HL-1 cells were grown on glass coverslips and individually transfected with SK3 FL -EGFP, SK3 Δ1–277 –EGFP and SK3 Δ626–720 –EGFP.…”

Section: Methodsmentioning

confidence: 99%

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Yang

Camara

Aldakkak

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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We provide evidence for location and function of a small conductance, Ca2+-activated K+ (SKCa) channel isoform 3 (SK3) in mitochondria (m) of guinea pig, rat and human ventricular myocytes. SKCa agonists protected isolated hearts and mitochondria against ischemia/reperfusion (IR) injury; SKCa antagonists worsened IR injury. Intravenous infusion of a SKCa channel agonist/antagonist, respectively, in intact rats was effective in reducing/enhancing regional infarct size induced by coronary artery occlusion. Localization of SK3 in mitochondria was evidenced by Western blot of inner mitochondrial membrane, immunocytochemical staining of cardiomyocytes, and immunogold labeling of isolated mitochondria. We identified a SK3 splice variant in guinea pig (SK3.1, aka SK3a) and human ventricular cells (SK3.2) by amplifying mRNA, and show mitochondrial expression in mouse atrial tumor cells (HL-1) by transfection with full length and truncated SK3.1 protein. We found that the Nterminus is not required for mitochondrial trafficking but the C-terminus beyond the Ca2+ calmodulin binding domain is required for Ca2+ sensing to induce mK+ influx and/or promote mitochondrial localization. In isolated guinea pig mitochondria and in SK3 overexpressed HL-1 cells, mK+ influx was driven by adding CaCl2. Moreover, there was a greater fall in membrane potential (ΔΨm), and enhanced cell death with simulated cell injury after silencing SK3.1 with siRNA. Although SKCa channel opening protects the heart and mitochondria against IR injury, the mechanism for favorable bioenergetics effects resulting from SKCa channel opening remains unclear. SKCa channels could play an essential role in restraining cardiac mitochondria from inducing oxidative stress-induced injury resulting from mCa2+ overload.

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Section: Methodsmentioning

confidence: 99%

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Yang

Camara

Aldakkak

et al. 2017

Biochimica et Biophysica Acta (BBA) - Bioenergetics

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“…Comparing astrocytes from wild-type animals and from connexin43-null mice, it was reported during preparation of this work that Cx43 is involved in K ϩ sequestration in astrocyte mitochondria. The authors concluded that mitochondria play a key role in cytosolic K ϩ handling in astrocytes by employing Cx43, besides the mitochondrial ATP-sensitive K ϩ channels (24).…”

Section: Discussionmentioning

confidence: 99%

Calcium-induced permeability transition in rat brain mitochondria is promoted by carbenoxolone through targeting connexin43

Azarashvili

Baburina

Grachev

et al. 2011

American Journal of Physiology-Cell Physiology

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“…Apart from being present at the sarcolemma, Cx43 has been identified in mitochondria of cardiomyocytes (Boengler et al, 2005), astrocytes (Kozoriz et al, 2010a), endothelial cells (Kiec-Wilk et al, 2012; Mohammad & Kowluru, 2011;Trudeau et al, 2012), stem cells (Lu et al, 2012), hepatocytes (Vinken et al, 2013) and pancreatic cancer cells (Sun et al, 2012). …”

Section: Mitochondrial CX 43mentioning

confidence: 99%

Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

Schulz

Görge

Görbe

et al. 2015

Pharmacology & Therapeutics

189

172

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Connexins are widely distributed proteins in the body that are crucially important for heart and brain function. Six connexin subunits form a connexon or hemichannel in the plasma membrane. Interactions between two hemichannels in a head-to-head arrangement result in the formation of a gap junction channel. Gap junctions are necessary to coordinate cell function by passing electrical current flow between heart and nerve cells or by allowing exchange of chemical signals and energy substrates. Apart from its localisation at the sarcolemma of cardiomyocytes and brain cells, connexins are also found in mitochondria where they are involved in the regulation of mitochondrial matrix ion fluxes and respiration. Connexin expression is affected by age and gender as well as several pathophysiological alterations such as hypertension, hypertrophy, diabetes, hypercholesterolemia, ischemia, post-myocardial infarction remodelling or heart failure, and post-translationally connexins are modified by phosphorylation/de-phosphorylation and nitros(yl)ation which can modulate channel activity. Using knockout/knockin technology as well as pharmacological approaches, one of the connexins, namely connexin 43, has been identified to be important for cardiac and brain ischemia/reperfusion injury as well as protection from it. Therefore, the current review will focus on the importance of connexin 43 for irreversible injury of heart and brain tissue following ischemia/reperfusion and will highlight the importance of connexin 43 as an emerging therapeutic target in cardio- and neuroprotection.

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Temporary Sequestration of Potassium by Mitochondria in Astrocytes

Abstract: Increases in extracellular potassium concentration ([K؉

Cited by 41 publications

References 78 publications

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Identity and function of a cardiac mitochondrial small conductance Ca 2+ -activated K + channel splice variant

Calcium-induced permeability transition in rat brain mitochondria is promoted by carbenoxolone through targeting connexin43

Connexin 43 is an emerging therapeutic target in ischemia/reperfusion injury, cardioprotection and neuroprotection

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