S-nitrosation of mitochondrial Connexin 43 regulates mitochondrial function: implication for cardioprotection

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SoetkampDaniel_2014_09_05.pdf (4.97 MB)

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2014

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DOI:
http://dx.doi.org/10.22029/jlupub-14069

Abstract

S-nitrosation of connexin 43 formed channels alters dye uptake in astrocytes and gap junctional communication in endothelial cells. Apart from forming channels in the cell surface membrane of several cell types, connexin 43 is also located at the inner membrane of myocardial subsarcolemmal mitochondria, but not in interfibrillar mitochondria. The absence or pharmacological blockade of mitochondrial connexin 43 decreases mitochondrial dye and potassium uptake. A lack of mitochondrial connexin 43 is associated with the loss of cardioprotection by ischemic preconditioning, which is mediated by formation of reactive oxygen species. Whether or not mitochondrial Lucifer Yellow, ion uptake, or reactive oxygen generation are affected by S-nitrosation of mitochondrial connexin 43 and whether or not cardioprotective interventions influence S-nitrosation of mitochondrial connexin 43 remains unknown.Subsarcolemmal mitochondria from rat hearts showed an increased Lucifer Yellow uptake in response to nitric oxide donors (S-nitroso-N-acetyl-DL-penicillamine (SNAP): 38.4 ± 7.1%, p<0.05; S-nitrosoglutathione (GSNO): 28.1 ± 7.4%, p<0.05) and an increased refilling rate of potassium (SNAP: 227.9 ± 30.1%, p<0.05; GSNO: 122.6 ± 28.1%, p<0.05). These effects were abolished following blockade of connexin 43 hemichannel by carbenoxolone as well as in interfibrillar mitochondria, which lack connexin 43. Unlike potassium, the sodium permeability was not affected by application of nitric oxide. Furthermore, mitochondrial reactive oxygen species formation was enhanced in response to nitric oxide application compared to control treatment group (SNAP: 22.9 ± 1.8%, p<0.05; GSNO: 40.6 ± 7.1%, p<0.05), but decreased following nitric oxide treatment in interfibrillar mitochondria compared to control treated interfibrillar mitochondria (SNAP: 14.4 ± 4%, p<0.05; GSNO: 13.8 ± 4%, p<0.05). Administration of nitric oxide donors to isolated subsarcolemmal mitochondria or nitrite application into the cavity of left ventricles in mice in vivo enhanced S-nitrosation of mitochondrial connexin 43 by 109.2 ± 15.8% and by 59.3 ± 18.2%, respectively (p<0.05). Ischemic preconditioning by 4 cycles of ischemia and reperfusion, enhanced S-nitrosation of mitochondrial connexin 43 by 41.6 ± 1.7% (p<0.05) in comparison to subsarcolemmal mitochondria from control perfused rat hearts. These data suggest that S-nitrosation of mitochondrial connexin 43 increases mitochondrial permeability, especially for potassium and leads to increased formation of reactive oxygen species. The increased amount of S-nitrosated mitochondrial connexin 43 by ischemic preconditioning or nitrite administration may link nitric oxide and connexin 43 in the signal transduction cascade of cardioprotection by preconditioning.

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