Mitochondrial connexin 43 impacts on respiratory complex i activity and mitochondrial oxygen consumption

Kerstin Boengler, Marisol Ruiz-Meana, Sabine Gent, Elvira Ungefug, Daniel Soetkamp, Elisabet Miro-Casas, Alberto Cabestrero, Celia Fernandez-Sanz, Martina Semenzato, Fabio Di Lisa, Susanne Rohrbach, David Garcia-Dorado, Gerd Heusch, Rainer Schulz

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Abstract

Connexin 43(Cx43) is present at the sarcolemma and the inner membrane of cardiomyocyte subsarcolemmal mitochondria (SSM). Lack or inhibition of mitochondrial Cx43 is associated with reduced mitochondrial potassium influx, which might affect mitochondrial respiration. Therefore, we analysed the importance of mitochondrial Cx43 for oxygen consumption. Acute inhibition of Cx43 in rat left ventricular (LV) SSM by 18α glycyrrhetinic acid (GA) or Cx43 mimetic peptides (Cx43-MP) reduced ADP-stimulated complex I respiration and ATP generation. Chronic reduction of Cx43 in conditional knockout mice (Cx43Cre-ER(T)/fl + 4-OHT, 5-10% of Cx43 protein compared with control Cx43fl/fl mitochondria) reduced ADP-stimulated complex I respiration of LV SSM to 47.8 ± 2.4 nmol O2/min.mg protein (n = 8) from 61.9 ± 7.4 nmol O2/min.mg protein in Cx43fl/fl mitochondria (n = 10, P < 0.05), while complex II respiration remained unchanged. The LV complex I activities (% of citrate synthase activity) of Cx43Cre-ER(T)/fl+4-OHT mice (16.1 ± 0.9%, n = 9) were lower than in Cx43fl/fl mice (19.8 ± 1.3%, n = 8, P < 0.05); complex II activities were similar between genotypes. Supporting the importance of Cx43 for respiration, in Cx43-overexpressing HL-1 cardiomyocytes complex I respiration was increased, whereas complex II respiration remained unaffected. Taken together, mitochondrial Cx43 is required for optimal complex I activity and respiration and thus mitochondrial ATP-production. © 2011 The Authors. Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
Original languageEnglish
Pages (from-to)1649-1655
JournalJournal of Cellular and Molecular Medicine
Volume16
Issue number8
DOIs
Publication statusPublished - 1 Aug 2012

Keywords

  • 18α glycyrrhetinic acid
  • Connexin 43
  • Mitochondria
  • Respiration

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    Boengler, K., Ruiz-Meana, M., Gent, S., Ungefug, E., Soetkamp, D., Miro-Casas, E., Cabestrero, A., Fernandez-Sanz, C., Semenzato, M., Lisa, F. D., Rohrbach, S., Garcia-Dorado, D., Heusch, G., & Schulz, R. (2012). Mitochondrial connexin 43 impacts on respiratory complex i activity and mitochondrial oxygen consumption. Journal of Cellular and Molecular Medicine, 16(8), 1649-1655. https://doi.org/10.1111/j.1582-4934.2011.01516.x