Mitochondriales Connexin 43: Regulation und Funktion
Final Report Abstract
Intercellular communication is crucial for spreading of excitation and therefore for the maintenance of normal cardiac function. Cell-cell communication is achieved via gap junctional channels that connect the cytoplasm of adjacent cells and such channels are formed by connexin proteins. In humans, connexins (Cx) comprise a family of 21 members that have molecular weights in the range of 26 to 60 kDa. Connexin 43 (Cx43) is the most abundant Cx isoform in the heart and it is expressed in ventricular cardiomyocytes. Connexin proteins are integral transmembrane proteins containing four transmembrane domains, two extracellular and one intracellular loop, and amino- and carboxytermini are cytoplasmic. Six connexins assemble into hexamers, referred to as connexons or hemichannels. Hemichannels are transported to the plasma membrane and two hemichannels from adjacent cells dock together forming gap junctions which allow the passage of molecules with molecular weights of up to 1 kDa. A carboxyterminal fragment of Cx43 is reported to translocate to the nucleus where it influences cell proliferation; indeed, we could demonstrate that partial knockdown of Cx43 modifies the expression of other cytosolic proteins, namely nitric oxide synthases. Cx43 are located also in mitochondria: however, as demonstrated here, expression is limited mainly to sub-sarcolemmal mitochondria but not interfibrillar mitochondria. The import into mitochondria requires the interaction between Cx43, heat shock protein 90 and TOM20 (translocase of the outer membrane 20) and can be modified by phosphorylation of serine epitopes at the C-terminus as shown using epitope-replacement mice. Within the inner mitochondrial membrane, Cx43 is suggested to form hemichannels and by use of Cx43-inhibiting drugs or Cx43-deficient mitochondria its involvement in the regulation of mitochondrial oxygen consumption was proven. Using specific inhibitors or activators of Cx43 hemichannels also indicated there importance for the development of irreversible ischemia/reperfusion injury. The effects on mitochondrial function and ischemia/reperfusion injury were dependent on Cx43 and could not be mediated by other Cxs since replacement of Cx43 by Cx32 abbrogated both protective effects. Finally, since Cx43 expression is affected by age and comorbidities, mice with an inducible cardiomyocyte Cx43 overexpression have been generated and will be used to restore Cx43 expression in disease states to hopefully restore a cardioprotective phenotype.
Publications
- . Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria. Basic Res Cardiol. 2009 Mar;104(2):141-7
Boengler K, Stahlhofen S, van de Sand A, Gres P, Ruiz-Meana M, Garcia-Dorado D, Heusch G, Schulz R
(See online at https://dx.doi.org/10.1007/s00395-009-0007-5) - Connexin43 in cardiomyocyte mitochondria contributes to mitochondrial potassium uptake. Cardiovasc Res. 2009 Sep 1;83(4):747-56
Miro-Casas E, Ruiz-Meana M, Agullo E, Stahlhofen S, Rodríguez-Sinovas A, Cabestrero A, Jorge I, Torre I, Vazquez J, Boengler K, Schulz R, Heusch G, Garcia-Dorado D
(See online at https://dx.doi.org/10.1093/cvr/cvp157) - Cholesterol diet leads to attenuation of ischemic preconditioning-induced cardiac protection: the role of connexin 43. Am J Physiol Heart Circ Physiol. 2011 May;300(5):H1907-13
Görbe A, Varga ZV, Kupai K, Bencsik P, Kocsis GF, Csont T, Boengler K, Schulz R, Ferdinandy P
(See online at https://dx.doi.org/10.1152/ajpheart.01242.2010) - Pharmacological modulation of connexin-formed channels in cardiac pathophysiology. Br J Pharmacol. 2011 Jun;163(3):469-83
De Vuyst E, Boengler K, Antoons G, Sipido KR, Schulz R, Leybaert L
(See online at https://dx.doi.org/10.1111/j.1476-5381.2011.01244.x) - Cardiomyocyte-specific deletion of survivin causes global cardiac conduction defects. Basic Res Cardiol. 2012;107(6):299
Schrickel JW, Lickfett L, Lewalter T, Tiemann K, Nickenig G, Baba H, Heusch G, Schulz R, Levkau B
(See online at https://doi.org/10.1007/s00395-012-0299-8) - Mitochondrial connexin 43 impacts on respiratory complex I activity and mitochondrial oxygen consumption. J Cell Mol Med. 2012 Aug;16(8):1649-55
Boengler K, Ruiz-Meana M, Gent S, Ungefug E, Soetkamp D, Miro-Casas E, Cabestrero A, Fernandez-Sanz C, Semenzato M, Di Lisa F, Rohrbach S, Garcia-Dorado D, Heusch G, Schulz R
(See online at https://doi.org/10.1111/j.1582-4934.2011.01516.x) - Selective inhibition of Cx43 hemichannels by Gap19 and its impact on myocardial ischemia/reperfusion injury. Basic Res Cardiol. 2013 Jan;108(1):309
Wang N, De Vuyst E, Ponsaerts R, Boengler K, Palacios-Prado N, Wauman J, Lai CP, De Bock M, Decrock E, Bol M, Vinken M, Rogiers V, Tavernier J, Evans WH, Naus CC, Bukauskas FF, Sipido KR, Heusch G, Schulz R, Bultynck G, Leybaert L
(See online at https://doi.org/10.1007/s00395-012-0309-x)
