Connexin 43 in Mitochondria: Functional Importance

Rainer Schulz, Kerstin Boengler, Marisol Ruiz-Meana, David Garcia-Dorado, Gerd Heusch

Connexin43 is transported into the cytosol towards the inner mitochondrial membrane of cardiomyocytes in a HSP90/TOM/TIM-dependent manner. Experiments with the membrane-permeant cross-linking agent dimethylsuberimidate indicate the presence of connexin 43 oligomers; the C-terminus of mitochondrial connexin 43 is directed towards the intermembrane space. In mice deficient for mitochondrial connexin 43, the uptake of the connexin 43 hemichannel-permeant dye Lucifer Yellow is reduced, and mitochondrial potassium influx – as assessed by PBFI fluorescence – is also reduced. ADP-induced mitochondrial respiration with glutamate/malate as substrates is reduced by the connexin 43-hemichannel blocker 18&alpha -glycyrrhetinic acid or connexin 43-mimetic peptides, and these results were confirmed in genetically connexin 43-deficient mice. All results obtained so far are consistent with the hypothesis that in cardiomyocytes mitochondrial connexin 43 contributes to the regulation of mitochondrial potassium flux and respiration, potentially by forming hemichannel-like structures or modulating existing ion transporters. Clearly, mitochondrial connexin 43 is involved in the protection by ischemic and pharmacological preconditioning, but not in that by ischemic postconditioning. The aging-associated loss of mitochondrial connexin 43 is related to the loss of protection by ischemic preconditioning.