Mitochondrial connexin 43 impacts on respiratory complex I activity and mitochondrial oxygen consumption.
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 (Cx43(Cre-ER(T)/fl) + 4-OHT, 5-10% of Cx43 protein compared with control Cx43(fl/fl) mitochondria) reduced ADP-stimulated complex I respiration of LV SSM to 47.8 ± 2.4 nmol O(2)/min.*mg protein (n = 8) from 61.9 ± 7.4 nmol O(2)/min.*mg protein in Cx43(fl/fl) mitochondria (n = 10, P < 0.05), while complex II respiration remained unchanged. The LV complex I activities (% of citrate synthase activity) of Cx43(Cre-ER(T)/fl) +4-OHT mice (16.1 ± 0.9%, n = 9) were lower than in Cx43(fl/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.
Institut für Pathophysiologie, Universitätsklinikum Essen, Essen, Germany.
Kerstin
K
Boengler
Marisol
M
Ruiz-Meana
Sabine
S
Gent
Elvira
E
Ungefug
Daniel
D
Soetkamp
Elisabet
E
Miro-Casas
Alberto
A
Cabestrero
Celia
C
Fernandez-Sanz
Martina
M
Semenzato
Fabio
F
Di Lisa
Susanne
S
Rohrbach
David
D
Garcia-Dorado
Gerd
G
Heusch
Rainer
R
Schulz
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D018031:Connexin 43 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D042967:Electron Transport Complex I / Q000378:metabolism*; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism
D018031:Connexin 43; D010455:Peptides; C119129:18alpha-glycyrrhetinic acid; D000255:Adenosine Triphosphate; D042967:Electron Transport Complex I; D006034:Glycyrrhetinic Acid