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Diabetes 56:786-794, 2007
DOI: 10.2337/db06-0187
© 2007 by the American Diabetes Association
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AMP-Activated Protein Kinase {alpha}2 Deficiency Affects Cardiac Cardiolipin Homeostasis and Mitochondrial Function

Yoni Athéa1,2,3, Benoît Viollet4,5,6,7, Philippe Mateo1,2,3, Delphine Rousseau2,3,8, Marta Novotova9, Anne Garnier1,2,3, Sophie Vaulont4,5,6,7, James R. Wilding1,2,3, Alain Grynberg2,3,8, Vladimir Veksler1,2,3, Jacqueline Hoerter1,2,3, and Renée Ventura-Clapier1,2,3

1 Institut National de la Santé et de la Recherche Médicale U769, Châtenay-Malabry, France
2 Université Paris-Sud 11, Châtenay-Malabry, France
3 Institut Fédératif de Recherche 141, Châtenay-Malabry, France
4 Institut Cochin, Département Endocrinologie Métabolisme et Cancer, Paris, France
5 Institut National de la Santé et de la Recherche Médicale U567, Paris, France
6 Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8104, Paris, France
7 Université Paris 5, Faculté de Médecine René Descartes, Unité mixte 3, Paris, France
8 Institut National de la Recherche Agronomique-Unité Mixte de Recherche 1154, Châtenay-Malabry, France
9 Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic

Address correspondence and reprint requests to Renée Ventura-Clapier, INSERM U-769, Université Paris-Sud, 5 rue J6B Clément, F-92296 Châtenay-Malabry, France. E-mail: renee.ventura{at}u-psud.fr

Abbreviations: ALCAT1, acyl-CoA:lysocardiolipin acyltransferase 1; AMPK, AMP-activated protein kinase; CDS2, CTP:PA cytidylyltransferase; CK, creatine kinase; COX, cytochrome c oxidase; CPT-1, carnitine palmitoyl transferase 1; FADH2, reduced flavine adenine dinucleotide; G3P, glycerol-3-phosphate; MDH, malate dehydrogenase; mi-CK, mitochondrial creatine kinase; NAO, 10N-nonyl acridine orange; OMC, oxoglutarate/malate carrier; PGC-1{alpha}, peroxisome proliferator–activated receptor-{gamma} coactivator-1{alpha}

AMP-activated protein kinase (AMPK) plays an important role in controlling energy homeostasis and is envisioned as a promising target to treat metabolic disorders. In the heart, AMPK is involved in short-term regulation and in transcriptional control of proteins involved in energy metabolism. Here, we investigated whether deletion of AMPK{alpha}2, the main cardiac catalytic isoform, alters mitochondrial function and biogenesis. Body weight, heart weight, and AMPK{alpha}1 expression were similar in control littermate and AMPK{alpha}2–/– mice. Despite normal oxygen consumption in perfused hearts, maximal oxidative capacity, measured using saponin permeabilized cardiac fibers, was ~30% lower in AMPK{alpha}2–/– mice with octanoate, pyruvate, or glutamate plus malate but not with succinate as substrates, showing an impairment at complex I of the respiratory chain. This effect was associated with a 25% decrease in mitochondrial cardiolipin content, the main mitochondrial membrane phospholipid that is crucial for complex I activity, and with a 13% decrease in mitochondrial content of linoleic acid, the main fatty acid of cardiolipins. The decrease in cardiolipin content could be explained by mRNA downregulation of rate-limiting enzymes of both cardiolipin synthesis (CTP:PA cytidylyltransferase) and remodeling (acyl-CoA:lysocardiolipin acyltransferase 1). These data reveal a new role for AMPK{alpha}2 subunit in the regulation of cardiac muscle oxidative capacity via cardiolipin homeostasis.


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 Am. J. Physiol. Heart Circ. Physiol.Home page
K. Carvajal, E. Zarrinpashneh, O. Szarszoi, F. Joubert, Y. Athea, P. Mateo, B. Gillet, S. Vaulont, B. Viollet, X. Bigard, et al.
Dual cardiac contractile effects of the {alpha}2-AMPK deletion in low-flow ischemia and reperfusion
Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H3136 - H3147.
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