RT Journal Article
SR Electronic
T1 AMP-Activated Protein Kinase α2 Deficiency Affects Cardiac Cardiolipin Homeostasis and Mitochondrial Function
JF Diabetes
JO Diabetes
FD American Diabetes Association
SP 786
OP 794
DO 10.2337/db06-0187
VO 56
IS 3
A1 Athéa, Yoni
A1 Viollet, Benoît
A1 Mateo, Philippe
A1 Rousseau, Delphine
A1 Novotova, Marta
A1 Garnier, Anne
A1 Vaulont, Sophie
A1 Wilding, James R.
A1 Grynberg, Alain
A1 Veksler, Vladimir
A1 Hoerter, Jacqueline
A1 Ventura-Clapier, Renée
YR 2007
UL http://diabetes.diabetesjournals.org/content/56/3/786.abstract
AB 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 AMPKα2, the main cardiac catalytic isoform, alters mitochondrial function and biogenesis. Body weight, heart weight, and AMPKα1 expression were similar in control littermate and AMPKα2−/− mice. Despite normal oxygen consumption in perfused hearts, maximal oxidative capacity, measured using saponin permeabilized cardiac fibers, was ∼30% lower in AMPKα2−/− 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 AMPKα2 subunit in the regulation of cardiac muscle oxidative capacity via cardiolipin homeostasis.