AMP-activated protein kinase alpha2 deficiency affects cardiac cardiolipin homeostasis and mitochondrial function.
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 AMPKalpha2, the main cardiac catalytic isoform, alters mitochondrial function and biogenesis. Body weight, heart weight, and AMPKalpha1 expression were similar in control littermate and AMPKalpha2(-/-) mice. Despite normal oxygen consumption in perfused hearts, maximal oxidative capacity, measured using saponin permeabilized cardiac fibers, was approximately 30% lower in AMPKalpha2(-/-) 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 AMPKalpha2 subunit in the regulation of cardiac muscle oxidative capacity via cardiolipin homeostasis.
Athéa
Yoni
Y
INSERM U-769, Université Paris-Sud 11, 5 rue J6B Clément, F-92296 Châtenay-Malabry, France.
Viollet
Benoît
B
Mateo
Philippe
P
Rousseau
Delphine
D
Novotova
Marta
M
Garnier
Anne
A
Vaulont
Sophie
S
Wilding
James R
JR
Grynberg
Alain
A
Veksler
Vladimir
V
Hoerter
Jacqueline
J
Ventura-Clapier
Renée
R
D055372:AMP-Activated Protein Kinases; D000818:Animals; D002308:Cardiolipins / Q000378:metabolism*; D004734:Energy Metabolism; D005227:Fatty Acids / Q000378:metabolism; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism*; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000648:ultrastructure; D019301:Oleic Acid / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
D002308:Cardiolipins; D005227:Fatty Acids; D009097:Multienzyme Complexes; D010743:Phospholipids; D019301:Oleic Acid; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose