Article

AMP-activated protein kinase alpha2 deficiency affects cardiac cardiolipin homeostasis and mitochondrial function.

INSERM U-769, Université Paris-Sud 11, 5 rue J6B Clément, F-92296 Châtenay-Malabry, France.
Diabetes (impact factor: 8.29). 04/2007; 56(3):786-94. DOI:10.2337/db06-0187 pp.786-94
Source: PubMed

ABSTRACT 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.

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Keywords

AMP-activated protein kinase
 
AMPKalpha1 expression
 
AMPKalpha2 subunit
 
Body weight
 
cardiac muscle oxidative capacity
 
cardiolipin content
 
cardiolipin homeostasis
 
cardiolipin synthesis
 
cardiolipins
 
energy homeostasis
 
main cardiac catalytic isoform
 
main mitochondrial membrane phospholipid
 
maximal oxidative capacity
 
metabolic disorders
 
mitochondrial cardiolipin content
 
mitochondrial content
 
mRNA downregulation
 
normal oxygen consumption
 
perfused hearts
 
transcriptional control