AMP-activated protein kinase α2 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 AMPK alpha 2, the main cardiac catalytic isoform, alters mitochondrial function and biogenesis. Body weight, heart weight, and AMPK alpha 2 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 similar to 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:Iysocardiolipin acyltransferase 1). These data reveal a new role for AMPKa2 subunit in the regulation of cardiac muscle oxidative capacity via cardiolipin homeostasis.