MIFed About Metabolism

Abstract

AMP (adenosine monophosphate)-activated protein kinase (AMPK), which modulates metabolic pathways in response to changes in cellular energy status, stimulates glucose uptake and glycolysis in the ischemic heart, limiting myocardial injury. Noting that macrophage migration inhibition factor (MIF, a cytokine implicated in the pathogenesis of various inflammatory conditions) stimulates glycolysis and is expressed in cardiomyocytes, Miller et al . investigated its role in cardiac AMPK activation. AMPK activation in hypoxic rat heart muscle was associated with increased MIF release, whereas antibodies directed against MIF inhibited hypoxia-stimulated activation of AMPK and glucose uptake. Ischemia triggered MIF release from isolated mouse heart, and phosphorylation and activation of AMPK in response to ischemia was decreased in mice lacking MIF ( Mif –/– mice), as was stimulation of glucose uptake during ischemia-reperfusion. Hearts from Mif –/– mice showed decreased post-ischemic function compared with those from wild-type mice and larger infarcts after coronary occlusion-reperfusion. Short interfering RNA directed against CD74 (the ligand-binding component of the MIF receptor complex) decreased hypoxia-stimulated AMPK phosphorylation in fibroblasts, and the effects of MIF or hypoxia on AMPK phosphorylation in COS-7/M6 cells depended on expression of CD74 and CD44 (the signal-transducing component). Human fibroblasts with MIF promoter polymorphism that led to decreased expression and secretion showed decreased AMPK phosphorylation during hypoxia, which was restored by exogenous MIF. Thus, the authors conclude that MIF acts as a local factor to activate AMPK during cardiac ischemia, linking inflammation with cardiac metabolism, and suggest that MIF genotyping could help predict risk of ischemic injury in individuals with coronary artery disease. E. J. Miller, J. Li, L. Leng, C. McDonald, T. Atsumi, R. Bucala, L. H. Young, Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451 , 578-582 (2008). [PubMed]