GLP-1 promotes mitochondrial metabolism in vascular smooth muscle cells by enhancing endoplasmic reticulum–mitochondria coupling
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Incretin GLP-1 has important metabolic effects on several tissues, mainly through the regulation of glucose uptake and usage. One mechanism for increasing cell metabolism is modulating endoplasmic reticulum (ER)–mitochondria communication, as it allows for a more efficient transfer of Ca2+ into the mitochondria, thereby increasing activity. Control of glucose metabolism is essential for proper vascular smooth muscle cell (VSMC) function. GLP-1 has been shown to produce varied metabolic actions, but whether it regulates glucose metabolism in VSMC remains unknown. In this report, we show that GLP- 1 increases mitochondrial activity in the aortic cell line A7r5 by increasing ER–mitochondria coupling. GLP-1 increases intracellular glucose and diminishes glucose uptake without altering glycogen content. ATP, mitochondrial potential and oxygen consumption increase at 3 h of GLP-1 treatment, paralleled by increased Ca2+ transfer from the ER to the mitochondria. Furthermore, GLP-1 increases levels of Mitofusin-2 (Mfn2), an ER-mitochondria tethering protein, via a PKA-dependent mechanism. Accordingly, PKA inhibition and Mfn2 down-regulation prevented mitochondrial Ca2+ increases in GLP-1 treated cells. Inhibiting both Ca2+ release from the ER and Ca2+ entry into mitochondria as well as diminishing Mfn2 levels blunted the increase in mitochondrial activity in response to GLP-1. Altogether, these results strongly suggest that GLP-1 increases ER–mitochondria communication in VSMC, resulting in higher mitochondrial activity.
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This research was funded in part by Comision Nacional de Ciencia y Tecnologia (CONICYT), Chile (FONDECYT 1110180 to M.C.; ANILLO ACT1111 to M.C.; FONDAP 15130011 to M.C.). P.M. holds a CONICYT Master fellowship. G.T. and F.P. hold a CONICYT Ph.D. fellowship.
DOI: DOI: 10.1016/j.bbrc.2014.03.004
Quote ItemBiochemical and Biophysical Research Communications 446 (2014) 410–416