GLP-1 promotes mitochondrial metabolism in vascular smooth muscle cells by enhancing endoplasmic reticulum-mitochondria coupling

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• 作者：Pablo E. Morales¹ ; Gloria Torres¹ ; Cristian Sotomayor-Flores ; Daniel Peñ ; a-Oyarzú ; n ; Pablo Rivera-Mejí ; as ; Felipe Paredes ; Mario Chiong ; ^{mchiong@uchile.cl" class="auth_mail}
• 关键词：GLP-1 ; VSMC ; Mitochondrial metabolism ; ER&ndash ; mitochondria coupling ; PKA ; Mitofusin-2
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：28 March, 2014
• 年：2014
• 卷：446
• 期：1
• 页码：410-416
• 全文大小：698 K

文摘

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.