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The fasting-feeding metabolic transition regulates mitochondrial dynamics
The FASEB Journal ( IF 4.8 ) Pub Date : 2021-09-27 , DOI: 10.1096/fj.202100929r
Mauricio Castro-Sepúlveda 1, 2 , Béatrice Morio 3 , Mauro Tuñón-Suárez 1 , Sebastian Jannas-Vela 1 , Francisco Díaz-Castro 4, 5 , Jennifer Rieusset 3 , Hermann Zbinden-Foncea 1, 6
Affiliation  

In humans, insulin resistance has been linked to an impaired metabolic transition from fasting to feeding (metabolic flexibility; MetFlex). Previous studies suggest that mitochondrial dynamics response is a putative determinant of MetFlex; however, this has not been studied in humans. Thus, the aim of this study was to investigate the mitochondrial dynamics response in the metabolic transition from fasting to feeding in human peripheral blood mononuclear cells (PBMCs). Six male subjects fasted for 16 h (fasting), immediately after which they consumed a 75-g oral glucose load (glucose). In both fasting and glucose conditions, blood samples were taken to obtain PBMCs. Mitochondrial dynamics were assessed by electron microscopy images. We exposed in vitro acetoacetate-treated PBMCs to the specific IP3R inhibitor Xestospongin B (XeB) to reduce IP3R-mediated mitochondrial Ca2+ accumulation. This allowed us to evaluate the role of ER-mitochondria Ca2+ exchange in the mitochondrial dynamic response to substrate availability. To determine whether PBMCs could be used in obesity context (low MetFlex), we measured mitochondrial dynamics in mouse spleen-derived lymphocytes from WT and ob/ob mice. We demonstrated that the transition from fasting to feeding reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs. In addition, we demonstrated that IP3R activity is key in the mitochondrial dynamics response when PBMCs are treated with a fasting-substrate in vitro. In murine mononuclear-cells, we confirmed that mitochondria-ER interactions are regulated in the fasted-fed transition and we further highlight mitochondria-ER miscommunication in PBMCs of diabetic mice. In conclusion, our results demonstrate that the fasting/feeding transition reduces mitochondria-ER interactions, induces mitochondrial fission and reduces mitochondrial cristae density in human PBMCs, and that IP3R activity may potentially play a central role.

中文翻译:

禁食-进食代谢转变调节线粒体动力学

在人类中,胰岛素抵抗与从禁食到进食的代谢转变受损有关(代谢灵活性;MetFlex)。以前的研究表明,线粒体动力学响应是 MetFlex 的一个推定决定因素;然而,这尚未在人类中进行过研究。因此,本研究的目的是研究人类外周血单核细胞 (PBMC) 从禁食到进食的代谢转变中的线粒体动力学响应。六名男性受试者禁食 16 小时(禁食),之后立即消耗 75 克口服葡萄糖负荷(葡萄糖)。在空腹和葡萄糖条件下,采集血液样本以获得 PBMC。通过电子显微镜图像评估线粒体动力学。2+积累。这使我们能够评估 ER-线粒体 Ca 2+ 的作用线粒体对底物可用性的动态响应中的交换。为了确定 PBMC 是否可用于肥胖环境(低 MetFlex),我们测量了来自 WT 和 ob/ob 小鼠的小鼠脾脏淋巴细胞的线粒体动力学。我们证明了从禁食到进食的转变减少了线粒体-ER 相互作用,诱导了线粒体裂变并降低了人类 PBMC 中的线粒体嵴密度。此外,我们证明了在体外用禁食底物处理 PBMC 时,IP3R 活性是线粒体动力学反应的关键。在鼠单核细胞中,我们证实线粒体-ER 相互作用在禁食-进食过渡中受到调节,我们进一步强调了糖尿病小鼠 PBMC 中线粒体-ER 的错误交流。综上所述,
更新日期:2021-09-27
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