Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice

IF 37 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2026-02-17 DOI:10.1016/j.cmet.2026.01.012

Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G. Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Marc Claret

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Abstract

Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of Mfn2 in ECs (Mfn2^iΔEC), but not of Mfn1^iΔEC, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions in vivo. Notably, Mfn2^iΔEC mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2^iΔEC mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.

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内皮细胞中Mfn2的缺失触发了线粒体促生反应，改善了小鼠的全身代谢和健康寿命

内皮细胞（ECs）是关键的代谢守门人，但其在代谢健康中的作用尚不清楚。鉴于线粒体在能量代谢中的核心作用，线粒体处于理想的位置，使ec能够适应不断变化的代谢需求。在这里，我们探讨了ec中线粒体动力学蛋白影响全身代谢状态的假设。内皮细胞中Mfn2的遗传缺陷（Mfn2iΔEC）而不是Mfn1iΔEC，诱导脂肪血管的促线粒体反应，增强抗氧化防御、线粒体适应性和脂质氧化，最终改善代谢结果。培养的内皮细胞通过叉头盒1 （FOXO1）依赖性轴分泌丝裂因子生长分化因子15 (GDF15)，在体内应激条件下也观察到这种反应。值得注意的是，Mfn2iΔEC小鼠内皮和循环GDF15水平升高，GDF15的中和部分减弱了它们的代谢益处。与促分裂激活一致，Mfn2iΔEC小鼠显示出对饮食引起的肥胖和延迟年龄相关衰退的保护。因此，血管有丝分裂适应作为一种促进全身代谢健康的新机制而出现。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.