Deficiency of mitophagy receptor FUNDC1 impairs mitochondrial quality and aggravates dietary-induced obesity and metabolic syndrome

There is overwhelming evidence for an association between impaired mitochondrial function and metabolic syndrome. Mitophagy, a process that selectively removes damaged mitochondria <i>via</i> a specialized form of autophagy, is essential for mitochondrial quality control (mitochondrial QC) and metabolic homeostasis. We thus addressed the potential role of defective mitophagy in the pathogenesis of metabolic disorders. Mice lacking <i>Fundc1</i>, a newly characterized mitophagy receptor, develop more severe obesity and insulin resistance when fed a high-fat diet (HFD). Ablation of <i>Fundc1</i> results in defective mitophagy and impaired mitochondrial QC <i>in vitro</i> and in white adipose tissue (WAT). In addition, there is more pronounced WAT remodeling with more adipose tissue-associated macrophages infiltration, more M1 macrophage polarization and thus an elevated inflammatory response. Mechanistically, hyperactivation of MAPK/JNK leads to insulin insensitivity, which can be inhibited by knocking out <i>Mapk8</i>/<i>Jnk1</i> in <i>fundc1</i> KO mice. Our results demonstrate that dysregulated mitochondrial QC due to defective mitophagy receptor FUNDC1 links with metabolic disorders <i>via</i> MAPK signaling and inflammatory responses. <b>Abbreviations</b>: ATMs: adipose tissue macrophages; BAT: brown adipose tissue; BMDMs: bone marrow-derived macrophages; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPT/ALT: glutamic pyruvic transaminase, soluble; H&amp;E staining: hematoxylin and eosin staining; HFD: high-fat diet; LIR: LC3-interacting region; mitochondrial QC: mitochondrial quality control; mito-ROS: mitochondrial ROS; mtDNA: mitochondrial DNA; RT-PCR: real-time-PCR; T2D: type 2 diabetes; WAT: white adipose tissue

现有大量确凿证据表明，线粒体功能受损与代谢综合征之间存在密切关联。线粒体自噬（mitophagy）是一种通过特化自噬途径选择性清除受损线粒体的过程，对线粒体质量控制（mitochondrial QC）与代谢稳态至关重要。因此，本研究针对性探究了受损线粒体自噬在代谢紊乱发病机制中的潜在作用。新鉴定的线粒体自噬受体Fundc1基因敲除小鼠，在饲喂高脂饮食（HFD）后会出现更为严重的肥胖与胰岛素抵抗表型。体外实验与白色脂肪组织（WAT）中均证实，Fundc1基因敲除会导致线粒体自噬缺陷与线粒体质量控制受损。此外，该模型小鼠还表现出更为显著的白色脂肪组织重塑，伴随更多脂肪组织驻留巨噬细胞浸润、更显著的M1型巨噬细胞极化，进而引发炎症反应增强。机制层面，MAPK/JNK通路的过度激活会导致胰岛素抵抗，而在Fundc1基因敲除小鼠中敲除Mapk8/Jnk1可有效抑制这一过程。本研究结果表明，由线粒体自噬受体FUNDC1缺陷引发的线粒体质量控制失调，可通过MAPK信号通路与炎症反应参与代谢紊乱的发生发展。**缩写说明**：ATMs：脂肪组织巨噬细胞（adipose tissue macrophages）；BAT：棕色脂肪组织（brown adipose tissue）；BMDMs：骨髓来源巨噬细胞（bone marrow-derived macrophages）；GOT1/AST：可溶性谷草转氨酶1（glutamic-oxaloacetic transaminase 1, soluble）；GPT/ALT：可溶性谷丙转氨酶（glutamic pyruvic transaminase, soluble）；H&E染色：苏木精-伊红染色（hematoxylin and eosin staining）；HFD：高脂饮食（high-fat diet）；LIR：LC3相互作用区域（LC3-interacting region）；mitochondrial QC：线粒体质量控制（mitochondrial quality control）；mito-ROS：线粒体活性氧（mitochondrial ROS）；mtDNA：线粒体DNA（mitochondrial DNA）；RT-PCR：实时荧光定量PCR（real-time-PCR）；T2D：2型糖尿病（type 2 diabetes）；WAT：白色脂肪组织（white adipose tissue）