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.