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Autophagy. 2019 Mar 22:1-17. doi: 10.1080/15548627.2019.1596482. [Epub ahead of print]

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

Wu H1, Wang Y2, Li W1,3, Chen H1, Du L1, Liu D1,3, Wang X1, Xu T2, Liu L1, Chen Q1,3,4.

Author information

1
a State Key Laboratory of Membrane Biology, Institute of Zoology , Chinese Academy of Sciences , Beijing , China.
2
b National Laboratory of Biomacromolecules, Institute of Biophysics , Chinese Academy of Sciences , Beijing , China.
3
c College of Life Sciences , University of Chinese Academy of Sciences , Beijing , China.
4
d Tianjin Key Laboratory of Protein Science, College of Life Sciences , Nankai University , Tianjin , China.

Abstract

There is overwhelming evidence for an association between impaired mitochondrial function and metabolic syndrome. Mitophagy, a process that selectively removes damaged mitochondria via 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 Fundc1, a newly characterized mitophagy receptor, develop more severe obesity and insulin resistance when fed a high-fat diet (HFD). Ablation of Fundc1 results in defective mitophagy and impaired mitochondrial QC in vitro 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 Mapk8/Jnk1 in fundc1 KO mice. Our results demonstrate that dysregulated mitochondrial QC due to defective mitophagy receptor FUNDC1 links with metabolic disorders via MAPK signaling and inflammatory responses. Abbreviations: 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&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.

KEYWORDS:

FUNDC1; MAPK; insulin resistance; mitochondrial QC; mitophagy; obesity

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