Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis.

Lei Liu, Yanjun Li, Jianing Wang, Di Zhang, Hao Wu, Wenhui Li, Huifang Wei, Na Ta, Yuyuan Fan, Yujiao Liu, Xiaohui Wang, Jun Wang, Xin Pan, Xudong Liao, Yushan Zhu, Quan Chen

EMBO reports 2021 Mar 03

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Mitophagy is an essential cellular autophagic process that selectively removes superfluous and damaged mitochondria, and it is coordinated with mitochondrial biogenesis to fine tune the quantity and quality of mitochondria. Coordination between these two opposing processes to maintain the functional mitochondrial network is of paramount importance for normal cellular and organismal metabolism. However, the underlying mechanism is not completely understood. Here we report that PGC-1α and nuclear respiratory factor 1 (NRF1), master regulators of mitochondrial biogenesis and metabolic adaptation, also transcriptionally upregulate the gene encoding FUNDC1, a previously characterized mitophagy receptor, in response to cold stress in brown fat tissue. NRF1 binds to the classic consensus site in the promoter of Fundc1 to upregulate its expression and to enhance mitophagy through its interaction with LC3. Specific knockout of Fundc1 in BAT results in reduced mitochondrial turnover and accumulation of functionally compromised mitochondria, leading to impaired adaptive thermogenesis. Our results demonstrate that FUNDC1-dependent mitophagy is directly coupled with mitochondrial biogenesis through the PGC-1α/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis. © 2021 The Authors.

Citation

Lei Liu, Yanjun Li, Jianing Wang, Di Zhang, Hao Wu, Wenhui Li, Huifang Wei, Na Ta, Yuyuan Fan, Yujiao Liu, Xiaohui Wang, Jun Wang, Xin Pan, Xudong Liao, Yushan Zhu, Quan Chen. Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis. EMBO reports. 2021 Mar 03;22(3):e50629