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Mitophagy receptor FUNDC1 is regulated by PGC‐1α/NRF1 to fine tune mitochondrial homeostasis
Author(s) -
Liu Lei,
Li Yanjun,
Wang Jianing,
Zhang Di,
Wu Hao,
Li Wenhui,
Wei Huifang,
Ta Na,
Fan Yuyuan,
Liu Yujiao,
Wang Xiaohui,
Wang Jun,
Pan Xin,
Liao Xudong,
Zhu Yushan,
Chen Quan
Publication year - 2021
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.202050629
Subject(s) - mitophagy , nrf1 , mitochondrial biogenesis , mitochondrion , microbiology and biotechnology , biology , downregulation and upregulation , ppargc1a , biogenesis , autophagy , transcription factor , genetics , gene , coactivator , apoptosis
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.