State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
EMBO Rep. 2021 Mar 3;22(3):e50629. doi: 10.15252/embr.202050629. Epub 2021 Feb 8.
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.
线粒体自噬是一种重要的细胞自噬过程，它选择性地去除多余和受损的线粒体，并与线粒体生物发生相协调，以精细调节线粒体的数量和质量。这两个相反过程之间的协调对于维持正常的细胞和机体代谢的功能性线粒体网络至关重要。然而，其潜在机制尚不完全清楚。在这里，我们报告说，PGC-1α 和核呼吸因子 1（NRF1），线粒体生物发生和代谢适应的主要调节因子，也在冷应激条件下，在棕色脂肪组织中转录上调先前表征的线粒体自噬受体 FUNDC1 基因的表达。NRF1 结合到 Fundc1 启动子中的经典共识位点，以上调其表达，并通过与 LC3 的相互作用增强线粒体自噬。BAT 中 Fundc1 的特异性敲除导致线粒体周转率降低和功能受损的线粒体积累，从而导致适应性产热受损。我们的结果表明，通过 PGC-1α/NRF1 途径，FUNDC1 依赖性线粒体自噬与线粒体生物发生直接偶联，该途径决定了线粒体的数量、质量和周转率，并有助于适应性产热。
