Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis
Mitophagy receptor FUNDC1 is regulated by PGC-1α/NRF1 to fine tune mitochondrial homeostasis
复制标题
Mitophagy 受体 FUNDC1 受 PGC-1α/NRF1 调节，以微调线粒体稳态。
DOI：
10.15252/embr.202050629
复制
发表时间：
2021-02-08
期刊：
影响因子：
7.7
通讯作者：
Chen, Quan
中科院分区：
文献类型：
--
作者：
Liu, Lei;Li, Yanjun;Chen, Quan
有丝分裂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，并与线粒体的生物发生相协调，以微调线粒体的数量和质量。这两个相反的过程之间的协调，以维持功能的线粒体网络，是至关重要的正常细胞和生物新陈代谢。然而，其潜在的机制还没有完全被理解。在这里，我们报道了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者，也在转录上上调了编码Fundc1的基因，Fundc1是一种先前特征的吞线体受体，对棕色脂肪组织中的冷应激做出反应。NRF1结合于Fundc1启动子中的经典共识部位，通过与Lc3的相互作用上调其表达并增强其吞噬作用。BAT中Fundc1的特异性敲除导致线粒体周转减少和功能受损的线粒体的积累，导致适应性产热受损。我们的结果表明，依赖于Fundc1的有丝分裂与线粒体的生物发生是通过PGC-1α/NRF1途径直接耦合的，该途径决定了线粒体的数量、质量和周转，并有助于适应性产热。
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-1 alpha 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-1 alpha/NRF1 pathway, which dictates mitochondrial quantity, quality, and turnover and contributes to adaptive thermogenesis.