College of Life Sciences, Beijing Normal University, Beijing, China.
National Institute of Biological Sciences, Beijing, China.
EMBO J. 2023 Jul 3;42(13):e113033. doi: 10.15252/embj.2022113033. Epub 2023 Mar 10.
Mitophagy is a fundamental quality control mechanism of mitochondria. Its regulatory mechanisms and pathological implications remain poorly understood. Here, via a mitochondria-targeted genetic screen, we found that knockout (KO) of FBXL4, a mitochondrial disease gene, hyperactivates mitophagy at basal conditions. Subsequent counter screen revealed that FBXL4-KO hyperactivates mitophagy via two mitophagy receptors BNIP3 and NIX. We determined that FBXL4 functions as an integral outer-membrane protein that forms an SCF-FBXL4 ubiquitin E3 ligase complex. SCF-FBXL4 ubiquitinates BNIP3 and NIX to target them for degradation. Pathogenic FBXL4 mutations disrupt SCF-FBXL4 assembly and impair substrate degradation. Fbxl4 mice exhibit elevated BNIP3 and NIX proteins, hyperactive mitophagy, and perinatal lethality. Importantly, knockout of either Bnip3 or Nix rescues metabolic derangements and viability of the Fbxl4 mice. Together, beyond identifying SCF-FBXL4 as a novel mitochondrial ubiquitin E3 ligase restraining basal mitophagy, our results reveal hyperactivated mitophagy as a cause of mitochondrial disease and suggest therapeutic strategies.
自噬是线粒体的一种基本质量控制机制。其调节机制和病理意义仍知之甚少。在这里，我们通过线粒体靶向基因筛选发现，线粒体疾病基因 FBXL4 的敲除（KO）在基础条件下高度激活自噬。随后的反筛显示，FBXL4-KO 通过两种自噬受体 BNIP3 和 NIX 高度激活自噬。我们确定 FBXL4 作为一种完整的外膜蛋白发挥作用，形成 SCF-FBXL4 泛素 E3 连接酶复合物。SCF-FBXL4 泛素化 BNIP3 和 NIX 以将它们靶向降解。致病性 FBXL4 突变破坏 SCF-FBXL4 组装并损害底物降解。Fbxl4 小鼠表现出升高的 BNIP3 和 NIX 蛋白、过度活跃的自噬和围产期致死性。重要的是，敲除 Bnip3 或 Nix 均可挽救 Fbxl4 小鼠的代谢紊乱和活力。总之，除了确定 SCF-FBXL4 作为一种新的线粒体泛素 E3 连接酶抑制基础自噬外，我们的结果还揭示了过度活跃的自噬是线粒体疾病的原因，并提出了治疗策略。
