FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.
FBXL4 suppresses mitophagy by restricting the accumulation of NIX and BNIP3 mitophagy receptors.
复制标题
DOI：
10.15252/embj.2022112767
复制
发表时间：
2023-07-03
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
为了维持线粒体的质量和数量，细胞通过线粒体自噬选择性地去除受损或过多的线粒体，这是一种特殊的自噬形式。线粒体自噬是在多种条件下诱导的，包括缺氧、细胞分化和线粒体损伤。然而，在稳态条件下控制特定功能失调线粒体去除以微调线粒体含量的机制尚不清楚。在这里，我们报道了SCFFBXL4，一种SKP1/CUL1/F‐box蛋白泛素连接酶复合物，定位于非应激细胞的线粒体外膜，并介导线粒体自噬受体NIX和BNIP3的组成泛素化和降解，以抑制线粒体自噬的基础水平。我们证明，导致脑病mtDNA缺失综合征（MTDPS13）的FBXL4致病变异不能有效地与核心SCF泛素连接酶机制相互作用或介导NIX和BNIP3的降解。因此，我们揭示了FBXL4通过阻止NIX和BNIP3积累来积极抑制线粒体自噬的分子机制。我们提出，在FBXL4相关的mtDNA耗竭综合征中，NIX和BNIP3转换的失调导致过度的基础线粒体自噬。稳定状态的泛素化和NIX和BNIP3的转换限制了基础的线粒体自噬，并且在MTDPS13中失调，导致线粒体自噬升高与脑病mtDNA耗竭综合征相关。
To maintain both mitochondrial quality and quantity, cells selectively remove damaged or excessive mitochondria through mitophagy, which is a specialised form of autophagy. Mitophagy is induced in response to diverse conditions, including hypoxia, cellular differentiation and mitochondrial damage. However, the mechanisms that govern the removal of specific dysfunctional mitochondria under steady‐state conditions to fine‐tune mitochondrial content are not well understood. Here, we report that SCFFBXL4, an SKP1/CUL1/F‐box protein ubiquitin ligase complex, localises to the mitochondrial outer membrane in unstressed cells and mediates the constitutive ubiquitylation and degradation of the mitophagy receptors NIX and BNIP3 to suppress basal levels of mitophagy. We demonstrate that the pathogenic variants of FBXL4 that cause encephalopathic mtDNA depletion syndrome (MTDPS13) do not efficiently interact with the core SCF ubiquitin ligase machinery or mediate the degradation of NIX and BNIP3. Thus, we reveal a molecular mechanism whereby FBXL4 actively suppresses mitophagy by preventing NIX and BNIP3 accumulation. We propose that the dysregulation of NIX and BNIP3 turnover causes excessive basal mitophagy in FBXL4‐associated mtDNA depletion syndrome. Steady‐state ubiquitylation and turnover of NIX and BNIP3 limits basal mitophagy and is dysregulated in MTDPS13, accounting for the elevated mitophagy associated with this encephalopathic mtDNA depletion syndrome.