PDF(Pubmed)
Abstract：
Mitophagy is a critical mitochondrial quality control process that selectively removes dysfunctional or excess mitochondria through the autophagy-lysosome system. The process is tightly controlled to ensure cellular and physiological homeostasis. Insufficient mitophagy can result in failure to remove damaged mitochondria and consequent cellular degeneration, but it is equally important to appropriately restrain mitophagy to prevent excessive mitochondrial depletion. Here, we discuss our recent discovery that the SKP1-CUL1-F-box (SCF)-FBXL4 (F-box and leucine-rich repeat protein 4) E3 ubiquitin ligase localizes to the mitochondrial outer membrane, where it constitutively mediates the ubiquitination and degradation of BNIP3L/NIX and BNIP3 mitophagy receptors to suppress mitophagy. The post-translational regulation of BNIP3L and BNIP3 is disrupted in mitochondrial DNA depletion syndrome 13 (MTDPS13), a multi-systemic disorder caused by mutations in the FBXL4 gene and characterized by elevated mitophagy and mitochondrial DNA/mtDNA depletion in patient fibroblasts. Our results demonstrate that mitophagy is not solely stimulated in response to specific conditions but is instead also actively suppressed through the continuous degradation of BNIP3L and BNIP3 mediated by the SCF-FBXL4 ubiquitin ligase. Thus, cellular conditions or signaling events that prevent the FBXL4-mediated turnover of BNIP3L and BNIP3 on specific mitochondria are expected to facilitate their selective removal.
摘要：
线粒体自噬是一个关键的线粒体质量控制过程，它通过自噬-溶酶体系统选择性地去除功能失调或过量的线粒体。严格控制该过程以确保细胞和生理稳态。线粒体自噬不足会导致无法清除受损的线粒体，从而导致细胞变性。但适当抑制线粒体自噬以防止线粒体过度耗竭同样重要。这里,我们讨论了我们最近的发现，SKP1-CUL1-F-box（SCF）-FBXL4（F-box和富含亮氨酸的重复蛋白4）E3泛素连接酶定位于线粒体外膜，其中它组成介导BNIP3L/NIX和BNIP3线粒体自噬受体的泛素化和降解以抑制线粒体自噬。在线粒体DNA耗竭综合征13（MTDPS13）中，BNIP3L和BNIP3的翻译后调节被破坏，由FBXL4基因突变引起的多系统疾病，其特征是患者成纤维细胞中线粒体自噬和线粒体DNA/mtDNA消耗升高。我们的结果表明，线粒体自噬不仅受到特定条件的刺激，而且还通过SCF-FBXL4泛素连接酶介导的BNIP3L和BNIP3的连续降解而受到积极抑制。因此，预期阻止FBXL4介导的BNIP3L和BNIP3在特定线粒体上的周转的细胞条件或信号传导事件有助于它们的选择性去除。
