FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome
FBXL4 mutations cause excessive mitophagy via BNIP3/BNIP3L accumulation leading to mitochondrial DNA depletion syndrome
复制标题
DOI：
10.1038/s41418-023-01205-1
复制
发表时间：
2023-08-11
影响因子：
12.4
通讯作者：
Wang, Chenji
中科院分区：
文献类型：
--
作者：
Chen, Yingji;Jiao, Dongyue;Wang, Chenji
线粒体是在真核细胞中发现的重要细胞器，其通过氧化磷酸化（OXPHOS）在ATP产生中起关键作用。线粒体DNA耗竭综合征（MTDPS）是一组以线粒体DNA拷贝数减少为特征的遗传性疾病，导致OXPHOS和线粒体功能缺陷。Cullin 1-RING泛素连接酶复合物（CRL 1）的底物结合衔接子FBXL 4中的突变与MTDPS 13型（MTDPS 13）相关。在这里，我们证明，FBXL 4直接与线粒体自噬货物受体BNIP 3和BNIP 3L相互作用，通过泛素-蛋白酶体途径通过组装活性CRL 1（FBXL 4）复合物促进其降解。然而，MTDPS 13相关的FBXL 4突变损害了活性CRL 1（FBXL 4）复合物的组装。这导致BNIP 3/3L蛋白的显著积累和甚至在基础水平下的稳健的线粒体自噬。在携带源自患者的FBXL 4突变和由MTDPS 13患者人诱导多能干细胞（hiPSC）诱导的皮质神经元（CN）的敲入（KI）小鼠中观察到过度的线粒体自噬。总之，我们的研究结果表明，BNIP 3/BNIP 3L依赖性线粒体自噬的异常激活损害线粒体稳态，并成为FBXL 4突变的MTDPS 13的基础。
Mitochondria are essential organelles found in eukaryotic cells that play a crucial role in ATP production through oxidative phosphorylation (OXPHOS). Mitochondrial DNA depletion syndrome (MTDPS) is a group of genetic disorders characterized by the reduction of mtDNA copy number, leading to deficiencies in OXPHOS and mitochondrial functions. Mutations in FBXL4, a substrate-binding adaptor of Cullin 1-RING ubiquitin ligase complex (CRL1), are associated with MTDPS, type 13 (MTDPS13). Here, we demonstrate that, FBXL4 directly interacts with the mitophagy cargo receptors BNIP3 and BNIP3L, promoting their degradation through the ubiquitin-proteasome pathway via the assembly of an active CRL1(FBXL4) complex. However, MTDPS13-associated FBXL4 mutations impair the assembly of an active CRL1(FBXL4) complex. This results in a notable accumulation of BNIP3/3L proteins and robust mitophagy even at basal levels. Excessive mitophagy was observed in Knockin (KI) mice carrying a patient-derived FBXL4 mutation and cortical neurons (CNs)-induced from MTDPS13 patient human induced pluripotent stem cells (hiPSCs). In summary, our findings suggest that abnormal activation of BNIP3/BNIP3L-dependent mitophagy impairs mitochondrial homeostasis and underlies FBXL4-mutated MTDPS13.