State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
Key Laboratory of Systems Health Science of Zhejiang Province, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China.
Nat Commun. 2022 May 3;13(1):2412. doi: 10.1038/s41467-022-30178-x.
Human neurodegenerative disorders often exhibit similar pathologies, suggesting a shared aetiology. Key pathological features of Parkinson's disease (PD) are also observed in other neurodegenerative diseases. Pantothenate Kinase-Associated Neurodegeneration (PKAN) is caused by mutations in the human PANK2 gene, which catalyzes the initial step of de novo CoA synthesis. Here, we show that fumble (fbl), the human PANK2 homolog in Drosophila, interacts with PINK1 genetically. fbl and PINK1 mutants display similar mitochondrial abnormalities, and overexpression of mitochondrial Fbl rescues PINK1 loss-of-function (LOF) defects. Dietary vitamin B5 derivatives effectively rescue CoA/acetyl-CoA levels and mitochondrial function, reversing the PINK1 deficiency phenotype. Mechanistically, Fbl regulates Ref(2)P (p62/SQSTM1 homolog) by acetylation to promote mitophagy, whereas PINK1 regulates fbl translation by anchoring mRNA molecules to the outer mitochondrial membrane. In conclusion, Fbl (or PANK2) acts downstream of PINK1, regulating CoA/acetyl-CoA metabolism to promote mitophagy, uncovering a potential therapeutic intervention strategy in PD treatment.
人类神经退行性疾病常表现出相似的病理学特征，提示存在共同的病因。帕金森病 (PD) 的主要病理学特征也存在于其他神经退行性疾病中。泛酸激酶相关神经退行性变 (PKAN) 是由人类 PANK2 基因突变引起的，该基因催化从头合成 CoA 的初始步骤。在这里，我们表明果蝇中的人类 PANK2 同源物 fumble (fbl) 与 PINK1 在遗传上相互作用。fbl 和 PINK1 突变体显示出相似的线粒体异常，并且过表达线粒体 Fbl 可挽救 PINK1 功能丧失 (LOF) 缺陷。膳食维生素 B5 衍生物可有效挽救 CoA/乙酰 CoA 水平和线粒体功能，逆转 PINK1 缺乏表型。从机制上讲，Fbl 通过乙酰化调节 Ref(2)P（p62/SQSTM1 同源物）来促进线粒体自噬，而 PINK1 通过将 mRNA 分子锚定在外膜上来调节 fbl 翻译。总之，Fbl（或 PANK2）作为 PINK1 的下游因子，调节 CoA/乙酰 CoA 代谢以促进线粒体自噬，为 PD 治疗揭示了一种潜在的治疗干预策略。
