Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism.
Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism.
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DOI：
10.1038/s41467-022-30178-x
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发表时间：
2022-05-03
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
人类神经退行性疾病通常表现出相似的病理学，表明有共同的病因。帕金森病（PD）的关键病理特征也见于其他神经退行性疾病。泛酸激酶相关神经变性（PKAN）是由人PANK 2基因突变引起的，PANK 2基因催化CoA从头合成的初始步骤。在这里，我们表明，摸索（fbl），人类PANK 2同源果蝇，与PINK 1基因相互作用。fbl和PINK 1突变体显示出相似的线粒体异常，线粒体Fbl的过表达挽救了PINK 1功能丧失（LOF）缺陷。膳食维生素B5衍生物有效地挽救CoA/乙酰辅酶A水平和线粒体功能，逆转PINK 1缺乏表型。Fbl通过乙酰化调节Ref（2）P（p62/SQSTM 1同源物）以促进线粒体自噬，而PINK 1通过将mRNA分子锚定到线粒体外膜来调节fbl翻译。总之，Fbl（或PANK 2）作用于PINK 1的下游，调节CoA/乙酰CoA代谢以促进线粒体自噬，揭示了PD治疗中的潜在治疗干预策略。PKAN和PD是两种具有重叠病理生理学的不同疾病。在这里，作者表明他们的致病基因PANK 2和PINK 1相互作用。PANK 2通过CoA代谢调节线粒体自噬，而PINK 1监督PANK 2在线粒体上的翻译。
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. PKAN and PD are two distinct diseases with overlapping pathophysiology. Here, authors show that their pathogenic genes PANK2 and PINK1 interact. PANK2 regulates mitophagy via CoA metabolism, while PINK1 supervises PANK2 translation on mitochondria.
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影响因子：
2.4
作者：
Cornille E;Abou-Hamdan M;Khrestchatisky M;Nieoullon A;de Reggi M;Gharib B
通讯作者：
Gharib B
影响因子：
2.5
作者：
Klopstock, T;Elstner, M;Hörtnagel, K
通讯作者：
Hörtnagel, K
影响因子：
168.9
作者：
Kalia, Lorraine V.;Lang, Anthony E.
通讯作者：
Lang, Anthony E.
影响因子：
0.9
作者：
Christou YP;Tanteles GA;Kkolou E;Ormiston A;Konstantopoulos K;Beconi M;Marshall RD;Plotkin H;Kleopa KA
通讯作者：
Kleopa KA
影响因子：
3.7
作者：
Benabdellah, Karim;Cobo, Marien;Martin, Francisco
通讯作者：
Martin, Francisco