Pantothenate kinase 2 interacts with PINK1 to regulate mitochondrial quality control via acetyl-CoA metabolism

• Published in: Nature communications Vol. 13; no. 1; pp. 2412 - 16
• Main Authors: Huang, Yunpeng, Wan, Zhihui, Tang, Yinglu, Xu, Junxuan, Laboret, Bretton, Nallamothu, Sree, Yang, Chenyu, Liu, Boxiang, Lu, Rongze Olivia, Lu, Bingwei, Feng, Juan, Cao, Jing, Hayflick, Susan, Wu, Zhihao, Zhou, Bing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.05.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/44; 13/51; 13/89; 14; 14/35; 14/63; 42; 42/109; 42/89; 631/337/574; 631/80/39/2348; 64; 64/24; 692/699/375/364; 692/699/375/365/1718; 82/83; Abnormalities; Acetyl Coenzyme A - metabolism; Acetylation; Animals; Drosophila - genetics; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Homology; Humanities and Social Sciences; Kinases; Metabolism; Mitochondria; Mitochondria - metabolism; Movement disorders; mRNA; multidisciplinary; Mutation; Neurodegeneration; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Pantothenate kinase; Parkinson Disease - metabolism; Parkinson's disease; Pathophysiology; Phenotypes; Phosphotransferases (Alcohol Group Acceptor) - genetics; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Protein Kinases - genetics; Protein Kinases - metabolism; Protein Serine-Threonine Kinases; PTEN-induced putative kinase; Quality control; Science; Science (multidisciplinary); Translation
• ISSN: 2041-1723; 2041-1723
• 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. 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.