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

Yunpeng Huang, Zhihui Wan, Yinglu Tang, Junxuan Xu, Bretton Laboret, Sree Nallamothu, Chenyu Yang, Boxiang Liu, Rongze Olivia Lu, Bingwei Lu, Juan Feng, Jing Cao, Susan Hayflick, Zhihao Wu () and Bing Zhou ()
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Yunpeng Huang: Tsinghua University
Zhihui Wan: Tsinghua University
Yinglu Tang: Southern Methodist University
Junxuan Xu: Tsinghua University
Bretton Laboret: Southern Methodist University
Sree Nallamothu: Southern Methodist University
Chenyu Yang: Southern Methodist University
Boxiang Liu: Stanford University School of Medicine
Rongze Olivia Lu: University of Texas Austin
Bingwei Lu: Stanford University
Juan Feng: Tsinghua University
Jing Cao: Southern Methodist University
Susan Hayflick: Oregon Health and Science University
Zhihao Wu: Southern Methodist University
Bing Zhou: Tsinghua University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30178-x

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