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Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model.
Yi, Juan; Wang, He-Ling; Lu, Guang; Zhang, Hailong; Wang, Lina; Li, Zhen-Yu; Wang, Liming; Wu, Yihua; Xia, Dajing; Fang, Evandro F; Shen, Han-Ming.
Afiliación
  • Yi J; School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
  • Wang HL; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
  • Lu G; Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • Zhang H; School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
  • Wang L; School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu, China.
  • Li ZY; College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, China.
  • Wang L; School of Biomedical Sciences, Hunan University, Changsha, China.
  • Wu Y; School of Public Health, Zhejiang University, Hangzhou, China.
  • Xia D; School of Public Health, Zhejiang University, Hangzhou, China.
  • Fang EF; Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Lørenskog, Norway.
  • Shen HM; The Norwegian Centre on Healthy Ageing (NO-Age), Oslo, Norway.
Autophagy ; : 1-22, 2024 Aug 01.
Article en En | MEDLINE | ID: mdl-39051473
ABSTRACT
Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Caenorhabditis elegans (C. elegans) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) C. elegans model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.Abbreviations AD, Alzheimer disease; ATG, autophagy related; BafA1, bafilomycin A1; CALCOCO2/NDP52, calcium binding and coiled-coil domain 2; CCCP, carbonyl cyanide m-chlorophenyl hydrazone; COX4/COX IV, cytochrome c oxidase subunit 4; EBSS, Earle's balanced salt; ECAR, extracellular acidification rate; GFP, green fluorescent protein; IA, isoamyl alcohol; IMM, inner mitochondrial membrane; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MMP, mitochondrial membrane potential; mtDNA, mitochondrial DNA; nDNA, nuclear DNA; O/A, oligomycin-antimycin; OCR, oxygen consumption rate; OMM, outer mitochondrial membrane; OPTN, optineurin; PARL, presenilin associated rhomboid like; PINK1, PTEN induced kinase 1; PRKN, parkin RBR E3 ubiquitin protein ligase; p-Ser65-Ub, phosphorylation of Ub at Ser65; TIMM23, translocase of inner mitochondrial membrane 23; TOMM, translocase of outer mitochondrial membrane; USP10, ubiquitin specific peptidase 10; USP13, ubiquitin specific peptidase 13; VAL, valinomycin; YFP, yellow fluorescent protein.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Autophagy Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Autophagy Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos