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Article: Aberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2R1441G mice

TitleAberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2<sup>R1441G</sup> mice
Authors
KeywordsAging
Dnm1l/DRP1
Knockin mice
Macroautophagy
Mitochondrial fission
Mitophagy
Mitochondria dysfunction
Parkinson disease
SQSTM1/p62
Ubiquitination
Issue Date2021
PublisherTaylor & Francis: STM, Behavioural Science and Public Health Titles. The Journal's web site is located at http://www.tandfonline.com/loi/kaup20#.VfwhQUaFOnI
Citation
Autophagy, 2021, v. 17 n. 10, p. 3196-3220 How to Cite?
AbstractMitochondrial dysfunction causes energy deficiency and nigrostriatal neurodegeneration which is integral to the pathogenesis of Parkinson disease (PD). Clearance of defective mitochondria involves fission and ubiquitin-dependent degradation via mitophagy to maintain energy homeostasis. We hypothesize that LRRK2 (leucine-rich repeat kinase 2) mutation disrupts mitochondrial turnover causing accumulation of defective mitochondria in aging brain. We found more ubiquitinated mitochondria with aberrant morphology associated with impaired function in aged (but not young) LRRK2R1441G knockin mutant mouse striatum compared to wild-type (WT) controls. LRRK2R1441G mutant mouse embryonic fibroblasts (MEFs) exhibited reduced MAP1LC3/LC3 activation indicating impaired macroautophagy/autophagy. Mutant MEFs under FCCP-induced (mitochondrial uncoupler) stress showed increased LC3-aggregates demonstrating impaired mitophagy. Using a novel flow cytometry assay to quantify mitophagic rates in MEFs expressing photoactivatable mito-PAmCherry, we found significantly slower mitochondria clearance in mutant cells. Specific LRRK2 kinase inhibition using GNE-7915 did not alleviate impaired mitochondrial clearance suggesting a lack of direct relationship to increased kinase activity alone. DNM1L/Drp1 knockdown in MEFs slowed mitochondrial clearance indicating that DNM1L is a prerequisite for mitophagy. DNM1L knockdown in slowing mitochondrial clearance was less pronounced in mutant MEFs, indicating preexisting impaired DNM1L activation. DNM1L knockdown disrupted mitochondrial network which was more evident in mutant MEFs. DNM1L-Ser616 and MAPK/ERK phosphorylation which mediate mitochondrial fission and downstream mitophagic processes was apparent in WT using FCCP-induced stress but not mutant MEFs, despite similar total MAPK/ERK and DNM1L levels. In conclusion, aberrant mitochondria morphology and dysfunction associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in mutant LRRK2 MEFs and mouse brain.
Persistent Identifierhttp://hdl.handle.net/10722/300606
ISSN
2023 Impact Factor: 14.6
2023 SCImago Journal Rankings: 4.035
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLiu, H-
dc.contributor.authorHo, PWL-
dc.contributor.authorLeung, CT-
dc.contributor.authorPang, SYY-
dc.contributor.authorChang, EES-
dc.contributor.authorChoi, ZYK-
dc.contributor.authorKung, MHW-
dc.contributor.authorRamsden, DB-
dc.contributor.authorHo, SL-
dc.date.accessioned2021-06-18T14:54:24Z-
dc.date.available2021-06-18T14:54:24Z-
dc.date.issued2021-
dc.identifier.citationAutophagy, 2021, v. 17 n. 10, p. 3196-3220-
dc.identifier.issn1554-8627-
dc.identifier.urihttp://hdl.handle.net/10722/300606-
dc.description.abstractMitochondrial dysfunction causes energy deficiency and nigrostriatal neurodegeneration which is integral to the pathogenesis of Parkinson disease (PD). Clearance of defective mitochondria involves fission and ubiquitin-dependent degradation via mitophagy to maintain energy homeostasis. We hypothesize that LRRK2 (leucine-rich repeat kinase 2) mutation disrupts mitochondrial turnover causing accumulation of defective mitochondria in aging brain. We found more ubiquitinated mitochondria with aberrant morphology associated with impaired function in aged (but not young) LRRK2R1441G knockin mutant mouse striatum compared to wild-type (WT) controls. LRRK2R1441G mutant mouse embryonic fibroblasts (MEFs) exhibited reduced MAP1LC3/LC3 activation indicating impaired macroautophagy/autophagy. Mutant MEFs under FCCP-induced (mitochondrial uncoupler) stress showed increased LC3-aggregates demonstrating impaired mitophagy. Using a novel flow cytometry assay to quantify mitophagic rates in MEFs expressing photoactivatable mito-PAmCherry, we found significantly slower mitochondria clearance in mutant cells. Specific LRRK2 kinase inhibition using GNE-7915 did not alleviate impaired mitochondrial clearance suggesting a lack of direct relationship to increased kinase activity alone. DNM1L/Drp1 knockdown in MEFs slowed mitochondrial clearance indicating that DNM1L is a prerequisite for mitophagy. DNM1L knockdown in slowing mitochondrial clearance was less pronounced in mutant MEFs, indicating preexisting impaired DNM1L activation. DNM1L knockdown disrupted mitochondrial network which was more evident in mutant MEFs. DNM1L-Ser616 and MAPK/ERK phosphorylation which mediate mitochondrial fission and downstream mitophagic processes was apparent in WT using FCCP-induced stress but not mutant MEFs, despite similar total MAPK/ERK and DNM1L levels. In conclusion, aberrant mitochondria morphology and dysfunction associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in mutant LRRK2 MEFs and mouse brain.-
dc.languageeng-
dc.publisherTaylor & Francis: STM, Behavioural Science and Public Health Titles. The Journal's web site is located at http://www.tandfonline.com/loi/kaup20#.VfwhQUaFOnI-
dc.relation.ispartofAutophagy-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectAging-
dc.subjectDnm1l/DRP1-
dc.subjectKnockin mice-
dc.subjectMacroautophagy-
dc.subjectMitochondrial fission-
dc.subjectMitophagy-
dc.subjectMitochondria dysfunction-
dc.subjectParkinson disease-
dc.subjectSQSTM1/p62-
dc.subjectUbiquitination-
dc.titleAberrant mitochondrial morphology and function associated with impaired mitophagy and DNM1L-MAPK/ERK signaling are found in aged mutant Parkinsonian LRRK2<sup>R1441G</sup> mice-
dc.typeArticle-
dc.identifier.emailLiu, H: liuhf@hku.hk-
dc.identifier.emailHo, PWL: hwl2002@hku.hk-
dc.identifier.emailLeung, CT: gctleung@HKUCC-COM.hku.hk-
dc.identifier.emailPang, SYY: syypang@hku.hk-
dc.identifier.emailChoi, ZYK: zoecyk@hku.hk-
dc.identifier.emailKung, MHW: mhwkung@hkucc.hku.hk-
dc.identifier.emailHo, SL: slho@hku.hk-
dc.identifier.authorityHo, PWL=rp00259-
dc.identifier.authorityHo, SL=rp00240-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1080/15548627.2020.1850008-
dc.identifier.pmid33300446-
dc.identifier.pmcidPMC8526027-
dc.identifier.scopuseid_2-s2.0-85106799500-
dc.identifier.hkuros322972-
dc.identifier.volume17-
dc.identifier.issue10-
dc.identifier.spage3196-
dc.identifier.epage3220-
dc.identifier.isiWOS:000597378500001-
dc.publisher.placeUnited States-

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