Document Detail


Mitochondrial metabolism in Parkinson's disease impairs quality control autophagy by hampering microtubule-dependent traffic.
MedLine Citation:
PMID:  22843496     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Abnormal presence of autophagic vacuoles is evident in brains of patients with Parkinson's disease (PD), in contrast to the rare detection of autophagosomes in a normal brain. However, the actual cause and pathological significance of these observations remain unknown. Here, we demonstrate a role for mitochondrial metabolism in the regulation of the autophagy-lysosomal pathway in ex vivo and in vitro models of PD. We show that transferring mitochondria from PD patients into cells previously depleted of mitochondrial DNA is sufficient to reproduce the alterations in the autophagic system observed in PD patient brains. Although the initial steps of this pathway are not compromised, there is an increased accumulation of autophagosomes associated with a defective autophagic activity. We prove that this functional decline was originated from a deficient mobilization of autophagosomes from their site of formation toward lysosomes due to disruption in microtubule-dependent trafficking. This contributed directly to a decreased proteolytic flux of α-synuclein and other autophagic substrates. Our results lend strong support for a direct impact of mitochondria in autophagy as defective autophagic clearance ability secondary to impaired microtubule trafficking is driven by dysfunctional mitochondria. We uncover mitochondria and mitochondria-dependent intracellular traffic as main players in the regulation of autophagy in PD.
Authors:
Daniela M Arduíno; A Raquel Esteves; Luísa Cortes; Diana F Silva; Bindi Patel; Manuela Grazina; Russell H Swerdlow; Catarina R Oliveira; Sandra M Cardoso
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-07-27
Journal Detail:
Title:  Human molecular genetics     Volume:  21     ISSN:  1460-2083     ISO Abbreviation:  Hum. Mol. Genet.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-16     Completed Date:  2013-04-03     Revised Date:  2013-07-12    
Medline Journal Info:
Nlm Unique ID:  9208958     Medline TA:  Hum Mol Genet     Country:  England    
Other Details:
Languages:  eng     Pagination:  4680-702     Citation Subset:  IM    
Affiliation:
CNC – Center for Neuroscience and Cell Biology, Institute of Biology, University of Coimbra, Coimbra, Portugal.
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MeSH Terms
Descriptor/Qualifier:
Aged
Autophagy / physiology
Brain / metabolism,  physiopathology
Cell Differentiation
Cells, Cultured
DNA, Mitochondrial / genetics
Humans
Lysosomes / metabolism*,  pathology
Microtubules / metabolism*,  pathology
Middle Aged
Mitochondria / metabolism*,  pathology
Neurons / cytology,  metabolism,  pathology
Parkinson Disease* / metabolism,  physiopathology
Protein Transport
Signal Transduction
Vacuoles / metabolism,  pathology
alpha-Synuclein / chemistry,  metabolism
Grant Support
ID/Acronym/Agency:
AG038072/AG/NIA NIH HHS; P30 AG035982/AG/NIA NIH HHS; P30AG035982/AG/NIA NIH HHS
Chemical
Reg. No./Substance:
0/DNA, Mitochondrial; 0/SNCA protein, human; 0/alpha-Synuclein
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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