Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency.
Animals
Autophagy
Ceramides
/ metabolism
Drosophila Proteins
/ deficiency
Drosophila melanogaster
/ genetics
Fibroblasts
/ metabolism
Humans
Lipid Metabolism
Mice
Mice, Knockout
Mitophagy
/ genetics
Oxidation-Reduction
Oxidoreductases
/ antagonists & inhibitors
Parkinson Disease
/ genetics
Protein Kinases
/ deficiency
Protein Serine-Threonine Kinases
/ deficiency
PINK1
Parkinson’s disease
ceramide
mitochondria
β-oxidation
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
26 10 2021
26 10 2021
Historique:
accepted:
14
09
2021
entrez:
23
10
2021
pubmed:
24
10
2021
medline:
15
12
2021
Statut:
ppublish
Résumé
Energy production via the mitochondrial electron transport chain (ETC) and mitophagy are two important processes affected in Parkinson's disease (PD). Interestingly, PINK1, mutations of which cause early-onset PD, plays a key role in both processes, suggesting that these two mechanisms are connected. However, the converging link of both pathways currently remains enigmatic. Recent findings demonstrated that lipid aggregation, along with defective mitochondria, is present in postmortem brains of PD patients. In addition, an increasing body of evidence shows that sphingolipids, including ceramide, are altered in PD, supporting the importance of lipids in the pathophysiology of PD. Here, we identified ceramide to play a crucial role in PINK1-related PD that was previously linked almost exclusively to mitochondrial dysfunction. We found ceramide to accumulate in mitochondria and to negatively affect mitochondrial function, most notably the ETC. Lowering ceramide levels improved mitochondrial phenotypes in
Identifiants
pubmed: 34686591
pii: 2025347118
doi: 10.1073/pnas.2025347118
pmc: PMC8639384
pii:
doi:
Substances chimiques
Ceramides
0
Drosophila Proteins
0
Oxidoreductases
EC 1.-
dihydroceramide desaturase
EC 1.3.1.-
Protein Kinases
EC 2.7.-
PINK1 protein, Drosophila
EC 2.7.11.1
PTEN-induced putative kinase
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: C.K. serves as medical consultant to Centogene for genetic testing in the field of movement disorders and dementia excluding Parkinson’s disease.
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