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Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency
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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639384/ https://www.ncbi.nlm.nih.gov/pubmed/34686591 http://dx.doi.org/10.1073/pnas.2025347118 |
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author | Vos, Melissa Dulovic-Mahlow, Marija Mandik, Frida Frese, Lisa Kanana, Yuliia Haissatou Diaw, Sokhna Depperschmidt, Julia Böhm, Claudia Rohr, Jonas Lohnau, Thora König, Inke R. Klein, Christine |
author_facet | Vos, Melissa Dulovic-Mahlow, Marija Mandik, Frida Frese, Lisa Kanana, Yuliia Haissatou Diaw, Sokhna Depperschmidt, Julia Böhm, Claudia Rohr, Jonas Lohnau, Thora König, Inke R. Klein, Christine |
author_sort | Vos, Melissa |
collection | PubMed |
description | 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 pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD. |
format | Online Article Text |
id | pubmed-8639384 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-86393842021-12-12 Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency Vos, Melissa Dulovic-Mahlow, Marija Mandik, Frida Frese, Lisa Kanana, Yuliia Haissatou Diaw, Sokhna Depperschmidt, Julia Böhm, Claudia Rohr, Jonas Lohnau, Thora König, Inke R. Klein, Christine Proc Natl Acad Sci U S A Biological Sciences 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 pink1-mutant flies and PINK1-deficient patient-derived fibroblasts, showing that the effects of ceramide are evolutionarily conserved. In addition, ceramide accumulation provoked ceramide-induced mitophagy upon PINK1 deficiency. As a result of the ceramide accumulation, β-oxidation in PINK1 mutants was decreased, which was rescued by lowering ceramide levels. Furthermore, stimulation of β-oxidation was sufficient to rescue PINK1-deficient phenotypes. In conclusion, we discovered a cellular mechanism resulting from PD-causing loss of PINK1 and found a protective role of β-oxidation in ETC dysfunction, thus linking lipids and mitochondria in the pathophysiology of PINK1-related PD. Furthermore, our data nominate β-oxidation and ceramide as therapeutic targets for PD. National Academy of Sciences 2021-10-22 2021-10-26 /pmc/articles/PMC8639384/ /pubmed/34686591 http://dx.doi.org/10.1073/pnas.2025347118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Vos, Melissa Dulovic-Mahlow, Marija Mandik, Frida Frese, Lisa Kanana, Yuliia Haissatou Diaw, Sokhna Depperschmidt, Julia Böhm, Claudia Rohr, Jonas Lohnau, Thora König, Inke R. Klein, Christine Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency |
title | Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency |
title_full | Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency |
title_fullStr | Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency |
title_full_unstemmed | Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency |
title_short | Ceramide accumulation induces mitophagy and impairs β-oxidation in PINK1 deficiency |
title_sort | ceramide accumulation induces mitophagy and impairs β-oxidation in pink1 deficiency |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8639384/ https://www.ncbi.nlm.nih.gov/pubmed/34686591 http://dx.doi.org/10.1073/pnas.2025347118 |
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