Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
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
_version_ 1784609134906179584
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
work_keys_str_mv AT vosmelissa ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT dulovicmahlowmarija ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT mandikfrida ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT freselisa ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT kananayuliia ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT haissatoudiawsokhna ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT depperschmidtjulia ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT bohmclaudia ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT rohrjonas ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT lohnauthora ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT koniginker ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency
AT kleinchristine ceramideaccumulationinducesmitophagyandimpairsboxidationinpink1deficiency