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Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons
Mitophagy, the selective removal of damaged mitochondria, is thought to be critical to maintain neuronal homeostasis. Mutations of proteins in the pathway cause neurodegenerative diseases, suggesting defective mitochondrial turnover contributes to neurodegeneration. In primary rat hippocampal neuron...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959996/ https://www.ncbi.nlm.nih.gov/pubmed/31934852 http://dx.doi.org/10.7554/eLife.50260 |
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author | Evans, Chantell S Holzbaur, Erika LF |
author_facet | Evans, Chantell S Holzbaur, Erika LF |
author_sort | Evans, Chantell S |
collection | PubMed |
description | Mitophagy, the selective removal of damaged mitochondria, is thought to be critical to maintain neuronal homeostasis. Mutations of proteins in the pathway cause neurodegenerative diseases, suggesting defective mitochondrial turnover contributes to neurodegeneration. In primary rat hippocampal neurons, we developed a mitophagy induction paradigm where mild oxidative stress induced low levels of mitochondrial damage. Mitophagy-associated proteins were sequentially recruited to depolarized mitochondria followed by sequestration into autophagosomes. The localization of these mitophagy events had a robust somal bias. In basal and induced conditions, engulfed mitochondria remained in non-acidified organelles for hours to days, illustrating efficient autophagosome sequestration but delayed lysosomal fusion or acidification. Furthermore, expression of an ALS-linked mutation in the pathway disrupted mitochondrial network integrity and this effect was exacerbated by oxidative stress. Thus, age-related decline in neuronal health or expression of disease-associated mutations in the pathway may exacerbate the slow kinetics of neuronal mitophagy, leading to neurodegeneration. |
format | Online Article Text |
id | pubmed-6959996 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-69599962020-01-16 Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons Evans, Chantell S Holzbaur, Erika LF eLife Cell Biology Mitophagy, the selective removal of damaged mitochondria, is thought to be critical to maintain neuronal homeostasis. Mutations of proteins in the pathway cause neurodegenerative diseases, suggesting defective mitochondrial turnover contributes to neurodegeneration. In primary rat hippocampal neurons, we developed a mitophagy induction paradigm where mild oxidative stress induced low levels of mitochondrial damage. Mitophagy-associated proteins were sequentially recruited to depolarized mitochondria followed by sequestration into autophagosomes. The localization of these mitophagy events had a robust somal bias. In basal and induced conditions, engulfed mitochondria remained in non-acidified organelles for hours to days, illustrating efficient autophagosome sequestration but delayed lysosomal fusion or acidification. Furthermore, expression of an ALS-linked mutation in the pathway disrupted mitochondrial network integrity and this effect was exacerbated by oxidative stress. Thus, age-related decline in neuronal health or expression of disease-associated mutations in the pathway may exacerbate the slow kinetics of neuronal mitophagy, leading to neurodegeneration. eLife Sciences Publications, Ltd 2020-01-14 /pmc/articles/PMC6959996/ /pubmed/31934852 http://dx.doi.org/10.7554/eLife.50260 Text en © 2020, Evans and Holzbaur http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Evans, Chantell S Holzbaur, Erika LF Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons |
title | Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons |
title_full | Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons |
title_fullStr | Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons |
title_full_unstemmed | Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons |
title_short | Degradation of engulfed mitochondria is rate-limiting in Optineurin-mediated mitophagy in neurons |
title_sort | degradation of engulfed mitochondria is rate-limiting in optineurin-mediated mitophagy in neurons |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959996/ https://www.ncbi.nlm.nih.gov/pubmed/31934852 http://dx.doi.org/10.7554/eLife.50260 |
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