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Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination

Dendritic spine injury underlies synaptic failure in many neurological disorders. Mounting evidence suggests a mitochondrial pathway of local nonapoptotic caspase signaling in mediating spine pruning. However, it remains unclear whether this caspase signaling plays a key role in spine loss when seve...

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Autores principales: Chen, Hao, Tian, Jing, Guo, Lan, Du, Heng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568535/
https://www.ncbi.nlm.nih.gov/pubmed/33067541
http://dx.doi.org/10.1038/s41598-020-74613-9
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author Chen, Hao
Tian, Jing
Guo, Lan
Du, Heng
author_facet Chen, Hao
Tian, Jing
Guo, Lan
Du, Heng
author_sort Chen, Hao
collection PubMed
description Dendritic spine injury underlies synaptic failure in many neurological disorders. Mounting evidence suggests a mitochondrial pathway of local nonapoptotic caspase signaling in mediating spine pruning. However, it remains unclear whether this caspase signaling plays a key role in spine loss when severe mitochondrial functional defects are present. The answer to this question is critical especially for some pathological states, in which mitochondrial deficits are prominent and difficult to fix. F1Fo ATP synthase is a pivotal mitochondrial enzyme and the dysfunction of this enzyme involves in diseases with spinopathy. Here, we inhibited F1Fo ATP synthase function in primary cultured hippocampal neurons by using non-lethal oligomycin A treatment. Oligomycin A induced mitochondrial defects including collapsed mitochondrial membrane potential, dissipated ATP production, and elevated reactive oxygen species (ROS) production. In addition, dendritic mitochondria underwent increased fragmentation and reduced positioning to dendritic spines along with increased caspase 3 cleavage in dendritic shaft and spines in response to oligomycin A. Concurring with these dendritic mitochondrial changes, oligomycin A-insulted neurons displayed spine loss and altered spine architecture. Such oligomycin A-mediated changes in dendritic spines were substantially prevented by the inhibition of caspase activation by using a pan-caspase inhibitor, quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh). Of note, the administration of Q-VD-OPh showed no protective effect on oligomycin A-induced mitochondrial dysfunction. Our findings suggest a pivotal role of caspase 3 signaling in mediating spine injury and the modulation of caspase 3 activation may benefit neurons from spine loss in diseases, at least, in those with F1Fo ATP synthase defects.
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spelling pubmed-75685352020-10-19 Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination Chen, Hao Tian, Jing Guo, Lan Du, Heng Sci Rep Article Dendritic spine injury underlies synaptic failure in many neurological disorders. Mounting evidence suggests a mitochondrial pathway of local nonapoptotic caspase signaling in mediating spine pruning. However, it remains unclear whether this caspase signaling plays a key role in spine loss when severe mitochondrial functional defects are present. The answer to this question is critical especially for some pathological states, in which mitochondrial deficits are prominent and difficult to fix. F1Fo ATP synthase is a pivotal mitochondrial enzyme and the dysfunction of this enzyme involves in diseases with spinopathy. Here, we inhibited F1Fo ATP synthase function in primary cultured hippocampal neurons by using non-lethal oligomycin A treatment. Oligomycin A induced mitochondrial defects including collapsed mitochondrial membrane potential, dissipated ATP production, and elevated reactive oxygen species (ROS) production. In addition, dendritic mitochondria underwent increased fragmentation and reduced positioning to dendritic spines along with increased caspase 3 cleavage in dendritic shaft and spines in response to oligomycin A. Concurring with these dendritic mitochondrial changes, oligomycin A-insulted neurons displayed spine loss and altered spine architecture. Such oligomycin A-mediated changes in dendritic spines were substantially prevented by the inhibition of caspase activation by using a pan-caspase inhibitor, quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh). Of note, the administration of Q-VD-OPh showed no protective effect on oligomycin A-induced mitochondrial dysfunction. Our findings suggest a pivotal role of caspase 3 signaling in mediating spine injury and the modulation of caspase 3 activation may benefit neurons from spine loss in diseases, at least, in those with F1Fo ATP synthase defects. Nature Publishing Group UK 2020-10-16 /pmc/articles/PMC7568535/ /pubmed/33067541 http://dx.doi.org/10.1038/s41598-020-74613-9 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Chen, Hao
Tian, Jing
Guo, Lan
Du, Heng
Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination
title Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination
title_full Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination
title_fullStr Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination
title_full_unstemmed Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination
title_short Caspase inhibition rescues F1Fo ATP synthase dysfunction-mediated dendritic spine elimination
title_sort caspase inhibition rescues f1fo atp synthase dysfunction-mediated dendritic spine elimination
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568535/
https://www.ncbi.nlm.nih.gov/pubmed/33067541
http://dx.doi.org/10.1038/s41598-020-74613-9
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