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Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity
Mitochondrial dysfunction is implicated in the pathogenesis of multiple neurological diseases, but elucidation of underlying mechanisms is limited experimentally by the inability to damage specific mitochondria in defined neuronal groups. We developed a precision chemoptogenetic approach to target n...
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/PMC7077989/ https://www.ncbi.nlm.nih.gov/pubmed/32180546 http://dx.doi.org/10.7554/eLife.51845 |
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author | Xie, Wenting Jiao, Binxuan Bai, Qing Ilin, Vladimir A Sun, Ming Burton, Charles E Kolodieznyi, Dmytro Calderon, Michael J Stolz, Donna B Opresko, Patricia L St Croix, Claudette M Watkins, Simon Van Houten, Bennett Bruchez, Marcel P Burton, Edward A |
author_facet | Xie, Wenting Jiao, Binxuan Bai, Qing Ilin, Vladimir A Sun, Ming Burton, Charles E Kolodieznyi, Dmytro Calderon, Michael J Stolz, Donna B Opresko, Patricia L St Croix, Claudette M Watkins, Simon Van Houten, Bennett Bruchez, Marcel P Burton, Edward A |
author_sort | Xie, Wenting |
collection | PubMed |
description | Mitochondrial dysfunction is implicated in the pathogenesis of multiple neurological diseases, but elucidation of underlying mechanisms is limited experimentally by the inability to damage specific mitochondria in defined neuronal groups. We developed a precision chemoptogenetic approach to target neuronal mitochondria in the intact nervous system in vivo. MG2I, a chemical fluorogen, produces singlet oxygen when bound to the fluorogen-activating protein dL5** and exposed to far-red light. Transgenic zebrafish expressing dL5** within neuronal mitochondria showed dramatic MG2I- and light-dependent neurobehavioral deficits, caused by neuronal bioenergetic crisis and acute neuronal depolarization. These abnormalities resulted from loss of neuronal respiration, associated with mitochondrial fragmentation, swelling and elimination of cristae. Remaining cellular ultrastructure was preserved initially, but cellular pathology downstream of mitochondrial damage eventually culminated in neuronal death. Our work provides powerful new chemoptogenetic tools for investigating mitochondrial homeostasis and pathophysiology and shows a direct relationship between mitochondrial function, neuronal biogenetics and whole-animal behavior. |
format | Online Article Text |
id | pubmed-7077989 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-70779892020-03-19 Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity Xie, Wenting Jiao, Binxuan Bai, Qing Ilin, Vladimir A Sun, Ming Burton, Charles E Kolodieznyi, Dmytro Calderon, Michael J Stolz, Donna B Opresko, Patricia L St Croix, Claudette M Watkins, Simon Van Houten, Bennett Bruchez, Marcel P Burton, Edward A eLife Biochemistry and Chemical Biology Mitochondrial dysfunction is implicated in the pathogenesis of multiple neurological diseases, but elucidation of underlying mechanisms is limited experimentally by the inability to damage specific mitochondria in defined neuronal groups. We developed a precision chemoptogenetic approach to target neuronal mitochondria in the intact nervous system in vivo. MG2I, a chemical fluorogen, produces singlet oxygen when bound to the fluorogen-activating protein dL5** and exposed to far-red light. Transgenic zebrafish expressing dL5** within neuronal mitochondria showed dramatic MG2I- and light-dependent neurobehavioral deficits, caused by neuronal bioenergetic crisis and acute neuronal depolarization. These abnormalities resulted from loss of neuronal respiration, associated with mitochondrial fragmentation, swelling and elimination of cristae. Remaining cellular ultrastructure was preserved initially, but cellular pathology downstream of mitochondrial damage eventually culminated in neuronal death. Our work provides powerful new chemoptogenetic tools for investigating mitochondrial homeostasis and pathophysiology and shows a direct relationship between mitochondrial function, neuronal biogenetics and whole-animal behavior. eLife Sciences Publications, Ltd 2020-03-17 /pmc/articles/PMC7077989/ /pubmed/32180546 http://dx.doi.org/10.7554/eLife.51845 Text en http://creativecommons.org/publicdomain/zero/1.0/ http://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (http://creativecommons.org/publicdomain/zero/1.0/) . |
spellingShingle | Biochemistry and Chemical Biology Xie, Wenting Jiao, Binxuan Bai, Qing Ilin, Vladimir A Sun, Ming Burton, Charles E Kolodieznyi, Dmytro Calderon, Michael J Stolz, Donna B Opresko, Patricia L St Croix, Claudette M Watkins, Simon Van Houten, Bennett Bruchez, Marcel P Burton, Edward A Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity |
title | Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity |
title_full | Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity |
title_fullStr | Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity |
title_full_unstemmed | Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity |
title_short | Chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity |
title_sort | chemoptogenetic ablation of neuronal mitochondria in vivo with spatiotemporal precision and controllable severity |
topic | Biochemistry and Chemical Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077989/ https://www.ncbi.nlm.nih.gov/pubmed/32180546 http://dx.doi.org/10.7554/eLife.51845 |
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