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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
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.
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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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