Protective mitochondrial fission induced by stress-responsive protein GJA1-20k

The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to in...

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Autores principales:	Daisuke Shimura, Esther Nuebel, Rachel Baum, Steven E Valdez, Shaohua Xiao, Junco S Warren, Joseph A Palatinus, TingTing Hong, Jared Rutter, Robin M Shaw
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	GJA1-20k mitochondria actin dynamics mitochondria dynamics ischemia/reperfusion organ protection Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/c3bc14cb68e44c329a4dd32fc8b22aec
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spelling	oai:doaj.org-article:c3bc14cb68e44c329a4dd32fc8b22aec2021-11-26T11:14:42ZProtective mitochondrial fission induced by stress-responsive protein GJA1-20k10.7554/eLife.692072050-084Xe69207https://doaj.org/article/c3bc14cb68e44c329a4dd32fc8b22aec2021-10-01T00:00:00Zhttps://elifesciences.org/articles/69207https://doaj.org/toc/2050-084XThe Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.Daisuke ShimuraEsther NuebelRachel BaumSteven E ValdezShaohua XiaoJunco S WarrenJoseph A PalatinusTingTing HongJared RutterRobin M ShaweLife Sciences Publications LtdarticleGJA1-20kmitochondriaactin dynamicsmitochondria dynamicsischemia/reperfusionorgan protectionMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	GJA1-20k mitochondria actin dynamics mitochondria dynamics ischemia/reperfusion organ protection Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	GJA1-20k mitochondria actin dynamics mitochondria dynamics ischemia/reperfusion organ protection Medicine R Science Q Biology (General) QH301-705.5 Daisuke Shimura Esther Nuebel Rachel Baum Steven E Valdez Shaohua Xiao Junco S Warren Joseph A Palatinus TingTing Hong Jared Rutter Robin M Shaw Protective mitochondrial fission induced by stress-responsive protein GJA1-20k
description	The Connexin43 gap junction gene GJA1 has one coding exon, but its mRNA undergoes internal translation to generate N-terminal truncated isoforms of Connexin43 with the predominant isoform being only 20 kDa in size (GJA1-20k). Endogenous GJA1-20k protein is not membrane bound and has been found to increase in response to ischemic stress, localize to mitochondria, and mimic ischemic preconditioning protection in the heart. However, it is not known how GJA1-20k benefits mitochondria to provide this protection. Here, using human cells and mice, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 s of GJA1-20k recruitment of actin. Interestingly, GJA1-20k mediated fission is independent of canonical Dynamin-Related Protein 1 (DRP1). We find that GJA1-20k-induced smaller mitochondria have decreased reactive oxygen species (ROS) generation and, in hearts, provide potent protection against ischemia-reperfusion injury. The results indicate that stress responsive internally translated GJA1-20k stabilizes polymerized actin filaments to stimulate non-canonical mitochondrial fission which limits ischemic-reperfusion induced myocardial infarction.
format	article
author	Daisuke Shimura Esther Nuebel Rachel Baum Steven E Valdez Shaohua Xiao Junco S Warren Joseph A Palatinus TingTing Hong Jared Rutter Robin M Shaw
author_facet	Daisuke Shimura Esther Nuebel Rachel Baum Steven E Valdez Shaohua Xiao Junco S Warren Joseph A Palatinus TingTing Hong Jared Rutter Robin M Shaw
author_sort	Daisuke Shimura
title	Protective mitochondrial fission induced by stress-responsive protein GJA1-20k
title_short	Protective mitochondrial fission induced by stress-responsive protein GJA1-20k
title_full	Protective mitochondrial fission induced by stress-responsive protein GJA1-20k
title_fullStr	Protective mitochondrial fission induced by stress-responsive protein GJA1-20k
title_full_unstemmed	Protective mitochondrial fission induced by stress-responsive protein GJA1-20k
title_sort	protective mitochondrial fission induced by stress-responsive protein gja1-20k
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/c3bc14cb68e44c329a4dd32fc8b22aec
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_version_	1718409559846944768

Protective mitochondrial fission induced by stress-responsive protein GJA1-20k

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