GJA1-20k attenuates Ang II-induced pathological cardiac hypertrophy by regulating gap junction formation and mitochondrial function

Fu, Yile; Tao, Liang; Peng, Fuhua; Zheng, Ningze; Q, Lin; Cai, Shaoyi; Wang, Qin

doi:10.1038/s41401-020-0459-6

Cited by 25 publications

(16 citation statements)

References 59 publications

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“…It is possible that the reason a central mediator of preconditioning has not been determined is that it has not been available for study. GJA1-20k was only first reported to occur endogenously in 2013 ( Smyth and Shaw, 2013 ) and its association with mitochondria and potential beneficial effects for survival of I/R was reported in the last 3 years ( Fu et al, 2017 ; Basheer et al, 2018 ; Wang et al, 2019 ; Fu et al, 2020 ; Ren et al, 2020 ). As a smaller isoform of Cx43 that contains the epitope of most anti-Cx43 antibodies, and is localized to mitochondria ( Fu et al, 2017 ), GJA1-20k could be central to the studies that implicated Cx43 as a mediator of preconditioning.…”

Section: Discussionmentioning

confidence: 99%

“…Endogenous induction of GJA1-20k may also explain other instances when smaller mitochondrial size correlates with a beneficial effect ( Coronado et al, 2018 ). Recent studies have identified that exogenous GJA1-20k can protect neurons subjected to traumatic brain injury ( Ren et al, 2020 ), hearts from ischemia ( Basheer et al, 2018 ) and angiotensin induced hypertrophy ( Fu et al, 2020 ). Furthermore, by mimicking the protection afforded by ischemic preconditioning, exogenous GJA1-20k is a promising therapeutic to protect hearts, brains and other organs against expected ischemic damage.…”

Section: Discussionmentioning

confidence: 99%

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

Shimura

Nuebel

Baum

et al. 2021

eLife

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Shimura

Nuebel

Baum

et al. 2021

eLife

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“…Inhibition of mTOR signaling increases expression of GJA1-20k via inhibition of capdependent protein translation to facilitate trafficking of the full-length isoform to the cell membrane [276]. GJA1-20k overexpression increases formation of Cx43 gap junctions, enhances mitochondrial biogenesis, and reduces ROS levels despite increased mitochondrial membrane potential and increased oxygen consumption in angiotensin II-induced cardiomyocyte hypertrophy [281]. Mitochondrial Cx43 can inhibit mPTP opening, which reduces ROS release [282].…”

Section: Connexin 43mentioning

confidence: 99%

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

Garbern

Lee

2021

Stem Cell Res Ther

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Current methods to differentiate cardiomyocytes from human pluripotent stem cells (PSCs) inadequately recapitulate complete development and result in PSC-derived cardiomyocytes (PSC-CMs) with an immature or fetal-like phenotype. Embryonic and fetal development are highly dynamic periods during which the developing embryo or fetus is exposed to changing nutrient, oxygen, and hormone levels until birth. It is becoming increasingly apparent that these metabolic changes initiate developmental processes to mature cardiomyocytes. Mitochondria are central to these changes, responding to these metabolic changes and transitioning from small, fragmented mitochondria to large organelles capable of producing enough ATP to support the contractile function of the heart. These changes in mitochondria may not simply be a response to cardiomyocyte maturation; the metabolic signals that occur throughout development may actually be central to the maturation process in cardiomyocytes. Here, we review methods to enhance maturation of PSC-CMs and highlight evidence from development indicating the key roles that mitochondria play during cardiomyocyte maturation. We evaluate metabolic transitions that occur during development and how these affect molecular nutrient sensors, discuss how regulation of nutrient sensing pathways affect mitochondrial dynamics and function, and explore how changes in mitochondrial function can affect metabolite production, the cell cycle, and epigenetics to influence maturation of cardiomyocytes.

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“…It is possible that the reason a central mediator of preconditioning has not been determined is that it has not been available for study. GJA1-20k was first reported to occur endogenously in 2013 (Smyth and Shaw, 2013) and its association with mitochondria and potential beneficial effects for survival of I/R was only reported in the last three years (Fu et al, 2017, Basheer et al, 2018, Fu et al, 2020, Ren et al, 2020, Wang et al, 2019. As a smaller isoform of Cx43 that contains the epitope of most anti-Cx43 antibodies, and is localized to mitochondria (Fu et al, 2017), GJA1-20k could be central to the studies that implicated Cx43 as a mediator of preconditioning.…”

Section: Discussionmentioning

confidence: 99%

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

Shimura

Nuebel

Baum

et al. 2021

Preprint

View full text Add to dashboard Cite

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, we identify that GJA1-20k polymerizes actin around mitochondria which induces focal constriction sites. Mitochondrial fission events occur within about 45 seconds 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.

show abstract

GJA1-20k attenuates Ang II-induced pathological cardiac hypertrophy by regulating gap junction formation and mitochondrial function

Cited by 25 publications

References 59 publications

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

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

Mitochondria and metabolic transitions in cardiomyocytes: lessons from development for stem cell-derived cardiomyocytes

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

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