Stress response protein GJA1-20k promotes mitochondrial biogenesis, metabolic quiescence, and cardioprotection against ischemia/reperfusion injury

Basheer, Wassim A.; Fu, Ying; Shimura, Daisuke; Xiao, Shaohua; Agvanian, Sosse; Hernandez, Diana; Hitzeman, Tara C.; Hong, TingTing; Shaw, Robin M.

doi:10.1172/jci.insight.121900

Cited by 70 publications

(119 citation statements)

References 74 publications

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“…It is also known as chaperone protein. It appears in Golgi apparatus earlier than GJA1‐Full Length (Basheer et al, ; Basheer & Shaw, ), and has obvious mitochondrial properties (Basheer, Fu, Shimura, et al, ). So we speculate that GJA1‐20 k may involve in the process of transporting functional GJA1 to the mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Astrocytes‐derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1‐20 k

Chen

Zheng

Hong

et al. 2020

J Tissue Eng Regen Med

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Astrocytes are more resistant to ischemia and hypoxia in the acute phase of brain injury after traumatic brain injury (TBI). Previous study showed that gap junction alpha 1 (GJA1) phosphorylation can increase the survival of damaged astrocytes. The GJA1‐20 k expression in neurons co‐culture with astrocytes was positively correlated with exosomes uptake. This study aims to explore the effect of exogenous GJA1‐20 k carried by astrocyte‐derived exosomes on neurons apoptosis and mitochondrial function after TBI. Astrocytes were co‐cultured with the neuron with/without damage from air pressure. Exosomes were isolated, extracted from the culture medium by differential ultra‐centrifugation, and verified by electron microscopy. Immunofluorescence staining, tunnel, western blot were employed to detect exosomes marker CD60, apoptosis, and mitochondrial function related protein expression and GJA1‐20 k in cell culture. A rat model of hydraulic injury TBI was built, and exosomes was transferred. 2,3,5‐Triphenyltetrazolium chloride (TTC) staining and immunohistochemistry staining of Nissl and microtubule associated protein 2 were used to detect the brain damage. A transwell stereo culture model of astrocytes and TBI‐like injured neuron was constructed. The exosomes derived from astrocytes promoted the recovery of damaged neuron by in vitro exosome treatment. Compared with GJA1‐20 k knockout exosome control group, GJA1‐20 k exosomes were uptaken by neuron and downregulated the apoptosis rate and upregulated mitochondrial function to promote neuronal recovery. Finally, the results were validated by TTC staining and damaged tissue sections of rat TBI model. This study contributes to a better understanding of the astrocyte‐neuron protection mechanism in TBI and provides a potential new target for the treatment of TBI.

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Section: Introductionmentioning

confidence: 99%

Astrocytes‐derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1‐20 k

Chen

Zheng

Hong

et al. 2020

J Tissue Eng Regen Med

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“…Autoregulation of full-length counterparts in facilitation of trafficking or ion channel function by internal translation products is just one facet of how this may impact disease. This is highlighted through the ability of GJA1-20k to 'moonlight' in regulation at the mitochondria [109,124], and that both GJA1-20k and the cleaved Ca V 1.2 C-terminus can impact transcription [125,126]. Regarding regulation, our findings on dynamic GJA1 mRNA UTR usage discussed above are unlikely relevant to just one gene, and it is our hope that they will inform studies identifying global shunting of translation through similar mechanisms across many mRNAs impacting cardiac function.…”

Section: Translation As a Regulator Of Cardiac Ion Channel Functionmentioning

confidence: 88%

“…Exogenous gene delivery of GJA1-20k to hearts prior to no flow ischemia maintains Cx43 localization at intercalated discs [110]. Using this model, it was demonstrated that GJA1-20k could also protect against damage from ischemia/reperfusion [109]. We recently found that chronic hypoxic stress in mouse and human cell lines, as well as human iPSC derived cardiomyocytes (HiPSC-CMs), reduces levels of GJA1-20k, and this is correlated with a reduction in Cx43 gap junction formation [93].…”

Section: Altered Connexin43 Protein Translation In Heart Diseasementioning

confidence: 96%

“…Alternative translation of GJA1 is also affected by cellular stress such as hypoxia/ischemia, and elevated levels of the MAPKs p38 and ERK [93]. An increase in GJA1-20k is observed in brain and heart tissue subject to ischemia [106,109]. In the heart, ischemia leads to a reduction in Cx43 levels at the intercalated disc.…”

Section: Altered Connexin43 Protein Translation In Heart Diseasementioning

confidence: 99%

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Translating Translation to Mechanisms of Cardiac Hypertrophy

Zeitz

Smyth

2020

JCDD

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Cardiac hypertrophy in response to chronic pathological stress is a common feature occurring with many forms of heart disease. This pathological hypertrophic growth increases the risk for arrhythmias and subsequent heart failure. While several factors promoting cardiac hypertrophy are known, the molecular mechanisms governing the progression to heart failure are incompletely understood. Recent studies on altered translational regulation during pathological cardiac hypertrophy are contributing to our understanding of disease progression. In this brief review, we describe how the translational machinery is modulated for enhanced global and transcript selective protein synthesis, and how alternative modes of translation contribute to the disease state. Attempts at controlling translational output through targeting of mTOR and its regulatory components are detailed, as well as recently emerging targets for pre-clinical investigation.

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“…The GJA1 protein is an element of the gap junctions, providing an intercellular diffusion path for low molecular weight molecules. The coded protein plays a key role in the synchronization of cardiac contractions and embryonic development through the formation of connections in the heart [21]. Bidirectional intracellular communication between oocytes and cumulus cells is crucial for the proper oocyte maturation [22].…”

Section: Discussionmentioning

confidence: 99%

Protein oligomerization is the biochemical process highly up-regulated in porcine oocytes before in vitro maturation (IVM)

Borys-Wójcik

Kocherova

Celichowski

et al. 2018

Medical Journal of Cell Biology

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A wide variety of mechanisms controlling oligomerization are observed. The dynamic nature of protein oligomerization is important for bioactivity control. The oocyte must undergo a series of changes to become a mature form before it can fully participate in the processes associated with its function as a female gamete. The growth of oocytes in the follicular environment is accompanied by surrounding somatic cumulus (CCs) and granulosa cells (GCs). It has been shown that oocytes tested before and after in vitro maturation (IVM) differ significantly in the transcriptomic and proteomic profiles. The aim of this study was to determine new proteomic markers for the oligomerization of porcine oocyte proteins that are associated with cell maturation competence. The Affymetrix microarray assay was performed to examine the gene expression profile associated with protein oligomerization in oocytes before and after IVM. In total, 12258 different transcriptomes were analyzed, of which 419 genes with lower expression in oocytes after IVM. We found 9 genes: GJA1, VCP, JUP, MIF, MAP3K1, INSR, ANGPTL4, EIF2AK3, DECR1, which were significantly down-regulated in oocytes after IVM (in vitro group) compared to oocytes analyzed before IVM (in vivo group). The higher expression of genes involved in the oligomerization of the protein before IVM indicates that they can be recognized as important markers of biological activation of proteins necessary for the further growth and development of pig embryos.

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Stress response protein GJA1-20k promotes mitochondrial biogenesis, metabolic quiescence, and cardioprotection against ischemia/reperfusion injury

Cited by 70 publications

References 74 publications

Astrocytes‐derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1‐20 k

Astrocytes‐derived exosomes induce neuronal recovery after traumatic brain injury via delivering gap junction alpha 1‐20 k

Translating Translation to Mechanisms of Cardiac Hypertrophy

Protein oligomerization is the biochemical process highly up-regulated in porcine oocytes before in vitro maturation (IVM)

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