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      GJA1-20k and Mitochondrial Dynamics

      review-article
      , * ,
      Frontiers in Physiology
      Frontiers Media S.A.
      GJA1-20k, connexin43, mitochondria, ischemia, trafficking, actin

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          Abstract

          Connexin 43 (Cx43) is the primary gap junction protein of mammalian heart ventricles and is encoded by the gene Gja1 which has a single coding exon and therefore cannot be spliced. We previously identified that Gja1 mRNA undergoes endogenous internal translation initiated at one of several internal AUG (M) start codons, generating N-terminal truncated protein isoforms that retain the C-terminus distal to the start site. GJA1-20k, whose translation initiates at mRNA M213, is usually the most abundant isoform in cells and greatly increases after ischemic and metabolic stress. GJA1-20k consists of a small segment of the last transmembrane domain and the complete C-terminus tail of Cx43, with a total size of about 20 kDa. The original role identified for GJA1-20k is as an essential subunit that facilitates the trafficking of full-length Cx43 hexameric hemichannels to cell-cell contacts, generating traditional gap junctions between adjacent cells facilitating, in cardiac muscle, efficient spread of electrical excitation. GJA1-20k deficient mice (generated by a M213L substitution in Gja1) suffer poor electrical coupling between cardiomycytes and arrhythmogenic sudden death two to 4 weeks after their birth. We recently identified that exogenous GJA1-20k expression also mimics the effect of ischemic preconditioning in mouse heart. Furthermore, GJA1-20k localizes to the mitochondrial outer membrane and induces a protective and DRP1 independent form of mitochondrial fission, preserving ATP production and generating less reactive oxygen species (ROS) under metabolic stress, providing powerful protection of myocardium to ischemic insult. In this manuscript, we focus on the detailed roles of GJA1-20k in mitochondria, and its interaction with the actin cytoskeleton.

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          Most cited references76

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          Mitochondrial fission, fusion, and stress.

          Mitochondrial fission and fusion play critical roles in maintaining functional mitochondria when cells experience metabolic or environmental stresses. Fusion helps mitigate stress by mixing the contents of partially damaged mitochondria as a form of complementation. Fission is needed to create new mitochondria, but it also contributes to quality control by enabling the removal of damaged mitochondria and can facilitate apoptosis during high levels of cellular stress. Disruptions in these processes affect normal development, and they have been implicated in neurodegenerative diseases, such as Parkinson's.
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            Mitochondrial form and function.

            Mitochondria are one of the major ancient endomembrane systems in eukaryotic cells. Owing to their ability to produce ATP through respiration, they became a driving force in evolution. As an essential step in the process of eukaryotic evolution, the size of the mitochondrial chromosome was drastically reduced, and the behaviour of mitochondria within eukaryotic cells radically changed. Recent advances have revealed how the organelle's behaviour has evolved to allow the accurate transmission of its genome and to become responsive to the needs of the cell and its own dysfunction.
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              Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium.

              Circulation, 74(5), 1124-1136
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                23 March 2022
                2022
                : 13
                : 867358
                Affiliations
                Nora Eccles Harrison Cardiovascular Research and Training Institute , University of Utah , Salt Lake City, UT, United States
                Author notes

                Edited by: Henrique Girao, University of Coimbra, Portugal

                Reviewed by: Eric C. Beyer, University of Chicago, United States

                Tania Martins-Marques, University of Coimbra, Portugal

                *Correspondence: Robin M. Shaw, Robin.Shaw@ 123456hsc.utah.edu

                This article was submitted to Vascular Physiology, a section of the journal Frontiers in Physiology

                Article
                867358
                10.3389/fphys.2022.867358
                8983841
                35399255
                46e6943a-3c59-4769-bb2e-9ef0934bc69a
                Copyright © 2022 Shimura and Shaw.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 01 February 2022
                : 08 March 2022
                Funding
                Funded by: National Heart, Lung, and Blood Institute , doi 10.13039/100000050;
                Award ID: R01HL152691 R01HL138577 R01HL159983
                Categories
                Physiology
                Review

                Anatomy & Physiology
                gja1-20k,connexin43,mitochondria,ischemia,trafficking,actin
                Anatomy & Physiology
                gja1-20k, connexin43, mitochondria, ischemia, trafficking, actin

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