%A Fu,Ying %A Zhang,Shan-Shan %A Xiao,Shaohua %A Basheer,Wassim A. %A Baum,Rachel %A Epifantseva,Irina %A Hong,TingTing %A Shaw,Robin M. %D 2017 %J Frontiers in Physiology %C %F %G English %K Gap junction protein,Cx43,Alternative translation,Mitochondria,Microtubules,Oxidative Stress %Q %R 10.3389/fphys.2017.00905 %W %L %M %P %7 %8 2017-November-07 %9 Original Research %+ Robin M. Shaw,Cedars-Sinai Medical Center, Cedars-Sinai Heart Institute,United States,robin.shaw@hsc.utah.edu %+ Robin M. Shaw,Department of Medicine, University of California,United States,robin.shaw@hsc.utah.edu %# %! GJA1-20k facilitates mitochondrial movement %* %< %T Cx43 Isoform GJA1-20k Promotes Microtubule Dependent Mitochondrial Transport %U https://www.frontiersin.org/articles/10.3389/fphys.2017.00905 %V 8 %0 JOURNAL ARTICLE %@ 1664-042X %X Connexin 43 (Cx43, encoded by GJA1) is a cell-cell communication gap junction protein expressed in all organ systems. It was recently found that GJA1 mRNA undergoes alternative translation to generate N-terminal truncated isoforms, of which GJA1-20k is the most abundant. Here we report a surprising finding that, unlike full length GJA1-43k, GJA1-20k has a strong tropism for mitochondria. Exploring function, we found that GJA1-20k appears to be an organelle chaperone and that overexpression of GJA1-20k is sufficient to rescue mitochondrial localization to the cell periphery upon exposure to hydrogen peroxide, which effectively limits the network fragmentation that occurs with oxidative stress. By high-resolution fluorescent imaging and electron microscopy, we determined that GJA1-20k is enriched at the interface between mitochondria and microtubules, appearing to load organelles for transport. Mutagenesis experiments revealed that although the microtubule-binding domain (MTBD) in GJA1-20k is not necessary for protein localization to mitochondria, the MTBD is essential for GJA1-20k to facilitate mitochondrial transport and maintain mitochondrial localization at the periphery. These results reveal an unexpected role for the alternatively translated isoform of the Cx43 gap junction protein, GJA1-20k, which is to facilitate microtubule-based mitochondrial transport and to maintain mitochondrial network integrity during cellular stress.