Interplay Between Cytosolic Free Zn2+ and Mitochondrion Morphological Changes in Rat Ventricular Cardiomyocytes

BİLLUR D., Tuncay E., Okatan E. N., OLĞAR Y., DURAK BATIGÜN A., DEĞİRMENCİ S., ...More

BIOLOGICAL TRACE ELEMENT RESEARCH, vol.174, no.1, pp.177-188, 2016 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 174 Issue: 1
  • Publication Date: 2016
  • Doi Number: 10.1007/s12011-016-0704-5
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.177-188
  • Eskisehir Osmangazi University Affiliated: No


The Zn2+ in cardiomyocytes is buffered by structures near T-tubulus and/or sarcoplasmic/endoplasmic reticulum (S(E)R) while playing roles as either an antioxidant or a toxic agent, depending on the concentration. Therefore, we aimed first to examine a direct effect of ZnPO4 (extracellular exposure) or Zn2+ pyrithione (ZnPT) (intracellular exposure) application on the structure of the mitochondrion in ventricular cardiomyocytes by using histological investigations. The light microscopy data demonstrated that Zn2+ exposure induced marked increases on cellular surface area, an indication of hypertrophy, in a concentration-dependent manner. Furthermore, a whole-cell patch-clamp measurement of cell capacitance also supported the hypertrophy in the cells. We observed marked increases in mitochondrial matrix/cristae area and matrix volume together with increased lysosome numbers in ZnPO4- or ZnPT-incubated cells by using transmission electron microscopy, again in a concentration-dependent manner. Furthermore, we observed notable clustering and vacuolated mitochondrion, markedly disrupted and damaged myofibrils, and electron-dense small granules in Zn2+-exposed cells together with some implications of fission-fusion defects in the mitochondria. Moreover, we observed marked depolarization in mitochondrial membrane potential during 1-mu M ZnPT minute applications by using confocal microscopy. We also showed that 1-mu M ZnPT incubation induced significant increases in the phosphorylation levels of GSK3 beta (Ser21 and Ser9), Akt (Ser473), and NF kappa B (Ser276 and Thr254) together with increased expression levels in ER stress proteins such as GRP78 and calregulin. Furthermore, a new key player at ER-mitochondria sites, promyelocytic leukemia protein (PML) level, was markedly increased in ZnPT-incubated cells. As a summary, our present data suggest that increased cytosolic free Zn2+ can induce marked alterations in mitochondrion morphology as well as depolarization in mitochondrion membrane potential and changes in some cytosolic signaling proteins as well as a defect in ER-mitochondria cross talk.