Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca² uptake through the mitochondrial ryanodine receptor in cardiacmyocytes.

Seidlmayer, Lea K.; Kuhn, Johannes; Berbner, Annette; Arias-Loza, Paula-Anahi; Williams, Tatjana; Kaspar, Mathias; Czolbe, Martin; Kwong, Jennifer Q.; Molkentin, Jeffery D.; Heinze, Katrin Gertrud; Dedkova, Elena N.; Ritter, Oliver

Aims Elevated levels of inositol 1,4,5-trisphosphate (IP3) in adult cardiac myocytes are typically associated with the development of cardiac hypertrophy, arrhythmias, and heart failure. IP3 enhances intracellular Ca2 release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca2 release affects mitochondrial function and determine the underlying mechanisms. Methods and results We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca2 elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca2 uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca2 (Ca2 m) but only ET-1 led to an increase in ATP concentration. ET-1-induced effects were prevented by cell treatment with the IP3 antagonist 2-aminoethoxydiphenyl borate and absent in myocytes from transgenic mice expressing an IP3 chelating protein (IP3 sponge). Furthermore, ET-1-induced mitochondrial Ca2 uptake was insensitive to the mitochondrial Ca2 uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using realtime polymerase chain reaction, we detected the presence of all three isoforms of IP3Rs and RyRs in murine ventricular myocytes with a dominant presence of type 2 isoform for both receptors. Conclusions Stimulation of IP3Rs with ET-1 induces Ca2 release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production.

INOSITOL trisphosphate; SARCOPLASMIC reticulum; BIOLOGICAL crosstalk; ADENOSINE triphosphate; CHEMICAL synthesis; RYANODINE receptors

Cardiovascular Research, 2016, Vol 112, Issue 1, p491

0008-6363

Academic Journal

10.1093/cvr/cvw185