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- Title
Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca<sup>2+</sup> uptake through the mitochondrial ryanodine receptor in cardiacmyocytes.
- Authors
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
- Abstract
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.
- Subjects
INOSITOL trisphosphate; SARCOPLASMIC reticulum; BIOLOGICAL crosstalk; ADENOSINE triphosphate; CHEMICAL synthesis; RYANODINE receptors
- Publication
Cardiovascular Research, 2016, Vol 112, Issue 1, p491
- ISSN
0008-6363
- Publication type
Article
- DOI
10.1093/cvr/cvw185