Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca2+ uptake through the mitochondrial ryanodine receptor in cardiac myocytes.
Inositol 1,4,5-trisphosphate-mediated sarcoplasmic reticulum-mitochondrial crosstalk influences adenosine triphosphate production via mitochondrial Ca2+ uptake through the mitochondrial ryanodine receptor in cardiac myocytes.
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DOI：
10.1093/cvr/cvw185
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发表时间：
2016-08
影响因子：
10.8
通讯作者：
L. Seidlmayer;Johannes Kuhn;Annette Berbner;P. Arias-Loza;T. Williams;Mathias Kaspar;M. Czolbe;J. Kwong;J. Molkentin;K. Heinze;E. Dedkova;O. Ritter
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作者：
L. Seidlmayer;Johannes Kuhn;Annette Berbner;P. Arias-Loza;T. Williams;Mathias Kaspar;M. Czolbe;J. Kwong;J. Molkentin;K. Heinze;E. Dedkova;O. Ritter
目的成年心肌细胞中1，4，5-三磷酸肌醇（IP 3）水平升高通常与心脏肥大、心律失常和心力衰竭的发生有关。IP 3通过位于肌浆网（SR）的IP 3受体（IP 3Rs）增强细胞内Ca（2+）释放。我们的目的是确定IP 3诱导的Ca（2+）释放是否影响线粒体功能，并确定潜在的机制。方法和结果我们比较了IP 3Rs和ryanodine受体（RyRs）介导的内皮素-1（ET-1）和异丙肾上腺素（ISO）刺激引起的细胞内Ca（2+）升高对线粒体Ca（2+）摄取和三磷酸腺苷（ATP）生成的影响。ET-1和异丙肾上腺素均可引起线粒体Ca（2+）（Ca（2 +）m）增加，但仅ET-1引起ATP浓度增加。ET-1诱导的影响被阻止细胞治疗与IP 3拮抗剂2-氨基乙氧基二苯基硼酸盐和缺乏从转基因小鼠表达的IP 3螯合蛋白（IP 3海绵）的肌细胞。此外，ET-1诱导的线粒体Ca（2+）摄取对线粒体Ca（2+）单向转运体抑制剂Ru 360不敏感，但可被RyRs 1型抑制剂丹曲林减弱。使用实时聚合酶链反应，我们检测到的存在下，所有三个亚型的IP 3Rs和RyRs在小鼠心室肌细胞与2型亚型的两种受体的主导存在。结论ET-1刺激IP 3Rs可诱导SR释放Ca（2+），Ca（2+）通过线粒体RyR通道进入线粒体，刺激线粒体ATP生成。
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 Ca(2+ )release via IP3 receptors (IP3Rs) located at the sarcoplasmic reticulum (SR). We aimed to determine whether IP3-induced Ca(2+ )release affects mitochondrial function and determine the underlying mechanisms. METHODS AND RESULTS We compared the effects of IP3Rs- and ryanodine receptors (RyRs)-mediated cytosolic Ca(2+ )elevation achieved by endothelin-1 (ET-1) and isoproterenol (ISO) stimulation, respectively, on mitochondrial Ca(2+ )uptake and adenosine triphosphate (ATP) generation. Both ET-1 and isoproterenol induced an increase in mitochondrial Ca(2+ )(Ca(2 +) 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 Ca(2+) uptake was insensitive to the mitochondrial Ca(2+ )uniporter inhibitor Ru360, however was attenuated by RyRs type 1 inhibitor dantrolene. Using real-time 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 Ca(2+ )release from the SR which is tunnelled to mitochondria via mitochondrial RyR leading to stimulation of mitochondrial ATP production.