期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：11389-11394
DOI：10.1073/pnas.1513047112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceWe demonstrate that intracellular Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in postischemic heart failure (HF). In particular, sarcoplasmic reticulum (SR) Ca2+ leak via type 2 ryanodine receptor (RyR2)--but not type 2 inositol 1,4,5-trisphosphate receptor (IP3R2)--channels plays a fundamental role in the pathophysiology of mitochondrial Ca2+ overload and dysfunction in HF. We present here a previously undisclosed molecular mechanism in HF with crucial implications in cardiac physiology. Indeed, our data establish a feedback loop between SR and mitochondria in which SR Ca2+ leak triggers mitochondrial dysfunction and increases the production of free radicals, which in turn lead to posttranslational modifications of RyR2 and enhance intracellular Ca2+ leak, thereby contributing to impaired cardiac function after myocardial infarction. Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial for excitation-contraction (E-C) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca2+ is essential for optimal function of these organelles. However, Ca2+ accumulation can impair mitochondrial function, leading to reduced ATP production and increased release of reactive oxygen species (ROS). Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca2+ plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca2+ release channels on cardiac SR: type 2 ryanodine receptors (RyR2s) and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine models harboring RyR2 mutations that either cause or inhibit SR Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial Ca2+ overload, dysmorphology, and malfunction. In contrast, cardiac-specific deletion of IP3R2 had no major effect on mitochondrial fitness in HF. Moreover, genetic enhancement of mitochondrial antioxidant activity improved mitochondrial function and reduced posttranslational modifications of RyR2 macromolecular complex. Our data demonstrate that leaky RyR2, but not IP3R2, channels cause mitochondrial Ca2+ overload and dysfunction in HF.
