2015 PNAS HF Santulli (First and Corresponding Author).pdf Gaetano Santulli Wenjun Xie Steven R. Reiken Andrew R.Marks 10.25376/hra.6083240.v1 https://hra.figshare.com/articles/dataset/2015_PNAS_HF_Santulli_First_and_Corresponding_Author_pdf/6083240 p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 8.0px Helvetica} span.s1 {font: 5.5px Helvetica} <p>Calcium (Ca2+) released from the sarcoplasmic reticulum (SR) is crucial</p> <p>for excitation–contraction (E–C) coupling. Mitochondria, the major</p> <p>source of energy, in the form of ATP, required for cardiac contractility,</p> <p>are closely interconnected with the SR, and Ca2+ is essential for optimal</p> <p>function of these organelles. However, Ca2+ accumulation can</p> <p>impair mitochondrial function, leading to reduced ATP production</p> <p>and increased release of reactive oxygen species (ROS). Oxidative</p> <p>stress contributes to heart failure (HF), but whether mitochondrial</p> <p>Ca2+ plays a mechanistic role in HF remains unresolved. Here, we</p> <p>show for the first time, to our knowledge, that diastolic SR Ca2+</p> <p>leak causes mitochondrial Ca2+ overload and dysfunction in a murine</p> <p>model of postmyocardial infarction HF. There are two forms of Ca2+</p> <p>release channels on cardiac SR: type 2 ryanodine receptors (RyR2s)</p> <p>and type 2 inositol 1,4,5-trisphosphate receptors (IP3R2s). Using murine</p> <p>models harboring RyR2 mutations that either cause or inhibit SR</p> <p>Ca2+ leak, we found that leaky RyR2 channels result in mitochondrial</p> <p>Ca2+ overload, dysmorphology, and malfunction. In contrast, cardiacspecific</p> <p>deletion of IP3R2 had no major effect on mitochondrial fitness</p> <p>in HF. Moreover, genetic enhancement of mitochondrial antioxidant</p> <p>activity improved mitochondrial function and reduced posttranslational</p> <p>modifications of RyR2 macromolecular complex. Our data demonstrate</p> <p>that leaky RyR2, but not IP3R2, channels cause mitochondrial</p> <p>Ca2+ overload and dysfunction in HF.</p> 2018-04-09 14:30:34 heart failure calcium mitochondria Medicine