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
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<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