P P P t test. AU, arbitrary units; ROS, reactive oxygen species.Marks, July 6, 2015 (sent for review June 15, 2015; reviewed by Geoffrey S.
Pitt). In particular, sarcoplasmic reticulum (SR) Ca 2 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 Ca 2 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 Ca 2 leak triggers mitochondrial dysfunction and increases the production of free radicals, which in turn lead to posttranslational modifications of RyR2 and enhance intracellular Ca 2 leak, thereby contributing to impaired cardiac function after myocardial infarction. Abstract Calcium (Ca 2 ) released from the sarcoplasmic reticulum (SR) is crucial for excitationcontraction (EC) coupling. Mitochondria, the major source of energy, in the form of ATP, required for cardiac contractility, are closely interconnected with the SR, and Ca 2 is essential for optimal function of these organelles. ![]() Oxidative stress contributes to heart failure (HF), but whether mitochondrial Ca 2 plays a mechanistic role in HF remains unresolved. Here, we show for the first time, to our knowledge, that diastolic SR Ca 2 leak causes mitochondrial Ca 2 overload and dysfunction in a murine model of postmyocardial infarction HF. There are two forms of Ca 2 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 Ca 2 leak, we found that leaky RyR2 channels result in mitochondrial Ca 2 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 Ca 2 overload and dysfunction in HF. RyR2 is essential for cardiac excitationcontraction (EC) coupling ( 2 ), whereas the role of IP3R2 in cardiomyocytes is less well understood ( 3 ). EC coupling requires energy in the form of ATP produced primarily by oxidative phosphorylation in mitochondria ( 4 8 ). Both increased and reduced mitochondrial Ca 2 levels have been implicated in mitochondrial dysfunction and increased reactive oxygen species (ROS) production in heart failure (HF) ( 6, 7, 9 17 ). Albeit Ca 2 is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and -ketoglutarate dehydrogenase) in the tricarboxylic acid (also known as Krebs) cycle ( 18, 19 ), excessive mitochondrial Ca 2 uptake has been associated with cellular dysfunction ( 14, 20 ). Furthermore, the exact source of mitochondrial Ca 2 has not been clearly established. Given the intimate anatomical and functional association between the sarcoplasmic reticulum (SR) and mitochondria ( 6, 21, 22 ), we hypothesized that SR Ca 2 release via RyR2 andor IP3R2 channels in cardiomyocytes could lead to mitochondrial Ca 2 accumulation and dysfunction contributing to oxidative overload and energy depletion. Results and Discussion Increased Mitochondrial Ca 2 in Failing Hearts. Cardiac mitochondrial Ca 2 ( Fig. A D and Fig. S1 ) and ROS ( Fig. E ) were significantly elevated in mice following myocardial infarction (MI). P Increased mitochondrial Ca 2 in post-MI heart failure. A ) Direct measurement of total Ca 2 content in mitochondria isolated from sham or failing ventricular samples of 6-mo-old WT, RyR2-S2808A, RyR2-S2808D, mCAT, and mCAT RyR2-S2808D mice. Mitochondria were purified from 6 mice in each experimental group. B D ) Mitochondrial Ca 2 dynamics in response to 3 Hz in cardiomyocytes ( n 2235) enzymatically isolated from at least 7 mice per group isolated from the indicated groups. E ) Mitochondrial ROS generation in ventricular cardiomyocytes isolated from the indicated mice using the mitochondria-targeted fluorescent indicator of superoxide production MitoSOX Red; n 120 ventricular myocytes from 4 mice in each group.
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