Mitochondrial calcium overload is a key determinant in heart failure

Abstract

Calcium (Ca 2+ ) 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 Ca 2+ is essential for optimal function of these organelles. However, Ca 2+ 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 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, cardiacspecific 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.ryanodine receptor | heart failure | mitochondria | calcium | IP3 receptor T ype 2 ryanodine receptor/Ca 2+ release channel (RyR2) and type 2 inositol 1,4,5-trisphosphate receptor (IP3R2) are the major intracellular Ca 2+ release channels in the heart (1-3). RyR2 is essential for cardiac excitation-contraction (E-C) coupling (2), whereas the role of IP3R2 in cardiomyocytes is less well understood (3). E-C 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)(10)(11)(12)(13)(14)(15)(16)(17). Albeit Ca 2+ is required for activation of key enzymes (i.e., pyruvate dehydrogenase phosphatase, isocitrate dehydrogenase, and α-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 and/or IP3R2 channels in cardiomyocytes could lead to mitochondrial Ca 2+ accumulation and dysfunction contributing to oxidative overload and energy depletion. Results and DiscussionIncreased Mitochondrial Ca...

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