Mitochondrial calcium overload is a key determinant in heart failure

Gaetano Santulli, Wenjun Xie, Steven R. Reiken, Andrew R. Marks

Research output: Contribution to journalArticle

152 Scopus citations

Abstract

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, 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 Ca2+ overload and dysfunction in HF.

Original languageEnglish (US)
Pages (from-to)11389-11394
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number36
DOIs
StatePublished - Sep 8 2015
Externally publishedYes

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Keywords

  • Calcium
  • Heart failure
  • IP3 receptor
  • Mitochondria
  • Ryanodine receptor

ASJC Scopus subject areas

  • General

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