ArticleProceedings of the National Academy of Sciences of the United States of America2015
Mitochondrial calcium overload is a key determinant in heart failure.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 366 papers.
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Who cites it
366 citing papers in PubMed, 538 citations in OpenAlex.
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- Early pre-symptomatic and sex-specific cardiac remodeling precedes heart failure in zebrafish with a human actin variant.Disease models & mechanisms · 2026Article
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- From Oxidative Stress to Fibrotic Remodeling: Integrating Redox Biology, Galectin-3, and Imaging Phenotypes in Heart Failure.Antioxidants (Basel, Switzerland) · 2026Review
- Loss of PINK1 causes age-dependent mitochondrial trafficking deficits in nigrostriatal dopaminergic neurons via aberrant p38 MAPK activation.NPJ Parkinson's disease · 2026Article
- Beyond the Powerhouse: Mitochondrial Crosstalk as a Master Regulator of Cardiac Metabolic Homeostasis and Failure.Journal of cardiovascular translational research · 2026Review
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- TIGAR deficiency enhances cardiac resilience through epigenetic programming of Parkin expression.JCI insight · 2026Article
- MYOM1 deficiency leads to dilated cardiomyopathy by disrupting the homeostasis of sarcoplasmic reticulum.Redox biology · 2026Article
- The case for space as a model of accelerated aging.Nature aging · 2026Review
- A perspective on the future of heart failure research.Journal of molecular and cellular cardiology plus · 2026Article
- Mitochondrial Calcium Dysregulation and Targeted Therapies in Heart Failure.Reviews in cardiovascular medicine · 2026Review
- Disrupted SR-Mitochondria Coupling Drives Ischemia-Reperfusion Vulnerability in the Middle-Aged Rat Heart.Biomedicines · 2026Article
- Mechanisms of Atrial Fibrillation in Heart Failure: Uncovering Therapeutic Targets in the Atrial Substrate.Current heart failure reports · 2026Review
- Mitochondrial DNA mutations and intercellular mitochondrial transfer in cancer: mechanisms, biological effects, and clinical potential.Biomarker research · 2026Review
- Doxorubicin-Induced Cardiac Remodeling: Mechanisms and Mitigation Strategies.Cardiovascular drugs and therapy · 2026Review
- Hypoxia, ROS, and HIF Signaling in I/R Injury: Implications and Future Prospects.Antioxidants (Basel, Switzerland) · 2026Review
- Artificial intelligence-driven design and optimization of mitochondria-targeted nanocarriers for chronic heart failure.Frontiers in bioengineering and biotechnology · 2026Review
306 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
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, 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 Ca2+ overload and dysfunction in HF.
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