Mitochondrial oxidative stress promotes atrial fibrillation

Xie, Wenjun; Santulli, Gaetano; Reiken, Steven; Yuan, Qi; Osborne, Brent W.; Chen, Bi Xing; Marks, Andrew R.

doi:10.1038/srep11427

Cited by 218 publications

(199 citation statements)

References 52 publications

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“…Mice harboring the IP3R2 flox/flox allele were bred with MHC-Cre transgenic mice to obtain a cardiac ventricularspecific ablation of IP3R2. A detailed description of materials and methods for in vivo experiments (31)(32)(33)(34)(35), isolation of adult cardiomyocytes (34,36), isolation of mitochondria (37), assessment of mitochondrial dynamics, Ca 2+ content, and membrane potential (34,37), real-time RT-qPCR (38,39), immunoprecipitation/immunoblot, and electron microscopy (40) can be found in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial calcium overload is a key determinant in heart failure

Santulli

Xie

Reiken

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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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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Section: Methodsmentioning

confidence: 99%

Mitochondrial calcium overload is a key determinant in heart failure

Santulli

Xie

Reiken

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

412

339

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“…These results indicate that the mechanism by which ox-LDL enhances endothelial ROS generation involves the disruption of mitochondrial respiratory function and the PKA pathway. Santulli et al 35 and Xie et al 36 reported that in addition to mitochondrial dysfunction, excess ROS production …”

Section: Mitochondrial Dysfunction Is Responsible For Excess Ros Genementioning

confidence: 99%

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1–Mediated Protein Kinase A/Uncoupling Protein 2 Pathway

Xiong

Wang

et al. 2016

Hypertension

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“…While highphos RyR2-pS2808 clusters represented the smaller population in untreated AMs ( Figure 3B), our analysis indicated their preferential association with AT structures, consistent with rapid junctional Ca 2+ release at AT sites. In addition, CaMK phosphorylation of the RyR2-S2814 site was identified as a mechanism of AF susceptibility in mice (31,32), and both RyR2-S2808 and RyR2-S2814 phosphorylation changes were identified in atrial samples from patients with AF (33,34). Consequently, we investigated RyR2-pS2814 phosphorylation in situ, finding axially aligned highphos clusters ( Figure 3E).…”

Section: S2808a/s2808amentioning

confidence: 99%