Adrenergic Signaling Regulates Mitochondrial Ca<sup>2+</sup> Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca<sup>2+</sup> Uniporter

O‐Uchi, Jin; Jhun, Bong Sook; Xu, Shangcheng; Hurst, Stephen; Raffaello, Anna; Liu, Xiaoyun; Yi, Bing; Zhang, Huiliang; Gross, Polina; Mishra, Jyotsna; Ainbinder, Alina; Kettlewell, Sarah; Smith, Godfrey L.; Dirksen, Robert T.; Wang, Wang; Meneghesso, Gaudenzio; Sheu, Shey Shing

doi:10.1089/ars.2013.5394

Cited by 73 publications

(109 citation statements)

References 78 publications

(85 reference statements)

Supporting

Mentioning

105

Contrasting

Order By: Relevance

“…1 B-D and Fig. S1), reconcile conflicting reports concerning mitochondrial Ca 2+ in failing hearts (7,10,12,13,15,17). …”

Section: Resultssupporting

confidence: 78%

“…The decrease in Δψ m observed in mitochondria from RyR2-S2808D ventricular cardiomyocytes (Fig. S3J) is consistent with a progressive decline in Δψ m due to increasing [Ca 2+ ] in cardiac mitochondria and is most likely due to elevated cytosolic [Ca 2+ ] caused by RyR2-mediated SR Ca 2+ leak (10). Supporting this view, mitochondria exposed to elevated [Ca 2+ ] exhibit reduced Δψ m , due to the large mitochondrial Ca 2+ current generated during local [Ca 2+ ] transients (28).…”

Section: Significancesupporting

confidence: 76%

“…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).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Mitochondrial calcium overload is a key determinant in heart failure

Santulli

Xie

Reiken

et al. 2015

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

410

328

View full text Add to dashboard Cite

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...

show abstract

“…1 B-D and Fig. S1), reconcile conflicting reports concerning mitochondrial Ca 2+ in failing hearts (7,10,12,13,15,17). …”

Section: Resultssupporting

confidence: 78%

Section: Significancesupporting

confidence: 76%

mentioning

confidence: 99%

See 1 more Smart Citation

Mitochondrial calcium overload is a key determinant in heart failure

Santulli

Xie

Reiken

et al. 2015

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

410

328

View full text Add to dashboard Cite

show abstract

“…NOVEMBER 18, 2016 • VOLUME 291 • NUMBER 47 through the close spatial relationship between ER and mitochondria (ER-mitochondrial tethering) (68,69). TRPM2-mediated Ca 2ϩ influx could also have a role in regulation of the mitochondrial calcium uniporter (70). The mechanisms through which calcium influx through TRPM2 regulates mitochondrial ROS are currently under investigation.…”

Section: Trpm2 Depletion Inhibits Mitochondrial Function and Survivalmentioning

confidence: 99%

Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics

Bao

Chen

Conrad

et al. 2016

Journal of Biological Chemistry

107

View full text Add to dashboard Cite

Edited by Xiao-Fan WangTransient receptor potential melastatin 2 (TRPM2) ion channel has an essential function in modulating cell survival following oxidant injury and is highly expressed in many cancers including neuroblastoma. Here, in xenografts generated from neuroblastoma cells in which TRPM2 was depleted with CRISPR/Cas9 technology and in in vitro experiments, tumor growth was significantly inhibited and doxorubicin sensitivity increased. The hypoxia-inducible transcription factor 1/2␣ (HIF-1/2␣) signaling cascade including proteins involved in oxidant stress, glycolysis, and mitochondrial function was suppressed by TRPM2 depletion. TRPM2-depleted SH-SY5Y neuroblastoma cells demonstrated reduced oxygen consumption and ATP production after doxorubicin, confirming impaired cellular bioenergetics. In cells in which TRPM2 was depleted, mitochondrial superoxide production was significantly increased, particularly following doxorubicin. Ectopic expression of superoxide dismutase 2 (SOD2) reduced ROS and preserved viability of TRPM2-depleted cells, however, failed to restore ATP levels. Mitochondrial reactive oxygen species (ROS) were also significantly increased in cells in which TRPM2 function was inhibited by TRPM2-S, and pretreatment of these cells with the antioxidant MitoTEMPO significantly reduced ROS levels in response to doxorubicin and protected cell viability. Expression of the TRPM2 pore mutant E960D, in which calcium entry through TRPM2 is abolished, also resulted in significantly increased mitochondrial ROS following doxorubicin treatment, showing the critical role of TRPM2-mediated calcium entry. These findings demonstrate the important function of TRPM2 in modulation of cell survival through mitochondrial ROS, and the potential of targeted inhibition of TRPM2 as a therapeutic approach to reduce cellular bioenergetics, tumor growth, and enhance susceptibility to chemotherapeutic agents.

show abstract

“…Consistent with previous reports, we found an increase in total mass of mitochondria in nonischemic HF. Moreover, MCU is known to be activated by phosphorylation 47. In nonischemic HF, we found that MCU was significantly more phosphorylated than in WT mice and I MCU was significantly increased in nonischemic HF group.…”

Section: Discussionmentioning

confidence: 65%

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Xie

Song

Liu

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundHeart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis.Methods and ResultsA model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol‐induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L‐type Ca2+ currents, increased Na+‐Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca2+ uniporter–specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+‐Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L‐type Ca2+ current, consistent with the experimental observations.ConclusionsMitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.

show abstract

Adrenergic Signaling Regulates Mitochondrial Ca²⁺ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca²⁺ Uniporter

Cited by 73 publications

References 78 publications

Mitochondrial calcium overload is a key determinant in heart failure

Mitochondrial calcium overload is a key determinant in heart failure

Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Contact Info

Product

Resources

About

Adrenergic Signaling Regulates Mitochondrial Ca2+ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca2+ Uniporter

Cited by 73 publications

References 78 publications

Mitochondrial calcium overload is a key determinant in heart failure

Mitochondrial calcium overload is a key determinant in heart failure

Depletion of the Human Ion Channel TRPM2 in Neuroblastoma Demonstrates Its Key Role in Cell Survival through Modulation of Mitochondrial Reactive Oxygen Species and Bioenergetics

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Contact Info

Product

Resources

About

Adrenergic Signaling Regulates Mitochondrial Ca²⁺ Uptake Through Pyk2-Dependent Tyrosine Phosphorylation of the Mitochondrial Ca²⁺ Uniporter

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy