Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity

Dong, Zhiwei; Shanmughapriya, Santhanam; Tomar, Dhanendra; Siddiqui, Naveed A.; Lynch, Solomon; Nemani, Neeharika; Breves, Sarah L.; Zhang, Xueqian; Tripathi, Archana; Palaniappan, Palaniappan; Riitano, Massimo F.; Worth, Alison M.; Seelam, Ajay; Carvalho, Edmund; Ramasamy, Subbiah; Jaña, Fabián; Soboloff, Jonathan; Peng, Yizhi; Cheung, Joseph Y.; Joseph, Suresh K.; Caplan, Jeffrey; Rajan, Sudarsan; Stathopulos, Peter B.; Madesh, Muniswamy

doi:10.1016/j.molcel.2017.01.032

Cited by 198 publications

(210 citation statements)

References 70 publications

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“…Finally, mitochondrial reactive oxygen species overproduction is observed in DOCA‐salt mice myocytes 15. Reactive oxygen species can oxidize Cys‐97 of MCU and increase MCU activity 13. Consistent with the latter 2 possibilities, we observed increased whole‐mitoplast MCU current.…”

Section: Discussionsupporting

confidence: 85%

“…Mitochondrial numbers and area are increased in HF 11, 12. Reactive oxygen species are increased in HF, and oxidation of the MCU Cys‐97 residue can increase MCU activity 13. Given these changes, it is plausible that mitochondrial Ca 2+ flux may increase in chronic mild or moderate HF models and thereby contribute to EADs in cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

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

Xie

Song

Liu

et al. 2018

JAHA

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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.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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

Xie

Song

Liu

et al. 2018

JAHA

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“…An increase in mitochondrial ROS in response to hypoxia stimulates the calcium signal in astrocytes and actives respiration . Mitochondrial calcium uptake is redox sensitive and can be regulated by ROS . A more prolonged elevation of ROS in mitochondria was shown to be involved in a number of cell processes, including cell proliferation .…”

mentioning

confidence: 99%

Role of mitochondrial ROS in the brain: from physiology to neurodegeneration

Angelova¹,

Abramov²

2018

FEBS Letters

603

402

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Edited by Wilhelm JustMitochondria are key cell organelles in that they are responsible for energy production and control many processes from signalling to cell death. The function of the mitochondrial electron transport chain is coupled with the production of reactive oxygen species (ROS) in the form of superoxide anion or hydrogen peroxide. As a result of the constant production of ROS, mitochondria are protected by highly efficient antioxidant systems. The rapidly changing levels of ROS in mitochondria, coupled with multiple essential cellular functions, make ROS apt for physiological signalling. Thus, mutations, environmental toxins and chronic ischaemic conditions could affect the mitochondrial redox balance and lead to the development of pathology. In long-living and non-mitotic cells such as neurons, oxidative stress induced by overproduction of mitochondrial ROS or impairment of the antioxidant defence results in a dysfunction of mitochondria and initiation of the cell death cascade. Mitochondrial ROS overproduction and changes in mitochondrial redox homeostasis have been shown to be involved in both a number of neurological conditions and a majority of neurodegenerative diseases. Here, we summarise the involvement of mitochondrial ROS in the mechanism of neuronal loss of major neurodegenerative disorders.

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“…Blocking L-type calcium channels in muscle cells causes poor repair, possibly by preventing translocation of dysferlin to the injury site [78]. ROS can also modulate calcium entry and release from intracellular organelles such as ER, mitochondria, and lysosomes [125,129]. Mitochondrial ROS activation of the lysosomal calcium channel MCOLN1 causes calcium release from lysosomes [130], and this may regulate lysosome exocytosis to facilitate repair.…”

Section: Signals and Effectors Of Plasma Membrane Repairmentioning

confidence: 99%

Cellular mechanisms and signals that coordinate plasma membrane repair

Horn

Jaiswal

2018

Cell. Mol. Life Sci.

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Plasma membrane forms the barrier between the cytoplasm and the environment. Cells constantly and selectively transport molecules across their plasma membrane without disrupting it. Any disruption in the plasma membrane compromises its selective permeability and is lethal, if not rapidly repaired. There is a growing understanding of the organelles, proteins, lipids, and small molecules that help cells signal and efficiently coordinate plasma membrane repair. This review aims to summarize how these subcellular responses are coordinated and how cellular signals generated due to plasma membrane injury interact with each other to spatially and temporally coordinate repair. With the involvement of calcium and redox signaling in single cell and tissue repair, we will discuss how these and other related signals extend from single cell repair to tissue level repair. These signals link repair processes that are activated immediately after plasma membrane injury with longer term processes regulating repair and regeneration of the damaged tissue. We propose that investigating cell and tissue repair as part of a continuum of wound repair mechanisms would be of value in treating degenerative diseases.

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Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity

Cited by 198 publications

References 70 publications

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

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

Role of mitochondrial ROS in the brain: from physiology to neurodegeneration

Cellular mechanisms and signals that coordinate plasma membrane repair

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Mitochondrial Ca2+ Uniporter Is a Mitochondrial Luminal Redox Sensor that Augments MCU Channel Activity

Cited by 198 publications

References 70 publications

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

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

Role of mitochondrial ROS in the brain: from physiology to neurodegeneration

Cellular mechanisms and signals that coordinate plasma membrane repair

Contact Info

Product

Resources

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

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