CaMKII (Ca
            <sup>2+</sup>
            /Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation

Nguyen, Emily K.; Koval, Olha M.; Noble, Paige; Broadhurst, Kim; Allamargot, Chantal; Wu, Meng; Strack, Stefan; Thiel, William H.; Grumbach, Isabella M.

doi:10.1161/atvbaha.118.310951

Cited by 52 publications

(63 citation statements)

References 55 publications

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“…Increased CaMKII is known to contribute to myocardial hypertrophy and arrhythmias by phosphorylation of nuclear and cytoplasmic target proteins 29,30,31 . CaMKII was recently identified in mitochondria 23,24,25 , and mitochondrial CaMKII inhibition protects against myocardial death, acutely, during the first hours after myocardial infarction 25 . However, the potential for excessive, chronic, mitochondrial CaMKII to contribute to specific myocardial disease phenotypes is unexplored.…”

Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

“…We also observed an increase in phosphorylated CaMKII in the cytosol from the same hearts ( Fig S1A). Additionally, we quantified phosphorylation of a known mitochondrial target of CaMKII, the mitochondrial Ca 2+ uniporter (MCU) 24,25 . Rapid mitochondrial matrix Ca 2+ entry is mediated by MCU 33,34 , and CaMKII increases MCU Ca 2+ entry 24,25 , although this finding has been disputed 35,36,37 .…”

Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

“…Additionally, we quantified phosphorylation of a known mitochondrial target of CaMKII, the mitochondrial Ca 2+ uniporter (MCU) 24,25 . Rapid mitochondrial matrix Ca 2+ entry is mediated by MCU 33,34 , and CaMKII increases MCU Ca 2+ entry 24,25 , although this finding has been disputed 35,36,37 . We used recently validated phosphospecific antibodies against MCU (pMCU) 24 , predicted CaMKII phosphorylation sites, and found an increase in phosphorylation of this CaMKII target in mitochondria from hearts after MI compared to sham operated hearts ( Fig 1A and B).…”

Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

“…Rapid mitochondrial matrix Ca 2+ entry is mediated by MCU 33,34 , and CaMKII increases MCU Ca 2+ entry 24,25 , although this finding has been disputed 35,36,37 . We used recently validated phosphospecific antibodies against MCU (pMCU) 24 , predicted CaMKII phosphorylation sites, and found an increase in phosphorylation of this CaMKII target in mitochondria from hearts after MI compared to sham operated hearts ( Fig 1A and B). Collectively, these results suggest that increased mitochondrial CaMKII activity occurs in response to myocardial infarction, and persists substantially beyond the perioperative episode.…”

Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

“…CaMKII also promotes dilated cardiomyopathy 13,22 , but the mechanism is unknown. CaMKII is present in the mitochondrial fraction of heart and vascular lysates 23,24 , and is found in the mitochondrial matrix 25 , but responses to sustained, pathological mitochondrial activation in heart are unknown.…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Luczak

Granger

et al. 2020

Preprint

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Despite the clear association between myocardial injury, heart failure and depressed myocardial energetics, little is known about upstream signals responsible for remodeling myocardial metabolism after pathological stress. We found increased mitochondrial calmodulin kinase II (CaMKII) activation and left ventricular dilation in mice one week after myocardial infarction (MI) surgery. In contrast, mice with genetic mitochondrial CaMKII inhibition were protected from left ventricular dilation and dysfunction after MI. Mice with myocardial and mitochondrial CaMKII over-expression (mtCaMKII) had severe dilated cardiomyopathy and decreased ATP that caused elevated cytoplasmic resting (diastolic) Ca 2+ concentration and reduced mechanical performance. We mapped a metabolic pathway that allowed us to rescue disease phenotypes in mtCaMKII mice, providing new insights into physiological and pathological metabolic consequences of CaMKII signaling in mitochondria. Our findings suggest myocardial dilation, a disease phenotype lacking specific therapies, can be prevented by targeted replacement of mitochondrial creatine kinase, or mitochondrial-targeted CaMKII inhibition. 7 10

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Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

Section: Increased Mitochondrial Camkii Activity In Failing Mouse Heartmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Luczak

Granger

et al. 2020

Preprint

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The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders

Bagheri‐Mohammadi

Farjami

Suha

et al. 2023

J of Cellular Biochemistry

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Mitochondrial calcium (Ca 2+ ) dynamics play critical roles in regulating vital physiological conditions in the brain. Importantly, Mitochondria-associated endoplasmic reticulum (ER) membranes serve different cellular functions including Ca 2+ signaling, bioenergetics, phospholipid biosynthesis, cholesterol esterification, programmed cell death, and communication between the two organelles. Several Ca 2+ -transport systems specialize at the mitochondria, ER, and their contact sites that provide tight control of mitochondrial Ca 2+ signaling at the molecular level. The biological function of Ca 2+ channels and transporters as well as the role of mitochondrial Ca 2+ signaling in cellular homeostasis can open new perspectives for investigation and molecular intervention. Emerging evidence suggests that abnormalities in ER/mitochondrial brain functions and dysregulation of Ca 2+ homeostasis are neuropathological hallmarks of neurological disorders like Alzheimer's disease, but little evidence is available to demonstrate their relationship to disease pathogenesis and therapeutic approaches. In recent years, the detection of the molecular mechanism regulating cellular Ca 2+ homeostasis and also mitochondrial functions have expanded the number of targeted treatments.The main experimental data identify beneficial effects, whereas some scientific trials did not meet the expectations. Together with an overview of the important function of mitochondria, this review paper introduced the possible tested therapeutic approaches that target mitochondria in the context of neurodegenerative diseases. Since these treatments in neurological disorders have shown different degrees of progress, it is essential to perform a detailed assessment of the significance of mitochondrial deterioration in neurodegenerative diseases and of a pharmacological treatment at this stage.

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WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension

Wang

Zhen

et al. 2021

Journal Cellular Physiology

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Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by proliferative vascular remodeling. Abnormal vascular smooth muscle cell (VSMC) phenotype switching is crucial to this process, highlighting the need for VSMC metabolic changes to cover cellular energy demand in CTEPH. We report that elevated Wnt family member 5B (WNT5B) expression is associated with vascular remodeling and promotes VSMC phenotype switching via mitochondrial dynamics regulation in CTEPH. Using primary culture of pulmonary artery smooth muscle cells, we show that high WNT5B expression activates VSMC proliferation and migration and results in mitochondrial fission via noncanonical Wnt signaling in CTEPH. Abnormal VSMC proliferation and migration were abolished by mitochondrial division inhibitor 1, an inhibitor of mitochondrial fission. Secreted frizzled‐related protein 2, a soluble scavenger of Wnt signaling, attenuates VSMC proliferation and migration by accelerating mitochondrial fusion. These findings indicate that WNT5B is an essential regulator of mitochondrial dynamics, contributing to VSMC phenotype switching in CTEPH.

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CaMKII (Ca ²⁺ /Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation

Abstract: These findings identify mitochondrial CaMKII as a key regulator of mitochondrial Ca uptake via MCU, thereby controlling mitochondrial translocation and VSMC migration after vascular injury.

Cited by 52 publications

References 55 publications

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders

WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension

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CaMKII (Ca 2+ /Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation

Abstract: These findings identify mitochondrial CaMKII as a key regulator of mitochondrial Ca uptake via MCU, thereby controlling mitochondrial translocation and VSMC migration after vascular injury.

Cited by 52 publications

References 55 publications

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

Mitochondrial CaMKII causes metabolic reprogramming, energetic insufficiency, and dilated cardiomyopathy

The mitochondrial calcium signaling, regulation, and cellular functions: A novel target for therapeutic medicine in neurological disorders

WNT5B promotes vascular smooth muscle cell dedifferentiation via mitochondrial dynamics regulation in chronic thromboembolic pulmonary hypertension

Contact Info

Product

Resources

About

CaMKII (Ca ²⁺ /Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation