Phosphorylation of dynamin-related protein 1 at Ser616 regulates mitochondrial fission and is involved in mitochondrial calcium uniporter-mediated neutrophil polarization and chemotaxis

Zheng, X.F. Steven; Chen, Mimi; Meng, Xiang‐Jin; Chu, Xinwei; Cheng, Can; Zou, Fei

doi:10.1016/j.molimm.2017.03.019

Cited by 31 publications

(30 citation statements)

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“…Recent evidence has shed a light on the crucial role of MCU and its regulators in cell migration. Independently of the role of MCU in cancer cell migration, different studies have highlighted the role of mitochondrial Ca 2+ homeostasis in immune cell polarization and chemotaxis [127] , [128] . Taken together, these data obtained in different specialized cells and animal models highlight the crucial and evolutionarily conserved function of MCU in cell migration from worms to vertebrates.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, in two models of ischemia/reperfusion injury, mitochondrial Ca 2+ was required for mitochondrial fragmentation by modulating Drp1 level [125] , [126] . Finally, a recent study highlighted the role for MCU in mitochondrial fragmentation via accumulation of Drp1 Ser616 required for neutrophil polarization and chemotaxis [127] . Those studies support the idea of a role of mitochondrial Ca 2+ uptake in mitochondrial dynamics.…”

Section: Mechanisms By Which Mcum Deficiency Alters Cell Migrationmentioning

confidence: 99%

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New insights into the role of mitochondrial calcium homeostasis in cell migration

Semet

Prudent

2018

Biochemical and Biophysical Research Communications

109

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Mitochondria are dynamic organelles involved in numerous physiological functions. Beyond their function in ATP production, mitochondria regulate cell death, reactive oxygen species (ROS) generation, immunity and metabolism. Mitochondria also play a key role in the buffering of cytosolic calcium, and calcium transported into the matrix regulates mitochondrial metabolism. Recently, the identification of the mitochondrial calcium uniporter (MCU) and associated regulators has allowed the characterization of new physiological roles for calcium in both mitochondrial and cellular homeostasis. Indeed, recent work has highlighted the importance of mitochondrial calcium homeostasis in regulating cell migration. Cell migration is a property common to all metazoans and is critical to embryogenesis, cancer progression, wound-healing and immune surveillance. Previous work has established that cytoplasmic calcium is a key regulator of cell migration, as oscillations in cytosolic calcium activate cytoskeletal remodelling, actin contraction and focal adhesion (FA) turnover necessary for cell movement. Recent work using animal models and in cellulo experiments to genetically modulate MCU and partners have shed new light on the role of mitochondrial calcium dynamics in cytoskeletal remodelling through the modulation of ATP and ROS production, as well as intracellular calcium signalling. This review focuses on MCU and its regulators in cell migration during physiological and pathophysiological processes including development and cancer. We also present hypotheses to explain the molecular mechanisms by which MCU may regulate mitochondrial dynamics and motility to drive cell migration.

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Section: Discussionmentioning

confidence: 99%

Section: Mechanisms By Which Mcum Deficiency Alters Cell Migrationmentioning

confidence: 99%

New insights into the role of mitochondrial calcium homeostasis in cell migration

Semet

Prudent

2018

Biochemical and Biophysical Research Communications

109

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“…The ability of Drp1 to promote fission is dependent on phosphorylation at serine 616 (S616) and dephosphorylation of serine 637 (S637) ( 112 , 113 ). Cytoplasmic Ca 2+ signaling is known to regulate the phosphorylation status of Drp1 through calcineurin-dependent dephosphorylation of S637 ( 112 , 114 ), and more recently it was found that blocking the MCU suppressed fission by decreasing Drp1 phosphorylation at S616 ( 115 ). These observations are relevant to this review because Drp1 is widely associated with tumor invasion and metastatic potential ( 104 , 116 – 118 ), and increased S616 is found in breast cancer and lymph node metastases ( 104 ).…”

Section: Mechanisms Of Mitochondrial Ca 2+ -Regulamentioning

confidence: 99%

The Regulation of Tumor Cell Invasion and Metastasis by Endoplasmic Reticulum-to-Mitochondrial Ca2+ Transfer

White

2017

Front. Oncol.

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Cell migration is one of the many processes orchestrated by calcium (Ca2+) signaling, and its dysregulation drives the increased invasive and metastatic potential of cancer cells. The ability of Ca2+ to function effectively as a regulator of migration requires the generation of temporally complex signals within spatially restricted microdomains. The generation and maintenance of these Ca2+ signals require a specific structural architecture and tightly regulated communication between the extracellular space, intracellular organelles, and cytoplasmic compartments. New insights into how Ca2+ microdomains are shaped by interorganellar Ca2+ communication have shed light on how Ca2+ coordinates cell migration by directing cellular polarization and the rearrangement of structural proteins. Importantly, we are beginning to understand how cancer subverts normal migration through the activity of oncogenes and tumor suppressors that impinge directly on the physiological function or expression levels of Ca2+ signaling proteins. In this review, we present and discuss research at the forefront of interorganellar Ca2+ signaling as it relates to cell migration, metastasis, and cancer progression, with special focus on endoplasmic reticulum-to-mitochondrial Ca2+ transfer.

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“…S7D,E " type="url"/> ). The mitochondrial Ca 2+ uniporter (MCU) is one of the major channels for mitochondrial Ca 2+ uptake, regulating migration of many cell types including primary human neutrophils ( Zheng et al, 2017 ). We further confirmed this observation by treating cells with the MCU inhibitor Ru360 and observed similar results in dHL-60 cells ( …”

Section: Resultsmentioning

confidence: 99%

Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton

Zhou

Hsu

Wang

et al. 2020

Journal of Cell Science

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Neutrophils rely on glycolysis for energy production. How mitochondria regulate neutrophil function is not fully understood. Here, we report that mitochondrial outer membrane protein Mitofusin 2 (Mfn2) regulates neutrophil homeostasis and chemotaxis in vivo. Mfn2-deficient neutrophils are released from the hematopoietic tissue, trapped in the vasculature in zebrafish embryos, and not capable of chemotaxis. Consistently, human neutrophil-like cells deficient with MFN2 fail to arrest on activated endothelium under sheer stress or perform chemotaxis on 2D surfaces. Deletion of Mfn2 results in a significant reduction of neutrophil infiltration to the inflamed peritoneal cavity in mice. Mechanistically, MFN2-deficient neutrophil-like cells display disrupted mitochondria-ER interaction, heightened intracellular calcium levels, and elevated Rac activation after chemokine stimulation. Restoring mitochondria-ER tether rescues the abnormal calcium levels, Rac hyperactivation, and chemotaxis defect resulted from MFN2 depletion. Finally, inhibition of Rac activation restores chemotaxis in MFN2-deficient neutrophils. Altogether, we identified that MFN2 regulates neutrophil migration via maintaining mitochondria-ER interaction to suppress Rac activation and uncovered a previously unrecognized role of MFN2 in regulating cell migration and the actin cytoskeleton.

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Phosphorylation of dynamin-related protein 1 at Ser616 regulates mitochondrial fission and is involved in mitochondrial calcium uniporter-mediated neutrophil polarization and chemotaxis

Cited by 31 publications

References 45 publications

New insights into the role of mitochondrial calcium homeostasis in cell migration

New insights into the role of mitochondrial calcium homeostasis in cell migration

The Regulation of Tumor Cell Invasion and Metastasis by Endoplasmic Reticulum-to-Mitochondrial Ca2+ Transfer

Mitofusin 2 regulates neutrophil adhesive migration and the actin cytoskeleton

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