CaMKII (Ca 2+ /Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation
| Autor: | Paige Noble, William H. Thiel, Chantal Allamargot, Isabella M. Grumbach, Emily K. Nguyen, Stefan Strack, Meng Wu, Kim Broadhurst, Olha M. Koval |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Myosin light-chain kinase Vascular smooth muscle Chemistry Mitochondrion Cell biology Focal adhesion 03 medical and health sciences 030104 developmental biology Mitochondrial matrix Ca2+/calmodulin-dependent protein kinase Phosphorylation Cardiology and Cardiovascular Medicine Uniporter |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 38:1333-1345 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective— The main objective of this study is to define the mechanisms by which mitochondria control vascular smooth muscle cell (VSMC) migration and impact neointimal hyperplasia. Approach and Results— The multifunctional CaMKII (Ca 2+ /calmodulin-dependent kinase II) in the mitochondrial matrix of VSMC drove a feed-forward circuit with the mitochondrial Ca 2+ uniporter (MCU) to promote matrix Ca 2+ influx. MCU was necessary for the activation of mitochondrial CaMKII (mtCaMKII), whereas mtCaMKII phosphorylated MCU at the regulatory site S92 that promotes Ca 2+ entry. mtCaMKII was necessary and sufficient for platelet-derived growth factor–induced mitochondrial Ca 2+ uptake. This effect was dependent on MCU. mtCaMKII and MCU inhibition abrogated VSMC migration and mitochondrial translocation to the leading edge. Overexpression of wild-type MCU, but not MCU S92A, mutant in MCU − /− VSMC rescued migration and mitochondrial mobility. Inhibition of microtubule, but not of actin assembly, blocked mitochondrial mobility. The outer mitochondrial membrane GTPase Miro-1 promotes mitochondrial mobility via microtubule transport but arrests it in subcellular domains of high Ca 2+ concentrations. In Miro-1 −/− VSMC, mitochondrial mobility and VSMC migration were abolished, and overexpression of mtCaMKII or a CaMKII inhibitory peptide in mitochondria (mtCaMKIIN) had no effect. Consistently, inhibition of mtCaMKII increased and prolonged cytosolic Ca 2+ transients. mtCaMKII inhibition diminished phosphorylation of focal adhesion kinase and myosin light chain, leading to reduced focal adhesion turnover and cytoskeletal remodeling. In a transgenic model of selective mitochondrial CaMKII inhibition in VSMC, neointimal hyperplasia was significantly reduced after vascular injury. Conclusions— These findings identify mitochondrial CaMKII as a key regulator of mitochondrial Ca 2+ uptake via MCU, thereby controlling mitochondrial translocation and VSMC migration after vascular injury. |
| Databáze: | OpenAIRE |
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