| First Author | Nguyen EK | Year | 2018 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 38 |
| Issue | 6 | Pages | 1333-1345 |
| PubMed ID | 29599132 | Mgi Jnum | J:285151 |
| Mgi Id | MGI:6385463 | Doi | 10.1161/ATVBAHA.118.310951 |
| Citation | Nguyen EK, et al. (2018) CaMKII (Ca(2+)/Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation. Arterioscler Thromb Vasc Biol 38(6):1333-1345 |
| abstractText | 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. |
