Journal article
CaMKII (Ca 2+ /Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation
Arteriosclerosis, thrombosis, and vascular biology, Vol.38(6), pp.1333-1345
06/2018
DOI: 10.1161/ATVBAHA.118.310951
PMCID: PMC5970052
PMID: 29599132
Abstract
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.
The multifunctional CaMKII (Ca
/calmodulin-dependent kinase II) in the mitochondrial matrix of VSMC drove a feed-forward circuit with the mitochondrial Ca
uniporter (MCU) to promote matrix Ca
influx. MCU was necessary for the activation of mitochondrial CaMKII (mtCaMKII), whereas mtCaMKII phosphorylated MCU at the regulatory site S92 that promotes Ca
entry. mtCaMKII was necessary and sufficient for platelet-derived growth factor-induced mitochondrial Ca
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
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
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.
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.
Details
- Title: Subtitle
- CaMKII (Ca 2+ /Calmodulin-Dependent Kinase II) in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration, and Neointima Formation
- Creators
- Emily K Nguyen - Interdisciplinary Program in Molecular and Cellular Biology (E.K.N.)Olha M Koval - From the Department of Internal Medicine, Carver College of Medicine (E.K.N., O.M.K., P.N., K.B., W.H.T., I.M.G.)Paige Noble - From the Department of Internal Medicine, Carver College of Medicine (E.K.N., O.M.K., P.N., K.B., W.H.T., I.M.G.)Kim Broadhurst - From the Department of Internal Medicine, Carver College of Medicine (E.K.N., O.M.K., P.N., K.B., W.H.T., I.M.G.)Chantal Allamargot - Central Microscopy Research Facility, Carver College of Medicine (C.A.)Meng Wu - Department of Biochemistry, Carver College of Medicine (M.W.)Stefan Strack - Department of Pharmacology, Carver College of Medicine (S.S.)William H Thiel - François Abboud Cardiovascular Research Center (W.H.T., I.M.G.)Isabella M Grumbach - Iowa City Veterans Affairs Healthcare System (I.M.G.), University of Iowa, Iowa City
- Resource Type
- Journal article
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.38(6), pp.1333-1345
- Publisher
- United States
- DOI
- 10.1161/ATVBAHA.118.310951
- PMID
- 29599132
- PMCID
- PMC5970052
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Grant note
- F30 HL131078 / NHLBI NIH HHS R01 HL108932 / NHLBI NIH HHS 14SDG18850071 / American Heart Association-American Stroke Association R21 NS087908 / NINDS NIH HHS T32 GM007337 / NIGMS NIH HHS I01 BX000163 / BLRD VA R01 NS056244 / NINDS NIH HHS
- Language
- English
- Date published
- 06/2018
- Academic Unit
- Pharmacy; Core Research Facilities; Pathology; Iowa Neuroscience Institute; Cardiovascular Medicine; Radiation Oncology; Neuroscience and Pharmacology; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984040020002771
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