Abstract
Abstract 687: CaMKII in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration and Neointimal Hyperplasia
Arteriosclerosis, thrombosis, and vascular biology, Vol.38(Suppl_1)
05/2018
DOI: 10.1161/atvb.38.suppl_1.687
Abstract
Objective:
To define the mechanisms by which mitochondria control VSMC migration and impact neointimal hyperplasia.
Approach and Results:
The multifunctional Ca
2+
/calmodulin-dependent kinase II (CaMKII) 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 PDGF-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 WT MCU, but not MCU S92A mutant in MCU
-/-
VSMC rescued migration and mitochondrial mobility. The outer mitochondrial membrane GTPase Miro-1 promotes mitochondrial mobility, but arrests it in subcellular domains of high Ca
2+
concentrations. In Miro-1
-/-
VSMC, mitochondrial mobility and VSMC migration were abolished, overexpression of mtCaMKII nor 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 following vascular injury.
Details
- Title: Subtitle
- Abstract 687: CaMKII in Mitochondria of Smooth Muscle Cells Controls Mitochondrial Mobility, Migration and Neointimal Hyperplasia
- Creators
- Emily K Nguyen - University of IowaOlha Koval - University of IowaIsabella Grumbach - University of Iowa
- Resource Type
- Abstract
- Publication Details
- Arteriosclerosis, thrombosis, and vascular biology, Vol.38(Suppl_1)
- DOI
- 10.1161/atvb.38.suppl_1.687
- ISSN
- 1079-5642
- eISSN
- 1524-4636
- Language
- English
- Date published
- 05/2018
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Internal Medicine
- Record Identifier
- 9984362752102771
Metrics
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