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 (Ca2+/calmodulin-dependent kinase II) in the mitochondrial matrix of VSMC drove a feed-forward circuit with the mitochondrial Ca2+uniporter (MCU) to promote matrix Ca2+influx. MCU was necessary for the activation of mitochondrial CaMKII (mtCaMKII), whereas mtCaMKII phosphorylated MCU at the regulatory site S92 that promotes Ca2+entry. mtCaMKII was necessary and sufficient for platelet-derived growth factor-induced mitochondrial Ca2+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 Ca2+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 Ca2+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 Ca2+uptake via MCU, thereby controlling mitochondrial translocation and VSMC migration after vascular injury.
Pharmacology, Toxicology and Pharmaceutical Science
3
5%
Other
6
10%
Unknown
25
42%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 4. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 08 April 2018.
All research outputs
#11,558,118
of 34,601,305 outputs
Outputs from Arteriosclerosis, Thrombosis, and Vascular Biology (Highwire)
#3,409
of 7,168 outputs
Outputs of similar age
#144,894
of 373,186 outputs
Outputs of similar age from Arteriosclerosis, Thrombosis, and Vascular Biology (Highwire)
#38
of 76 outputs
Altmetric has tracked 34,601,305 research outputs across all sources so far. This one has received more attention than most of these and is in the 65th percentile.
So far Altmetric has tracked 7,168 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.2. This one has gotten more attention than average, scoring higher than 50% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 373,186 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 59% of its contemporaries.
We're also able to compare this research output to 76 others from the same source and published within six weeks on either side of this one. This one is in the 46th percentile – i.e., 46% of its contemporaries scored the same or lower than it.
