Elsevier

Redox Biology

Volume 1, Issue 1, 2013, Pages 542-551
Redox Biology

Mitochondrial fission induced by platelet-derived growth factor regulates vascular smooth muscle cell bioenergetics and cell proliferation

https://doi.org/10.1016/j.redox.2013.10.011Get rights and content
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Highlights

  • PDGF promotes mitochondrial fragmentation in vascular smooth muscle cells.

  • PDGF increases metabolic reliance on fatty acids.

  • Mitochondrial fragmentation regulates proliferation and bioenergetics.

  • PDGF-induced bioenergetic and autophagic responses regulate de-differentiation.

Abstract

Vascular smooth muscle cells (VSMCs) develop a highly proliferative and synthetic phenotype in arterial diseases. Because such phenotypic changes are likely integrated with the energetic state of the cell, we hypothesized that changes in cellular metabolism regulate VSMC plasticity. VSMCs were exposed to platelet-derived growth factor-BB (PDGF) and changes in mitochondrial morphology, proliferation, contractile protein expression, and mitochondrial metabolism were examined. Exposure of VSMCs to PDGF resulted in mitochondrial fragmentation and a 50% decrease in the abundance of mitofusin 2. Synthetic VSMCs demonstrated a 20% decrease in glucose oxidation, which was accompanied by an increase in fatty acid oxidation. Results of mitochondrial function assays in permeabilized cells showed few changes due to PDGF treatment in mitochondrial respiratory chain capacity and coupling. Treatment of VSMCs with Mdivi-1—an inhibitor of mitochondrial fission—inhibited PDGF-induced mitochondrial fragmentation by 50% and abolished increases in cell proliferation; however, it failed to prevent PDGF-mediated activation of autophagy and removal of contractile proteins. In addition, treatment with Mdivi-1 reversed changes in fatty acid and glucose oxidation associated with the synthetic phenotype. These results suggest that changes in mitochondrial morphology and bioenergetics underlie the hyperproliferative features of the synthetic VSMC phenotype, but do not affect the degradation of contractile proteins. Mitochondrial fragmentation occurring during the transition to the synthetic phenotype could be a therapeutic target for hyperproliferative vascular disorders.

Abbreviations

ADP
adenine dinucleotide phosphate
ATP5A1
ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1
ATP5B
ATP synthase, H+ transporting, mitochondrial F1 complex, beta polypeptide
CPT1
carnitine palmitoyl transferase 1
DMEM
Delbucco's Eagle Modified Medium
Drp1
dynamin-related protein 1
EDTA
ethylenediaminetetraacetic acid
EGTA
ethylene glycol tetraacetic acid
MOPS
3-(N-morpholino)propanesulfonic acid
Fis1
mitochondrial fission 1 protein
FCCP
Carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone
FBS
fetal bovine serum
HEPES
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
NDUFB8
NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 8
NP-40
noniodet P40
LC3
(microtubule-associated protein 1 light chain 3)
Opa1
optic atrophy 1
PCNA
proliferating cell nuclear antigen
PDGF-BB
platelet-derived growth factor-BB
PVDF
polyvinylidene fluoride
SDS
sodium dodecyl sulfate
SDHB
succinate dehydrogenase subunit B
TMPD
N,N,N′,N′-tetramethyl-p-phenylenediamine
VSMC
vascular smooth muscle cells

Keywords

Metabolism
Oxidative phosphorylation
Restenosis
Atherosclerosis
Fusion
Extracellular flux

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