Decreasing Mitochondrial Fission Diminishes Vascular Smooth Muscle Cell Migration and Ameliorates Intimal Hyperplasia

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2015 Jan 15

PMID 25587046

Citations 54

Authors

Li Wang

Tianzheng Yu

Hakjoo Lee

Dawn K OBrien

Hiromi Sesaki

Yisang Yoon

Affiliations

Soon will be listed here.

Abstract

Aims: Vascular smooth muscle cell (VSMC) migration in response to arterial wall injury is a critical process in the development of intimal hyperplasia. Cell migration is an energy-demanding process that is predicted to require mitochondrial function. Mitochondria are morphologically dynamic, undergoing continuous shape change through fission and fusion. However, the role of mitochondrial morphology in VSMC migration is not well understood. The aim of the study is to understand how mitochondrial fission contributes to VSMC migration and provides its in vivo relevance in the mouse model of intimal hyperplasia.

Methods And Results: In primary mouse VSMCs, the chemoattractant PDGF induced mitochondrial shortening through the mitochondrial fission protein dynamin-like protein 1 (DLP1)/Drp1. Perturbation of mitochondrial fission by expressing the dominant-negative mutant DLP1-K38A or by DLP1 silencing greatly decreased PDGF-induced lamellipodia formation and VSMC migration, indicating that mitochondrial fission is an important process in VSMC migration. PDGF induced an augmentation of mitochondrial energetics as well as ROS production, both of which were found to be necessary for VSMC migration. Mechanistically, the inhibition of mitochondrial fission induced an increase of mitochondrial inner membrane proton leak in VSMCs, abrogating the PDGF-induced energetic enhancement and an ROS increase. In an in vivo model of intimal hyperplasia, transgenic mice expressing DLP1-K38A displayed markedly reduced ROS levels and neointima formation in response to femoral artery wire injury.

Conclusions: Mitochondrial fission is an integral process in cell migration, and controlling mitochondrial fission can limit VSMC migration and the pathological intimal hyperplasia by altering mitochondrial energetics and ROS levels.

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References

Yu T, Robotham J, Yoon Y . Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A. 2006; 103(8):2653-8. PMC: 1413838. DOI: 10.1073/pnas.0511154103. View

Hu Y, Mayr M, Metzler B, Erdel M, Davison F, Xu Q . Both donor and recipient origins of smooth muscle cells in vein graft atherosclerotic lesions. Circ Res. 2002; 91(7):e13-20. DOI: 10.1161/01.res.0000037090.34760.ee. View

Clempus R, Griendling K . Reactive oxygen species signaling in vascular smooth muscle cells. Cardiovasc Res. 2006; 71(2):216-25. PMC: 1934427. DOI: 10.1016/j.cardiores.2006.02.033. View

Szabadkai G, Simoni A, Bianchi K, De Stefani D, Leo S, Wieckowski M . Mitochondrial dynamics and Ca2+ signaling. Biochim Biophys Acta. 2006; 1763(5-6):442-9. DOI: 10.1016/j.bbamcr.2006.04.002. View

Campello S, Lacalle R, Bettella M, Manes S, Scorrano L, Viola A . Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J Exp Med. 2006; 203(13):2879-86. PMC: 2118173. DOI: 10.1084/jem.20061877. View

Benard G, Bellance N, James D, Parrone P, Fernandez H, Letellier T . Mitochondrial bioenergetics and structural network organization. J Cell Sci. 2007; 120(Pt 5):838-48. DOI: 10.1242/jcs.03381. View

Taguchi N, Ishihara N, Jofuku A, Oka T, Mihara K . Mitotic phosphorylation of dynamin-related GTPase Drp1 participates in mitochondrial fission. J Biol Chem. 2007; 282(15):11521-9. DOI: 10.1074/jbc.M607279200. View

Hom J, Gewandter J, Michael L, Sheu S, Yoon Y . Thapsigargin induces biphasic fragmentation of mitochondria through calcium-mediated mitochondrial fission and apoptosis. J Cell Physiol. 2007; 212(2):498-508. DOI: 10.1002/jcp.21051. View

Chang C, Blackstone C . Cyclic AMP-dependent protein kinase phosphorylation of Drp1 regulates its GTPase activity and mitochondrial morphology. J Biol Chem. 2007; 282(30):21583-7. DOI: 10.1074/jbc.C700083200. View

10.

Cribbs J, Strack S . Reversible phosphorylation of Drp1 by cyclic AMP-dependent protein kinase and calcineurin regulates mitochondrial fission and cell death. EMBO Rep. 2007; 8(10):939-44. PMC: 2002551. DOI: 10.1038/sj.embor.7401062. View

11.

Yu T, Sheu S, Robotham J, Yoon Y . Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res. 2008; 79(2):341-51. PMC: 2646899. DOI: 10.1093/cvr/cvn104. View

12.

Han X, Lu Y, Li S, Kaitsuka T, Sato Y, Tomizawa K . CaM kinase I alpha-induced phosphorylation of Drp1 regulates mitochondrial morphology. J Cell Biol. 2008; 182(3):573-85. PMC: 2500141. DOI: 10.1083/jcb.200802164. View

13.

Tondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S . SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 2009; 28(11):1589-600. PMC: 2693158. DOI: 10.1038/emboj.2009.89. View

14.

Mitra K, Wunder C, Roysam B, Lin G, Lippincott-Schwartz J . A hyperfused mitochondrial state achieved at G1-S regulates cyclin E buildup and entry into S phase. Proc Natl Acad Sci U S A. 2009; 106(29):11960-5. PMC: 2710990. DOI: 10.1073/pnas.0904875106. View

15.

Wakabayashi J, Zhang Z, Wakabayashi N, Tamura Y, Fukaya M, Kensler T . The dynamin-related GTPase Drp1 is required for embryonic and brain development in mice. J Cell Biol. 2009; 186(6):805-16. PMC: 2753156. DOI: 10.1083/jcb.200903065. View

16.

Bisaillon J, Motiani R, Gonzalez-Cobos J, Potier M, Halligan K, Alzawahra W . Essential role for STIM1/Orai1-mediated calcium influx in PDGF-induced smooth muscle migration. Am J Physiol Cell Physiol. 2010; 298(5):C993-1005. PMC: 2867390. DOI: 10.1152/ajpcell.00325.2009. View

17.

Shen J, Yang M, Ju D, Jiang H, Zheng J, Xu Z . Disruption of SM22 promotes inflammation after artery injury via nuclear factor kappaB activation. Circ Res. 2010; 106(8):1351-62. PMC: 2896867. DOI: 10.1161/CIRCRESAHA.109.213900. View

18.

Perez J, Hill B, Benavides G, Dranka B, Darley-Usmar V . Role of cellular bioenergetics in smooth muscle cell proliferation induced by platelet-derived growth factor. Biochem J. 2010; 428(2):255-67. PMC: 3641000. DOI: 10.1042/BJ20100090. View

19.

Yu T, Jhun B, Yoon Y . High-glucose stimulation increases reactive oxygen species production through the calcium and mitogen-activated protein kinase-mediated activation of mitochondrial fission. Antioxid Redox Signal. 2010; 14(3):425-37. PMC: 3025178. DOI: 10.1089/ars.2010.3284. View

20.

Qi X, Disatnik M, Shen N, Sobel R, Mochly-Rosen D . Aberrant mitochondrial fission in neurons induced by protein kinase C{delta} under oxidative stress conditions in vivo. Mol Biol Cell. 2010; 22(2):256-65. PMC: 3020920. DOI: 10.1091/mbc.E10-06-0551. View