EDITORIAL Cardiovascular Research (2015) 106, 175–177 doi:10.1093/cvr/cvv113 Mitochondrial dynamics regulate neointima formation Keigi Fujiwara1* and Shey-Shing Sheu 2 1 Department of Cardiology, Division of Internal Medicine, University of Texas MD Anderson Cancer Center, 2121 West Holcombe Blvd., Houston, TX 77030, USA; and 2Center for Translational Medicine, Department of Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, 1020 Locust Street, Room 543D, Philadelphia, PA 19107, USA Online publish-ahead-of-print 23 March 2015 This editorial refers to ‘Decreasing mitochondrial fission diminishes vascular smooth muscle cell migration and ameliorates intimal hyperplasia’ by L. Wang et al., pp. 272 –283. The opinions expressed in this article are not necessarily those of the Editors of Cardiovascular Research or of the European Society of Cardiology. * Corresponding author. Tel: +1 585 273 5714; fax: +1 585 273 1497, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: [email protected]. Downloaded from by guest on July 6, 2015 Imagine that you were asked to give a lecture on mitochondria. You may want to make a slide to show what a mitochondrion looks like, and for that, you might go to a public website to get images of mitochondria. What you find in such sites are nice drawings, many of which look like a klomp. This stereotypical image of the organelle is based on the twodimensional electron micrographs of thin sections. When one looks at mitochondria in live cells under a microscope, they come in all shapes and lengths; although their diameter appears to be more uniform (roughly 1 mm). What impresses a viewer is their dynamic nature: they move about within cells, often along microtubules, but more importantly, they change their length and shape. It is now known that short mitochondria are formed from long mitochondria through a process called fission, and long ones by fusion of small mitochondria. Fusion and fission of mitochondria are not random processes but are regulated by a set of different GTPase proteins. However, we do not yet fully understand how the shape of mitochondria relates to normal cellular physiology and to the pathophysiology of human diseases. In this issue, a beautifully illustrated paper by Wang et al. 1 shows that the size of mitochondria has a lot to do with cell migration, mitochondria energetics, and even neointima formation. Using cultured vascular smooth muscle cells, the authors first show that cell migration can be regulated by changing the shape of mitochondria. Most of mitochondria in cultured smooth muscle cells appear long and thread-like, but when the cells were treated with PDGF, a condition that induces locomotive activity of these cells, mitochondria became fragmented (Figure 1). When the investigators prevented mitochondria from becoming fragmented in PDGF-treated cells, motile activity of those cells was down-regulated. Furthermore, using mouse embryonic fibroblasts in an in vitro wound closure assay experiment, the authors observed that the cells at the front edge of the wound had fragmented mitochondria while those away from the wound contained long mitochondria. This experiment not only shows the functional correlation between mitochondrial morphology and cell motility but also suggests that this correlation is a general rule for cells. The mitochondrial fission needed to increase cell motility was mediated by dynamin-like protein 1(DLP1) which is also called dynamin-related protein 1 (DRP1), a protein known to pinch a mitochondrion into two, and PDGF was shown to dose-dependently activate (i.e. phosphorylate) DLP1. Indeed, cells overexpressing a dominant negative form of DLP1 failed to fragment mitochondria and to increase their migration when they were treated with PDGF. Through these and other in vitro experiments, the authors convincingly show that mitochondria fission is a requirement for increased cell motility. There are other studies that have focused on mitochondria dynamics and cell migration.2,3 The novel finding of this paper from Yoon’s lab is that fragmentation of mitochondria (in smooth muscle cells treated with PDGF) increases mitochondrial energetics, which is undoubtedly favourable or even necessary for increased motile activity of cells.1 The mechanisms responsible for the enhanced bioenergetics under physiological fission are still unclear.4 It is plausible that fragmentation could render mitochondria more susceptible to forming respiration supercomplexes, and/or more effective in Ca2+ uptake from endoplasmic reticulum (ER) due to higher surface to volume ratio of mitochondria-ER tethering, resulting in more ATP generation.5,6 In addition to this fissionmediated ATP generation, it has been shown that fission can enhance reactive oxygen species (ROS) generation,7 which also plays an important role in the migration and adhesion of cells.8 What do these mitochondrial dynamics have to do with human diseases? As evidenced by a recent review in New England Journal of Medicine,9 mitochondrial dynamics appears to play critical roles in many diseases. Dysregulated mitochondrial function and dynamics are tied to many forms of neurological diseases10,11 and to cancer.12 As for cardiovascular diseases, the role of mitochondria in ischemia-reperfusion injury of the heart is well-known.13 To see whether mitochondrial dynamics played a role in vascular diseases, Wang et al. generated transgenic mice expressing dominant-negative DLP1, which down-regulates mitochondrial fission, and wire-injured the endothelium of the femoral artery of these mice.1 They observed a significantly reduced formation of neointima in the transgenic animal. This is the first clear evidence establishing the correlation between mitochondrial dynamics and vascular pathology. This reduced neointima formation is presumably due to the decreased migratory activity of smooth muscle cells, which may partly be due to reduced ATP, ROS, and Ca2+ signalling. This and other in vivo observations are consistent with various results obtained in their in vitro studies. 176 Editorial Downloaded from by guest on July 6, 2015 Figure 1 Schematic illustration depicting mitochondrial morphology in resting (A) and migrating (B) vascular smooth muscle cells in culture. Most mitochondria in resting cells exhibit an elongated morphology. This morphology is achieved by mitochondrial fusion. When cells are stimulated to migrate (such as by PDGF as in this illustration), mitochondrial fission signalling is activated resulting in fragmentation of the mitochondria. Fragmented mitochondria are transported (presumably along microtubules) to the leading edge of the migrating cell. In vivo, PDGF may be released from the site of arterial injury (dotted line), causing smooth muscle cells to move into the intima. The idea to control human diseases by manipulating mitochondrial dynamics is not new.14 Now that we are aware of the important role of mitochondrial dynamics in atherosclerotic plaque formation, we may ask whether or not this pathology can be treated by manipulating mitochondrial function. Although this may be possible, we must first identify the molecules that mechanistically link DLP1 activation to atherogenesis. It is possible that smooth muscle cell migration is deeply involved in this, but at the same time, it may not be, since mitochondrial energetics regulates many aspects of cell physiology. In this regard, the study by Wang et al. 1 has opened a door to intriguing possibilities that may lead to new insights into the mechanism of atherogenesis. References 1. Wang L, Yu T, Lee H, O’Brien DK, Sesaki H, Yoon Y. Decreasing mitochondrial fission diminishes vascular smooth muscle cell migration and ameliorates intimal hyperplasia. Cardiovasc Res 2015;106:272 –283. 2. Campello S, Lacalle RA, Bettella M, Man˜es S, Scorrano L, Viola A. Orchestration of lymphocyte chemotaxis by mitochondrial dynamics. J Exp Med 2006;203: 2879– 2886. 3. Zhao J, Zhang J, Yu M, Xie Y, Huang Y, Wolff DW, Abel PW, Tu Y. Mitochondrial dynamics regulates migration and invasion of breast cancer cells. Oncogene 2013;32: 4814– 4824. 4. Yu T, Wang L, Yoon Y. Morphological control of mitochondrial bioenergetics. Front Biosci 2015;20:229 –246. 5. O-Uchi J, Jhun BS, Hurst S, Bisetto S, Gross P, Chen M, Kettlewell S, Park J, Oyamada H, Smith GL, Murayama T, Sheu SS. Overexpression of ryanodine receptor type 1 enhances mitochondrial fragmentation and Ca2+-induced ATP production in cardiac H9c2 myoblasts. Am J Physiol Heart Circ Physiol 2013;305:H1736 – H1751. 6. Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 2013;155:160 –171. 7. Yu T, Sheu SS, Robotham JL, Yoon Y. Mitochondrial fission mediates high glucose-induced cell death through elevated production of reactive oxygen species. Cardiovasc Res 2008;79:341–351. 8. Hurd TR, DeGennaro M, Lehmann R. Redox regulation of cell migration and adhesion. Trends Cell Biol 2012;22:107 – 115. Editorial 9. Archer SL. Mitochondrial dynamics — Mitochondrial fission and fusion in human diseases. N Engl J Med 2013;369:2236 –2251. 10. Itoh K, Nakamura K, Iijima M, Sesaki H. Mitochondrial dynamics in neurodegeneration. Trends Cell Biol 2013;23:64 –71. 11. Haun F, Nakamura T, Lipton S. Dysfunctional mitochondrial dynamics in the pathophysiology of neurodegenerative diseases. J. Cell Death 2013;6:27– 35. 177 12. Wallace DC. Mitochondria and cancer. Nat Rev Cancer 2012;12:685 – 698. 13. Ong S-B, Hall AR, Hausenloy DJ. Mitochondrial dynamics in cardiovascular health and disease. Antioxid Pedox Signal 2013;19:400 – 414. 14. Dromparis P, Michelakis ED. Mitochondria in vascular health and disease. Ann Rev Physiol 2013;75:95–126. Downloaded from by guest on July 6, 2015
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