Mitochondrial dynamics regulate neointima formation

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: kfujiwara1@mdanderson.org
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com.
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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.
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Editorial
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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
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diminishes vascular smooth muscle cell migration and ameliorates intimal hyperplasia.
Cardiovasc Res 2015;106:272 –283.
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Editorial
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