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MECHANOBIOLOGY
Golgi mechanics controls lipid metabolism
Cell metabolism ensures that cell dynamics and continued renewal are supported by a constant flow of matter that
consumes energy. A new study shows that cell metabolism is sensitive to mechanical cues, revealing that the level
of cell contraction modulates the production and storage of lipids, which could serve as fuel for energy production.
Manuel Théry and Mario Pende
T
he most straightforward and direct
impact of mechanical forces is in the
modulation of cell shape and tissue
architecture. Cell mechanics are intertwined
with cell physiology, and mechanical forces
also modulate cell functions and fate1.
For example, putting cells under tension
or stimulating the production of internal
contractile forces, stimulates cell cycle
progression2. Cell tensional states can also
direct the fate of stem cells, such as the
differentiation of mesenchymal stem cells
toward an adipogenic state3.
Through metabolism, cells renew their
components and consume resources to
produce usable energy, like ATP. Animal
cells utilize glucose, amino acids and lipids
coming from dietary food or body storage
to produce ATP. Metabolic adaptations
between external resources, internal storage
and energy production are central to tissue
homeostasis, and their deregulation is
intimately linked to the pathophysiology
of growth and development4. Links
between cell mechanics and metabolism
are emerging. There is a tight reciprocal
regulation between metabolism, adhesion
and signalling associated with integrins5.
Moreover, mechanical tension promotes
the production of ATP6. In this issue of
Nature Cell Biology, Romani et al. reveal that
contractile forces impact lipid-modifying
enzymes and the production of lipids7.
The study stems from a broad analysis
by mass spectrometry of metabolites
differentially affected by mechanical cues.
The authors show that the relaxation of
intracellular contractile forces, either
by plating cells on soft substrates or by
inhibiting the activity of myosins, leads to
a significant increase in the synthesis of
specific lipids through the sterol regulatory
element binding protein family (SREBP1
and SREBP2). SREBPs are master regulators
of lipogenesis, promoting the expression
of cholesterol, fatty acid, triglyceride and
phospholipid biosynthesis genes. SREBPs
are activated by protease-mediated cleavage
in the Golgi or endoplasmic reticulum (ER).
This cleavage is tightly controlled by factors
Nature Cell Biology | www.nature.com/naturecellbiology
a High contraction Low contraction
SREBP
SREBP ARF
SREBP Lipid
DAG
synthesis
ARF
DAG
LIPIN-1
LIPIN-1
b
Plasma membrane Nucleus
Golgi apparatus Endoplasmic
reticulum?
Fig. 1 | Mechanotransduction at the Golgi. a, Actomyosin contraction impacts Lipin-1 activity and,
therefore, on the content of DAG and ARF GTPases in the Golgi, which tend to prevent SREBP
shuttling from the ER to Golgi (left). Relaxation of actomyosin contraction (right) leads to SREBP
accumulation in the Golgi, where it is cleaved and is thereby capable of entering the nucleus promote
the expression of a program leading to lipid synthesis. b, Several mechano-sensitive organelles have
been well characterized; such as the plasma membrane and associated adhesion and contraction
machinery, as well as the nucleus and its associated networks of lamin and pore complexes. Here, the
work of Romani et al. reveals that the Golgi apparatus is also mechano-sensitive and is capable
of transducing mechanical forces into biochemical signalling. It is tempting to speculate that the ER,
which is physically connected to the nucleus and permanently exchanging material with the Golgi, is
also mechano-sensitive.
such as cholesterol, fatty acids, insulin, SREBP target genes are downregulated in
ER stress8, phosphatidylcholine (PC) and stiffened keloid scars compared to normal
diacylglycerol (DAG)9, all of which perturb tissue. In pluripotent stem cells, this lipid
the shuttling of proteins between the ER and accumulation by mechano-transduction
Golgi; and therefore, affect the subcellular participates in a pro-survival programme,
distribution of SREBPs and their proteases. possibly by providing new components of
In this study, relaxation of contractility is cellular membranes and/or energy through
shown to sharply decrease DAG content in fatty acid oxidation7.
Golgi membranes, leading to the inhibition The work by Romani et al.7 thus reveals a
of ARF-dependent, COPI-mediated previously unknown mechano-transduction
retrograde trafficking from the Golgi to pathway by which a mechanical force is
ER (Fig. 1a). The effects of actomyosin converted into a biochemical signal. Cells
relaxation are mimicked by the inhibition first sense physical cues by assembling their
of Lipin-1, a phosphatidic acid phosphatase cytoskeleton in a process called mechano-
(PAP) that converts phosphatidic acid reciprocity: cell internal architecture is set in
(PA) to DAG. Not only the biochemical accordance with external stimulation, with
composition of Golgi membranes, but also the orientation and contraction level of the
their mechanical properties are influenced actomyosin network matching the geometry
by cell contractility. In pathophysiological and stiffness of the extra-cellular matrix10.
settings, the authors demonstrate that This contractile state is further conveyed
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to the nucleus where it modulates gene
expression; several transcription factors, such
as β-catenin, serum response factor (SRF)
and Yes-associated protein (YAP), shuttle
in and out of the nucleus depending on the
mechanical state of the cell11. This study
highlights SREBPs as key transcriptional
targets in mechano-transduction. Lipin-1
is the signalling element that may mediate
the effect of cell contractility on SREBP
activity. An exciting avenue of research
will be to explore the causal link between
mechanical cues and Lipin-1 activity. Lipin-1
is heavily modified post-translationally, and
although SUMOylation, acetylation and
mTOR-dependent phosphorylation do not
seem to be involved, alternative pathways
may transduce mechanical forces to Lipin-1.
Moreover, Lipin-1 is mainly an ER-resident
protein, but can also associate with other
intracellular membranes and translocate to
the nucleus12. The authors also describe a
nuclear accumulation of Flag-tagged Lipin-1
in conditions of reduced contractility. To
elucidate how mechano-transduction directly
impinges on Lipin-1, mass spectrometry and
live imaging of endogenously tagged LPIN1
should be insightful.
Of note, lipids, such as PC and PA,
have previously been shown to influence
mechano-transduction. Inhibition of
phospholipase D (PLD), which converts
PC to PA, decreased YAP activation in
stiff environments, whereas exogenous PA
potentiated YAP activation13. However,
PLD inhibition in soft environments was
reported to activate YAP through the
inhibition of the GTPase RAP2 at the
plasma membrane14. To reconcile these
seemingly contradictory results, it is
possible that PA function and localization in
cellular membranes may differ depending
on the mechanical cues. Romani et al.7
show that reduced contractility leads to
DAG accumulation in whole cell extracts,
as assessed by mass spectrometry, while
diminishing DAG reporter levels in the
Golgi. An important challenge in the future
will be to reveal the precise lipid dynamics
in different cell compartments following
mechano-transduction. A combination of
in situ lipidomic analysis, rapid subcellular
fractionation and in vitro reconstitution
experiments may be useful. Lipid
composition of cellular membranes alters
signal transduction, protein trafficking,
membrane fluidity and curvature. In
particular, Lipin-1-dependent DAG
conversion from PA is expected to decrease
membrane curvature, which is sensed by the
ARF proteins. The present study raises the
question of whether actomyosin contractility
directly affects the physical and chemical
organizations of intracellular membranes.
This study demonstrates the role of the
Golgi apparatus in the cellular response to
mechanical cues, revealing both mechano-
sensitive and mechano-transduction
properties of this organelle. Focal adhesions
were first identified as mechano-sensitive
structures, as application of external forces
triggered their growth. Since then, the list of
mechano-sensitive organelles has expanded
(Fig. 1b). They have in common the role of
deformable elements, which act as sensors
and modulate specific biochemical reactions
in response to stretching. These include the
flattening of caveolae in plasma membranes,
the unfolding of talin in focal adhesions, the
bending of filaments, and the opening of ion
channels in plasma and nuclear membranes.
The present study echoes observations
suggesting that the actin network in the
Golgi is under tension15. Pressing beads
against the Golgi with optical tweezers can
be used to measure its apparent stiffness.
Relaxation of actomyosin makes the Golgi
softer15, concomitant with a decrease in
DAG content, as shown by Romani et al.7.
Together, these data show that physical
pressure is sufficient to change the dynamics
of the actin network in the Golgi and lipid
content in the Golgi membrane, leading to
DAG accumulation. This response occurred
rapidly, suggesting that it does not involve
de novo synthesis but rather relies on a local
force-dependent recruitment following
activation of a local sensor.
What is the sensor? How does the
Golgi sense these forces? Are there factors
coordinating the responses of different
compartments? Will the ER, squeezed
between the Golgi and the nucleus, soon
appear as another mechano-sensitive
organelle (Fig. 1b)? The current work
suggests that Lipin-1 may represent an
important element in answering these
questions. However, whether Lipin-1
transduces mechanical cues into signalling
exclusively through DAG levels in the Golgi
apparatus, or through ER stress16 or nucleus
shape12, remain to be clarified.
The discoveries by Romani et al. may
help us understand several important
physiological responses. Glucose- and
lipid-fuelled metabolisms are known
to differentially affect muscle function.
In skeletal muscles, fast-twitch fibres
mainly rely on anaerobic glycolysis and
are more suited for resistance training,
whereas slow-twitch fibres mainly rely
on lipid oxidation and are more suited
Nature Cell Biology | www.nature.com/naturecellbiology
for endurance training. Is the mechanism
described in this paper involved in the
well-established relationship between
slow-frequency contraction and oxidative
metabolism, as well as the relationship
between exercise, insulin sensitivity
and glucose versus lipid metabolism?
Of note, Lipin-1-deficiency in humans
causes rhabdomyolysis and a metabolic
myopathy with lipid accumulation16,
consistent with the key role for Lipin-1 in
mechano-transduction that is proposed
here. Similarly, the induction of SREBPs
by mechanical cues likely contributes to
the findings that cell relaxation promotes
adipogenic differentiation of mesenchymal
stem cells3. Finally, the stiffness of the
extracellular matrix is known to influence
tumour development. This study opens new
perspectives on how mechanical forces in
tumours can influence the activity of key
metabolic regulators. ❐
Manuel Théry1,2* and Mario Pende3,4,5*
1
Université Grenoble-Alpes, CEA, CNRS, INRA,
Biosciences & Biotechnology Institute of Grenoble,
Laboratoire de Phyiologie Cellulaire & Végétale,
CytoMorpho Lab, Grenoble, France. 2Université
Paris Diderot, INSERM, CEA, Hôpital Saint Louis,
Institut Universitaire d’Hematologie, UMRS1160,
CytoMorpho Lab, Paris, France. 3Institut Necker-
Enfants Malades, Paris, France. 4Inserm, U1151,
Paris, France. 5Université Paris Descartes, Sorbonne
Paris Cité, Paris, France.
*e-mail: manuel.thery@cea.fr;
mario.pende@inserm.fr
Published: xx xx xxxx
https://doi.org/10.1038/s41556-019-0289-2
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Competing interests
The authors declare no competing interests.