NEWS AND VIEWS

Mitochondria link metabolism and epigenetics

in haematopoiesis
John C. Schell and Jared Rutter
Due to their varied metabolic and signalling roles, mitochondria are important in mediating cell behaviour. By altering mitochondrial
function, two studies now identify metabolite-induced epigenetic changes that have profound effects on haematopoietic stem cell
fate and function.

Many aspects of the metabolic status of hae-
matopoietic stem cells (HSCs) have been
thoroughly described. Commonly character-
ized as residing in a hypoxic niche, their highly
glycolytic nature and low mitochondrial res-
piratory activity are key features. The changes
that occur during differentiation mirror what
can be observed in many other stem cell sys-
tems: a shift from relying largely on glycolysis
to increasing mitochondrial fuel oxidation1.
Perturbation of metabolic pathways due to
mutations can lead to impaired differen-
tiation and even predispose to leukaemia2,3.
Despite this knowledge, there is still much to
be learned about the role and regulation of
the organelle at the epicentre of metabolism,
the mitochondrion. While mitochondria may
seem dispensable due to the highly glycolytic
nature of HSCs, increasing evidence supports
the significance of roles for this organelle
beyond oxidative phosphorylation, including
biosynthesis, signalling, and epigenetic regu-
lation4–6. By perturbing the electron transport
chain directly and indirectly in HSCs and
progenitors, two papers have shown critical
roles for mitochondria in regulating HSC
function7,8 (Fig. 1).
Haematopoiesis is a powerful system in
which to study metabolism, as it allows exten-
sive characterization of functional properties
such as stemness and the differentiation poten-
tial of stem cells during each developmental
John C. Schell and Jared Rutter are in the
Department of Biochemistry and Howard Hughes
Medical Institute, University of Utah School of
Medicine, 15 North Medical Drive East, Room
5520A, Salt Lake City, Utah 84112‑5650, USA.
e-mail: Rutter@biochem.utah.edu
state9. Extremely thorough RNA sequencing
and proteomic profiling of human haemat-
opoietic cells differentiated ex vivo by Liu et al.7
revealed that key mitochondrial components
were regulated in a post-transcriptional man-
ner. This finding was traced to a signalling
pathway involving mTORC1-mediated regula-
tion of protein translation and mitochondrial
biogenesis, consistent with a previous report
(Fig. 1d)10. By utilizing in vivo tools to explore
fetal haematopoiesis, Ansó et  al.8 observed
striking effects on HSCs and progenitors fol-
lowing perturbation of mitochondrial function.
The loss of a required component of com-
plex III of the mitochondrial electron trans-
port chain, Rieske iron-sulfur protein (RISP),
in HSCs resulted in normal development until
embryonic day 15.5 (E15.5), but disruption of
the haematopoietic system and death occurred
only a few days later at E18.5. This promi-
nent effect was observed even though RISP-
knockout (KO) animals displayed an increased
number of BrdU-positive cells indicating
an increase in proliferation. Strikingly, the
researchers found no evidence of a disruption
in mitochondrial membrane potential, which
is required for most of the metabolic functions
carried out by mitochondria, not just ATP
production. A similar effect was also seen in
erythroid progenitors by Liu et al. using a more
global disruption of mitochondrial function
through mitochondrial transcription factor A
(TFAM) depletion. TFAM loss abrogates the
expression of mitochondria-encoding genes,
including core components of the oxidative
phosphorylation complexes11. TFAM knock-
down in proerythroblasts (ProEs) resulted in
substantial decreases in mitochondrial DNA,
mitochondrial mass, ATP, and membrane
potential. In both models, the liver, which is
the site of fetal haematopoiesis, exhibited an
increase in apoptosis and a corresponding loss
of cellularity (Fig. 1).
When characterizing the function of
RISP-KO cells, Ansó et  al. found consist-
ent defects in their ability to survive and to
maintain a functional haematopoietic system.
Colony formation, reconstitution assays and
competition of engrafted cells all pointed to a
severe defect when mitochondrial complex III
was lost. In addition, the findings were consist-
ent with a reduction in the expression of genes
that support HSC maintenance. This func-
tional characterization, using a multitude of
complementary approaches, nicely illustrates
the importance of mitochondria during stress
and homeostasis.
In both studies, the alterations that occur
in HSC and progenitor cell functions were
tied to changes in gene expression and mRNA
abundance. The link between mitochondria,
metabolites, and epigenetics is now becom-
ing increasingly appreciated and was a logi-
cal connection for both groups to pursue12.
Despite differences in their proposed mecha-
nisms, both groups found that mitochondrial
perturbation led to alterations in metabolites
alongside changes in histone and DNA modifi-
cations (Fig. 1b). Ansó et al. showed that RISP
deletion resulted in a constellation of metab-
olite imbalances. Most notably, succinate,
fumarate, and 2‑hydroxyglutarate increased
relative to α‑ketoglutarate, consistent with a
previous study of complex III mutation13. This
skewed balance is known to alter the activity
of α‑ketoglutarate-dependent dioxygenases,

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NEWS AND VIEWS

a following engraftment indicated a loss of stem

cell activity after RISP deletion. In a simple but
elegant experiment the authors showed that at
RISP an early time point following RISP loss, HSC
TFAM d numbers were maintained while progenitors
mTORC1 increased, suggesting a loss of quiescence and
re-entry into the cell cycle. Only three days
later, the HSC and progenitor numbers had
declined with both populations demonstrat-
mRNA ing increased apoptosis.
Post-transcriptional
regulation Collectively, this work illustrates the impor-
2-Hydroxyglutarate β-Hydroxybutyrate
tance of functional mitochondria in maintain-
b
ing fetal and adult HSC function. The observed
defects in haematopoiesis most likely origi-
DNA/histone Histone nated from metabolite imbalances that impinge
methylation acetylation on critical enzymes involved in epigenetic
modifications, subsequently leading to altered
transcript abundance. In this way, the authors
connected mitochondrial function with metab-
Gene expression changes Mitochondrial biogenesis olites that fundamentally alter the nuclear con-
trol of cell function. By delving deeper into the
roles of mitochondria, this work has expanded
c
RISP-KO our understanding of essential mitochondrial
TFAM-KO contributions, even in hypoxic and/or glyco-
lytic cells wherein ATP production, the most
commonly known function of this organelle,
might be limited.
Fetal stem cells (HSCs) Both papers demonstrate the essential func-
Progenitors ProE Differentiated cells tions of mitochondria in haematopoiesis and
consequently open up many additional lines
Figure 1 Mitochondrial regulation of haematopoiesis. (a) Loss of the mitochondrial complex III
subunit RISP in HSCs and TFAM in ProEs leads to metabolic alterations, most notably elevated
of inquiry. The effects of RISP and TFAM
2‑hydroxyglutarate downstream of RISP and β-hydroxybutyrate downstream of TFAM. (b) Metabolite deletion have far-ranging effects and while
alterations, especially increased 2‑hydroxyglutarate due to RISP loss, alter DNA and histone the authors pinpoint epigenetic regulation as
methylation, whereas β-hydroxybutyrate accumulation following TFAM knockout increases histone critically important, other mechanisms are cer-
acetylation. In this way, changes in mitochondrial function alter metabolite abundance and change the
epigenetic landscape. (c) These transcript changes lead to a defect in cell function and differentiation,
tainly involved as well. In the context of TFAM
with RISP-KO in HSCs reducing the progenitor pool and skewing erythrocyte progenitors towards a more depletion in ProEs, mitochondrial membrane
immature form. Later in haematopoiesis, at the proerythroblast (ProE) stage, loss of TFAM results in potential was lost, which would have numer-
a similar block in erythrocyte development. (d) mTORC1-mediated post-transcriptional regulation of ous effects besides respiration, including on
mitochondrial proteins was shown to be critical for mitochondrial biogenesis and essential for normal
development of the erythroid lineage. the biosynthesis of molecules that are critical
for erythrocyte function, particularly haem.
including the TET (ten-eleven translocation) abundance of β‑hydroxybutyrate, a metabolite It will be interesting to isolate specific mito-
and Jumonji domain DNA demethylases. The known to inhibit histone deacetylases (Fig. 1). chondrial functions, such as ATP production,
decreased NAD+/NADH ratio might further The fetal system is geared toward the rapid biosynthetic capacity, metabolite utilization,
exacerbate the accumulation of 2‑hydroxy- cell proliferation needed to establish the entire and signalling functions, to determine which
glutarate. Indeed, the authors established haematopoietic system, while the adult system of them are most essential in a given context.
that DNA and histone methylation were sig- is focused on a mix of proliferation and qui- This separation of function is challenging,
nificantly altered by RISP loss. They linked escence required for homeostasis. Ansó et al. but one example has recently emerged from
the observed hypermethylation with altered extended the characterization of RISP-KO the Chandel group14. Further research will be
transcript abundance and stem cell function, cells to the adult system to study whether needed to better understand the dynamism and
thereby connecting mitochondrial defects proliferating and quiescent HSCs displayed variation of metabolism and mitochondria in
to epigenetic marks and gene regulation. a differential dependence on mitochondrial the haematopoietic system. How responsive is
Likewise, Liu et al. found that TFAM deletion respiratory activity. Consistent with the fetal stem cell metabolism to diet and how would
in erythroid progenitors resulted in aberrant system, poly(I:C)-induced loss of RISP in any dietary changes affect HSC maintenance
histone acetylation in the promoters of haema- Mx1-Cre-expressing mice led to severe hae- and differentiation? Does the epigenetic link
topoietic-stem/progenitor-cell-specific genes. matopoietic defects and animal lethality between metabolism and mitochondria exist
This change correlated with an increase in the within three weeks. Competition experiments only in dysfunctional states or is it also crucial

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 NEWS AND VIEWS

in homeostatic gene regulation? It is possible
that these defects also underlie disease contexts
that affect mitochondrial function, for which
a connection has not yet been elucidated.
Another interesting question would be whether
the effect on adult quiescent HSCs is due to the
same epigenetic alterations observed in devel-
oping mice or a more direct metabolic effect, as
adult cells depend more heavily on mitochon-
drial oxidative metabolism. The metabolite
2‑hydroxyglutarate has been reported to pro-
mote oncogenesis, but whether it also regulates
physiological processes remains to be estab-
lished15. Although much of the research focus
is on alterations in demethylases, there are
many other enzymes that may be influenced
by 2‑hydroxyglutarate. As technology evolves
and sensitivity increases, it will be interesting
to sample smaller and smaller populations to
compare transcript and protein abundance to
further clarify the post-transcriptional regu-
lation of critical mitochondrial components
on the level of individual cells. These studies
provide an excellent foundation for additional
work into the critical roles of mitochondria
in the blood and other stem cell systems. By
continuing to explore the different properties
of this fascinating organelle, its indispensable
influence on cell fate and function will con-
tinue to be uncovered.
COMPETING FINANCIAL INTERESTS.
The authors declare no competing financial interests.
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(2014).
2. Figueroa, M. E. et al. Cancer Cell 18, 553–567 (2010).
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4. Birsoy, K. et al. Cell 162, 540–551 (2015).
5. Sullivan, L. B. et al. Cell 162, 552–563 (2015).
6. Chandel, N. S. Cell Metab. 22, 204–206 (2015).
7. Liu, X. et al. Nat. Cell Biol. 19, 626–638 (2017).
8. Ansó, E. et al. Nat. Cell Biol. 19, 614–625 (2017).
9. Spangrude, G.  J., Heimfeld, S. & Weissman, I.  L.
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Cell forces meet cell metabolism

Tadamoto Isogai, Jin Suk Park and Gaudenz Danuser

Epithelial cells form energetically costly cell–cell adhesions in response to mechanical forces. How cells obtain their energy
during this event is unclear. Activity of a key regulator of cell metabolism, the AMP-activated protein kinase (AMPK), is now
shown to be mechanoresponsive, and thus can bridge adhesion mechanotransduction and energy homeostasis.

Cells sense mechanical force through which
differentiation, development, and spatial ori-
entation are regulated. Force is transmitted
through cell–cell and cell–matrix adhesions1.
Each adhesion involves transmembrane recep-
tors promoting physical contact with the extra-
cellular subject. In cell–cell adhesions such
connections are established by the family of
cadherins, which form homo- and heterodi-
meric junctions2. Different combinations of
cadherin family members are expressed across
different tissues, but epithelia rely predomi-
nantly on E‑cadherin3.
The formation of cell–cell adhesions by
E‑cadherin is mechanochemically responsive,
that is, mechanical forces across the interacting
transmembrane receptors are sensed and trans-
lated into signals that promote reinforcement of
the adhesive connection, as well as activation
of effector signalling pathways. In particular,
epithelial cells, which line the endothelium,
reinforce cell–cell adhesions and the cortical
Tadamoto Isogai, Jin Suk Park and Gaudenz Danuser
are in the Department of Cell Biology, Lyda Hill
Department of Bioinformatics, UT Southwestern
Medical Center, Dallas, Texas 75390, USA.
e-mail: Gaudenz.Danuser@UTSouthwestern.edu
cytoskeleton to withstand forces such as those
from sheer stress. This process involves acute
remodelling of the underlying actin network,
which may use up to approximately 50% of total
ATP within a cell4. Yet, it is unclear how cells
ensure availability of this energy during force-
induced intercellular adhesion formation.
Glycolysis is a major energy-generating
pathway, whereby glucose is broken down to
produce energy stored as ATP. Recent emerg-
ing evidence suggests that glycolysis and cell
mechanics are coupled5,6. Studies have shown
that force transmission from extracellular
matrix through integrins stimulates signalling
cascades that regulate cell metabolism5. These
include the PI(3)K pathway that activates
AKT, which turns on glycolytic enzymes and
enhances HIF‑1α activity via mTOR. HIF‑1α
then directs glycolysis by driving the expres-
sion of glucose transporters5. In addition, a
recent report showed that PI(3)K-mediated
actin cytoskeletal rearrangements trigger
aldolase activation to stimulate glycolysis
and energy production6. Energy homeosta-
sis is maintained by AMPKs, which are het-
erotrimeric complexes that sense AMP/ATP
and ADP/ATP ratios within a cell7. In fact,
the activity of AMPK has been associated
previously with efficient assembly and disas-
sembly of cell–cell junctions8.
DeMali and colleagues now show that
AMPK is activated when cells experience exter-
nal mechanical forces and that force mediates
the formation of a complex containing AMPK,
E‑cadherin and liver kinase B1 (LKB1; ref. 9).
First and foremost, the authors demonstrate
that AMPK is activated by forces impinging on
E‑cadherin-mediated adhesions. This is dem-
onstrated elegantly through multiple experi-
mental approaches including application of
magnetic pulling force and sheer flow. Several
loss-of-function approaches demonstrate that
AMPK becomes phosphorylated and activated
in a force- and E‑cadherin-dependent manner.
Importantly, application of force to an unre-
lated adhesion receptor, syndecan‑1, did not
stimulate AMPK phosphorylation, empha-
sizing the specificity of E‑cadherin-mediated
action on AMPK activation9.
E-cadherins are connected intracellularly
with the actin cytoskeleton through additional
scaffolding proteins including catenins. Forces
sensed by E‑cadherin are transduced to the
RhoA–myosin II pathway that facilitates
intracellular contractility 2,10. Force-induced
phosphorylation of AMPK was accompanied

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