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Transcript
Mitochondrial function and cancer
Douglas C. Wallace
In addition to compartmentalizing the metabolic pathways and physiological states
of the cell, mitochondria generate much of the cellular energy, regulate the cellular
oxidation–reduction (redox) state, produce most of the cellular reactive oxygen
species (ROS), buffer cellular Ca2+ and initiate cellular apoptosis. Mitochondria
were first proposed to be relevant to cancer by Otto Warburg who reported that
cancer cells exhibited “aerobic glycolysis”. Although this was originally interpreted
as indicating that the function of the mitochondria was defective, we now
understand that cancer cells are in an altered metabolic state with increased
Supplement to Nature Publishing Group
CANCER
glycolytic metabolism and the continued use of oxygen. Mutations that occur in
nuclear-DNA-encoded mitochondrial proteins and mitochondrial-DNA-encoded
proteins can re-orient cellular metabolism towards glycolysis, glutaminolysis,
intense macromolecular biogenesis and the oxidoreduction of NADP+ to NADPH.
Both somatic and germline mitochondrial DNA mutations have been associated
with many types of cancers, and recent data indicate that cancer cells may tolerate
mitochondrial DNA mutations for two purposes: they alter cancer cell metabolism
and/or proliferation and they enable adaption to a changing environment.
HIF1α
Fumarate
HIF1β
Altered energetics
Activation of the PI3K–AKT pathway increases glucose uptake and metabolism. AKT phosphorylates and
inactivates FOXO, downregulating PGC1α and reducing mitochondrial biogenesis. Activation of MYC induces
glutaminolysis, in which glutamine is converted to α-ketoglutarate (αKG). Reductive carboxylation of αKG to
isocitrate can be facilitated by NADPH-linked IDH2, resulting in increased citrate synthesis. Mitochondrial
citrate can be exported into the cytosol, where isocitrate can be converted to αKG by NADP+-linked
IDH1. Mutant IDH1 or IDH2 oxidize NADPH back to NADP+ and reduce αKG to R(–)-2-hydroxyglutarate
((R)-2HG), an oncometabolite that affects DNA and histone methylation and HIF1α activity. SDH
mutations disrupt the TCA cycle causing the accumulation of succinate and perhaps also
increased ROS production. FH mutation causes the accumulation of succinate and fumarate,
both of which can inhibit prolyl hydroxylases (PHDs) and stabilize HIF1α. In addition,
fumarate can succinylate and inactivate KEAP1, resulting in the activation of NRF2. This
induces stress-response genes including HMOX1, which degrades haem to bilirubin.
This removes excess succinyl-CoA by condensation with glycine to
generate δ-aminolevulinic acid (δALA), the commitment step of
NAD+
Fatty acid
haem biosynthesis. Mutated enzymes are shown in orange.
synthesis
Citrate
PHD
Succinate
Pi
H+
II
CoQ
I
NAD+
NNT
IV
O2· –
F0
V
ANT
ADP
ATP
MnSOD
Mitochondrion
H2O2
(GSH)2
H+
NADPH
VDAC
½O2 H2O
O2
NADP+
H
+
III
e–
NADH
CHCHD4
Cyt c
H+
H2O2
GSSG
Mitochondrial DNA is
essential for cancer cells
and copy number
alterations and inherited
and somatic mutations
can modify mitochondrial
function
H 2O
Acetyl-CoA
Citrate
ATP
ADP
O2· –
Cu–ZnSOD
ROS
Oxaloacetate
Nicotinamide nucleotide transhydrogenase (NNT) uses the
energy of the mitochondrial membrane potential to transfer
reducing equivalents from NADP+ to NADPH. The increased
reducing potential of NADPH is then used to reduce
oxidized glutathione for the reduction of H2O2 to H2O,
change the thiol-disulfide balance of amino acids in
proteins to regulate transcription factors and enzymes,
and to drive macromolecular synthesis.
Cytosolic NADPH can be generated by the
BCL-2
pentose phosphate shunt, by the
conversion of malate to pyruvate and by
the action of IDH1. Alteration of these
Cyt c
pathways can increase ROS levels and
alter cellular metabolism and growth.
SMAC
BAX
FOS–JUN (SH)2
FOS–JUN (SO)2
APEOx
APERed
TRX1 (SH)2
TRX1 (SS)
Isocitrate
NADPH
IDH3
IDH1
α-ketoglutarate
Nucleus
α-ketoglutarate
HIF1α HIF1β
MXI1
HIF1α HIF1β
IDH1
Succinyl-CoA
NADP+
NADPH
Effects αKG-dependent
enzymes, DNA methylation,
histone methylation and HIF1α
δALA
I
PGC1α
NADPH
PKCδ
Cyt c
Retinol
p66SHC
III
Protein synthesis
ROS
Lactate
Pyruvate
LDHA
Haem
Glutaminolysis,
nucleotide synthesis,
LDHA expression and
bioenergetic pathways
II
ROS
mTORC1
NRF2 KEAP1
HMOX1
Induction of the
NRF2 stressresponse pathway
AKT
FOXO3A
NADP+
SDH
Succinate
Biliverdin
CREB
Malate
V
F0
Fumarate
PDH
CoQ
Biogenesis
Acetyl-CoA
IV
(R)-2HG
Acetyl-CoA
Oxaloacetate
FH
IDH2
NADP+
Citrate
Malate
α-ketoglutarate
(R)-2HG
Glycine
FOXO3A
MYC
ATP-citrate
lyase
IDH2
NADPH
Glutamate
NADPH
• Increased glycolysis
• Increased vascularization
• Induction of mitophagy
• Induction of COX4-2
• Inhibition of COX4-1
• Inhibition of PDH
NADP+
NADP+
Cell death
BAX
Isocitrate
Isocitrate
Go with the flow
Redox regulation
PKM2 PKM2
PKM2
PKM2 PKM2
PKM2
ATP
RHEB
AKT
P
P
TSC2
P
TSC1
AMPK
Phosphoenolpyruvate
Mitochondrial biogenesis
and antioxidant defences
LKB1
PI3K
3-phosphoglycerate
Macromolecular
synthesis
Bilirubin
Glycolysis
NADPH
NADP+
PTEN
Pentose phosphate
pathway and
nucleotide synthesis
Glutamine transporter,
such as SLC1A5
Glucose-6-phosphate
Unique to Abcam, the MitoSciences range has over
200 products in the areas of mitochondria,
metabolism and apoptosis, offering a portfolio of
tools in this highly evolving field of research.
These include:
•Highly validated monoclonal antibodies with
diverse species cross-reactivity
•Dipstick assays, which employ lateral-flow
technology
•Enzyme activity assays
•In-cell ELISA kits
•Western blotting antibody cocktails
•Cell fractionation kits
•Cellular assay kits, such as ROS detection, ATP
measurement and cell viability assays
•Mitochondrial lysates from a range of tissues
•Active proteins to the Pyruvate dehygrogenase
kinases
These also encompass a comprehensive range of
tools to analyse the Pyruvate Dehydrogenase and
Oxidative Phosphorylation pathway.
TIGAR
Glucose transporter,
such as GLUT1
Why don’t you pair up these research tools with
antibodies to study cancer metabolism?
We have over 25,000 antibodies in our cancer
range:
•Hypoxia
•Apoptosis
•Autophagy
•Cell cycle
•Cancer stem cells
•Signal transduction
and many more.
Growth factor
receptor
Glucose
Glutamine
Allow your metabolism research to go further.
AMP
•Aerobic glycolysis in cancer cells is accompanied
by the switch from pyruvate kinase isoform M1
(PKM1) to PKM2, which is regulated by growth
factors and tyrosine phosphorylation. When
oxidative stress in low, PKM2 is active and glucose
is metabolized through phosphoenolpyruvate and
pyruvate to lactate to generate ATP. However,
when oxidative stress is high, PMK2 activity is
reduced driving G6P into the pentose phosphate
pathway to generate NADPH and bolstering
antioxidant defences.
•For the cancer cell to generate the carbon
backbones for macromolecular synthesis, the flow
of carbon must be redirected away from the
mitochondrial terminal oxidizing machinery.
The acetyl-CoA that is required for lipid synthesis
and for modulating the epigenome and signal
transduction pathways is generated from the export
of citrate from the mitochondrion. In the cytosol,
citrate is cleaved by ATP-dependent citrate lyase to
oxaloacetate (OAA) and acetyl-CoA. The acetylCoA can then be used to synthesize fatty acids and
lipids. However, this appropriation of citrate
depletes the mitochondrion of OAA. This
deficiency is compensated in many cancers by the
activation of MYC that induces glutaminolysis.
•The regulation of acetyl-CoA production from
glycolytic sources is also modulated by the
mitochondrial protein kinase Cδ signalosome,
which is composed of PKCδ, p66SHC, cytochrome c
and retinol. This complex senses the redox status
of the ETC and ultimately modulates pyruvate
dehydrogenase activity to adjust the flow of
acetyl-CoA and reducing equivalents into the
mitochondrion.
•The promyelocytic leukaemia (PML) protein interacts
with endoplasmic reticulum mitochondrially
associated membranes and can inhibit Ca2+ release
into the outer membrane cleft. This reduces
mitochondrial uptake of Ca2+, which stabilizes
the mitochondrial permeability transition pore
inhibiting apoptosis, and increases cytosolic Ca2+
levels.
•Reduced mitochondrial DNA copy number and
other types of mitochondrial stress can activate
the mitochondrial retrograde signalling pathway
through a reduction in the mitochondrial
membrane potential. This results in increased
cytosolic Ca2+ levels, activation of calcineurin
and NF-κB, and activation of the nuclear
enhanceosome, which upregulates proteins
involved in Ca2+ regulation, tumorigenesis and
invasive growth (not shown).
Abcam also offers a growing range of non-antibody products such as
proteins, peptide, lysates, immunoassays, immunohistochemistry kits,
western blotting kits and kits for chromatin research. In total, our
extensive catalog contains over 86, 000 quality products, each
accompanied by a comprehensive and up-to-date datasheet that
includes customer reviews, frequently asked questions and scientific
paper citations. Our range is constantly expanding so visit our
website today and find out how our products could help advance
your research.
Discover more at www.abcam.com/mitochondriacancerposter
Author address
Douglas C. Wallace, Michael and Charles Barnett Endowed
Chair in Pediatric Mitochondrial Medicine and Metabolic
Disease and Director of the Center for Mitochondrial and
Epigenomic Medicine (CMEM), Children's Hospital of
Philadelphia. Professor, Department of Pathology and
Laboratory Medicine, University of Pennsylvania,
Colket Translational Research Building, Room 6060,
3501 Civic Center Boulevard, Philadelphia, PA 19104
E-mail: [email protected]
DCW and the Children's Hospital of Philadelphia are not
affiliated with Abcam.
Abbreviations
ANT; adenine nucleotide transporter; CHCHD4, coiled-coilhelix–coiled-coil-helix domain-containing protein 4; CoQ,
coenzyme Q; COX, cyctochrome c oxidase; Cu–ZnSOD,
copper–zinc superoxide dismutase; Cyt c, cytochrome c; ETC,
electron transport chain; FH, Fumarate hydratase; G6P,
glucose 6-phosphate; GLUT1, glucose transporter 1; GSH,
reduced glutathione; HIF1α, hypoxia-inducible factor 1α;
HMOX1, haemoxygenase 1; IDH, isocitrate dehydrogenase;
KEAP1; kelch-like ECH-associated protein 1; LDHA, lactate
dehyrogenase A; LKB1, liver kinase B1; MnSOD, manganese
superoxide dismutase; NNT, nicotinamide nucleotide
transhydrogenase; NRF2, nuclear factor erythroid related
factor 2; PDH, pyruvate dehydrogenase; PGC1α, peroxisome
proliferator-activated receptor-γ coactivator 1α; ROS,
reactive oxygen species; SCL1A5, solute carrier family 1
(neutral amino acid transporter) member 5; SDH, succinate
dehydrogenase TIGAR, TP53-induced glycolysis and
apoptosis regulator; TRX, thioredoxin; TSC1, hamartin; TSC2,
tuberin; VDAC, voltage-dependent anion channel.
Edited by Nicola McCarthy; copyedited by Darren Burgess;
designed by Lara Crow. © 2012 Nature Publishing Group.
http://www.nature.com/reviews/poster/mitochondria