Mitochondrial function and cancer
Douglas C. Wallace
In addition to compartmentalizing the metabolic pathways and physiological statesof the cell, mitochondria generate much of the cellular energy, regulate the cellularoxidation–reduction (redox) state, produce most of the cellular reactive oxygenspecies (ROS), buffer cellular Ca2+ and initiate cellular apoptosis. Mitochondria
were first proposed to be relevant to cancer by Otto Warburg who reported thatcancer 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 GroupCANCER

glycolytic metabolism and the continued use of oxygen. Mutations that occur innuclear-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 associatedwith many types of cancers, and recent data indicate that cancer cells may toleratemitochondrial DNA mutations for two purposes: they alter cancer cell metabolism
and/or proliferation and they enable adaption to a changing environment.

HIF1αFumarate

HIF1β

Altered energetics

Activation of the PI3K–AKT pathway increases glucose uptake and metabolism. AKT phosphorylates andinactivates 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 toisocitrate 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. SDHmutations 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 togenerate δ-aminolevulinic acid (δALA), the commitment step ofNAD+
Fatty acidhaem biosynthesis. Mutated enzymes are shown in orange.
synthesis
CitratePHD

Succinate
PiH+

II

CoQINAD+NNTIVO2· –F0V

ANTADPATPMnSOD
Mitochondrion

H2O2(GSH)2H+NADPHVDAC½O2 H2O

O2NADP+H+

III
e–NADHCHCHD4Cyt cH+

H2O2GSSG

Mitochondrial DNA isessential for cancer cells
and copy numberalterations and inheritedand somatic mutations
can modify mitochondrial
function

H 2O
Acetyl-CoACitrate

ATPADPO2· –Cu–ZnSOD

ROS

Oxaloacetate

Nicotinamide nucleotide transhydrogenase (NNT) uses theenergy 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 inproteins to regulate transcription factors and enzymes,
and to drive macromolecular synthesis.
Cytosolic NADPH can be generated by theBCL-2
pentose phosphate shunt, by theconversion of malate to pyruvate and by
the action of IDH1. Alteration of these
Cyt cpathways can increase ROS levels andalter cellular metabolism and growth.
SMAC
BAX

FOS–JUN (SH)2
FOS–JUN (SO)2APEOx
APERedTRX1 (SH)2
TRX1 (SS)

NucleusIsocitrate

IDH1IDH3

α-ketoglutarate

α-ketoglutarate

NADPH

HIF1α HIF1β

MXI1

HIF1α HIF1β

IDH1

Succinyl-CoA

NADP+

NADPH

Eﬀects αKG-dependent
enzymes, DNA methylation,
histone methylation and HIF1α

δALAI

PGC1αNADPH

PKCδ
Cyt cRetinol
p66SHCIII

Protein synthesis

ROS

LactatePyruvate
LDHA

Haem
Glutaminolysis,
nucleotide synthesis,
LDHA expression andbioenergetic pathways

IIROS

mTORC1

NRF2 KEAP1

HMOX1Induction of the
NRF2 stressresponse pathway

AKT

FOXO3A

NADP+SDH

Succinate

Biliverdin

CREB

MalateV
F0Fumarate
PDH

CoQ

Biogenesis

Acetyl-CoAIV(R)-2HG

Acetyl-CoA
OxaloacetateFH

IDH2NADP+Citrate

Malateα-ketoglutarate(R)-2HG

GlycineFOXO3A
MYC

ATP-citratelyase

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

AKTPP

TSC2P
TSC1

AMPK

Phosphoenolpyruvate

Mitochondrial biogenesis
and antioxidant defences

LKB1
PI3K

3-phosphoglycerate

MacromolecularsynthesisBilirubin

Glycolysis
NADPHNADP+PTEN

Pentose phosphatepathway andnucleotide synthesis

Glutamine transporter,
such as SLC1A5

Glucose-6-phosphate

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TIGAR

Glucose transporter,
such as GLUT1

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AMP• Aerobic glycolysis in cancer cells is accompaniedby the switch from pyruvate kinase isoform M1(PKM1) to PKM2, which is regulated by growth
factors and tyrosine phosphorylation. Whenoxidative stress in low, PKM2 is active and glucose
is metabolized through phosphoenolpyruvate andpyruvate to lactate to generate ATP. However,when oxidative stress is high, PMK2 activity isreduced driving G6P into the pentose phosphatepathway to generate NADPH and bolstering
antioxidant defences.
• For the cancer cell to generate the carbon
backbones for macromolecular synthesis, the flowof carbon must be redirected away from themitochondrial terminal oxidizing machinery.
The acetyl-CoA that is required for lipid synthesis
and for modulating the epigenome and signaltransduction pathways is generated from the exportof citrate from the mitochondrion. In the cytosol,
citrate is cleaved by ATP-dependent citrate lyase tooxaloacetate (OAA) and acetyl-CoA. The acetylCoA can then be used to synthesize fatty acids andlipids. However, this appropriation of citrate
depletes the mitochondrion of OAA. This
deficiency is compensated in many cancers by theactivation of MYC that induces glutaminolysis.
• The regulation of acetyl-CoA production fromglycolytic sources is also modulated by themitochondrial protein kinase Cδ signalosome,which is composed of PKCδ, p66SHC, cytochrome cand retinol. This complex senses the redox statusof the ETC and ultimately modulates pyruvate
dehydrogenase activity to adjust the flow ofacetyl-CoA and reducing equivalents into themitochondrion.
• The promyelocytic leukaemia (PML) protein interacts
with endoplasmic reticulum mitochondriallyassociated 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 andother 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 andinvasive growth (not shown).

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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 andEpigenomic Medicine (CMEM), Children's Hospital ofPhiladelphia. Professor, Department of Pathology andLaboratory Medicine, University of Pennsylvania,
Colket Translational Research Building, Room 6060,
3501 Civic Center Boulevard, Philadelphia, PA 19104
E-mail: wallaced1@email.chop.edu
DCW and the Children's Hospital of Philadelphia are notaffiliated 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, manganesesuperoxide 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 andapoptosis 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