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Mitochondrial Function and Cancer Douglas C Mitochondrial function and cancer Douglas C. Wallace In addition to compartmentalizing the metabolic pathways and physiological states glycolytic metabolism and the continued use of oxygen. Mutations that occur in of the cell, mitochondria generate much of the cellular energy, regulate the cellular nuclear-DNA-encoded mitochondrial proteins and mitochondrial-DNA-encoded oxidation–reduction (redox) state, produce most of the cellular reactive oxygen proteins can re-orient cellular metabolism towards glycolysis, glutaminolysis, species (ROS), buffer cellular Ca2+ and initiate cellular apoptosis. Mitochondria intense macromolecular biogenesis and the oxidoreduction of NADP+ to NADPH. were first proposed to be relevant to cancer by Otto Warburg who reported that Both somatic and germline mitochondrial DNA mutations have been associated cancer cells exhibited “aerobic glycolysis”. Although this was originally interpreted with many types of cancers, and recent data indicate that cancer cells may tolerate as indicating that the function of the mitochondria was defective, we now mitochondrial DNA mutations for two purposes: they alter cancer cell metabolism CANCER understand that cancer cells are in an altered metabolic state with increased and/or proliferation and they enable adaption to a changing environment. HIF1α Fumarate HIF1β PHD Go with the flow Altered energetics Succinate Redox regulation • Aerobic glycolysis in cancer cells is accompanied Activation of the PI3K–AKT pathway increases glucose uptake and metabolism. AKT phosphorylates and Pi Nicotinamide nucleotide transhydrogenase (NNT) uses the by the switch from pyruvate kinase isoform M1 inactivates FOXO, downregulating PGC1α and reducing mitochondrial biogenesis. Activation of MYC induces ADP ATP energy of the mitochondrial membrane potential to transfer (PKM1) to PKM2, which is regulated by growth glutaminolysis, in which glutamine is converted to α-ketoglutarate (αKG). Reductive carboxylation of αKG to Cu–ZnSOD O ·– reducing equivalents from NADP+ to NADPH. The increased ROS 2 H+ factors and tyrosine phosphorylation. When isocitrate can be facilitated by NADPH-linked IDH2, resulting in increased citrate synthesis. Mitochondrial + CHCHD4 reducing potential of NADPH is then used to reduce oxidative stress in low, PKM2 is active and glucose H+ H VDAC + H2O2 citrate can be exported into the cytosol, where isocitrate can be converted to αKG by NADP -linked Cyt c oxidized glutathione for the reduction of H2O2 to H2O, is metabolized through phosphoenolpyruvate and + II IV IDH1. Mutant IDH1 or IDH2 oxidize NADPH back to NADP and reduce αKG to R(–)-2-hydroxyglutarate CoQ F0 ANT change the thiol-disulfide balance of amino acids in pyruvate to lactate to generate ATP. However, I III ((R)-2HG), an oncometabolite that affects DNA and histone methylation and HIF1α activity. SDH V ADP proteins to regulate transcription factors and enzymes, when oxidative stress is high, PMK2 activity is – mutations disrupt the TCA cycle causing the accumulation of succinate and perhaps also e ½O2 H2O and to drive macromolecular synthesis. reduced driving G6P into the pentose phosphate Supplement to Nature Publishing Group Supplement to Nature ·– increased ROS production. FH mutation causes the accumulation of succinate and fumarate, NAD+ O2 ATP Cytosolic NADPH can be generated by the pathway to generate NADPH and bolstering NADH MnSOD both of which can inhibit prolyl hydroxylases (PHDs) and stabilize HIF1α. In addition, O2 BCL-2 pentose phosphate shunt, by the antioxidant defences. fumarate can succinylate and inactivate KEAP1, resulting in the activation of NRF2. This conversion of malate to pyruvate and by NADP+ (GSH) H O Mitochondrion • For the cancer cell to generate the carbon induces stress-response genes including HMOX1, which degrades haem to bilirubin. 2 2 2 the action of IDH1. Alteration of these backbones for macromolecular synthesis, the flow NNT H+ Mitochondrial DNA is Cyt c This removes excess succinyl-CoA by condensation with glycine to essential for cancer cells pathways can increase ROS levels and of carbon must be redirected away from the NADPH GSSG H2O generate δ-aminolevulinic acid (δALA), the commitment step of Fatty acid NAD+ and copy number SMAC alter cellular metabolism and growth. mitochondrial terminal oxidizing machinery. haem biosynthesis. Mutated enzymes are shown in orange. synthesis alterations and inherited BAX The acetyl-CoA that is required for lipid synthesis Acetyl-CoA and somatic mutations Cell death and for modulating the epigenome and signal can modify mitochondrial function BAX transduction pathways is generated from the export Citrate Citrate Oxaloacetate of citrate from the mitochondrion. In the cytosol, citrate is cleaved by ATP-dependent citrate lyase to Isocitrate ATP-citrate oxaloacetate (OAA) and acetyl-CoA. The acetyl- Isocitrate Isocitrate lyase CoA can then be used to synthesize fatty acids and Ox + NADP+ Acetyl-CoA Biogenesis FOS–JUN (SH)2 APE TRX1 (SH)2 NADP Citrate IDH2 Malate lipids. However, this appropriation of citrate IDH3 IDH1 NADPH Oxaloacetate depletes the mitochondrion of OAA. This FOS–JUN (SO) APERed TRX1 (SS) 2 NADPH deficiency is compensated in many cancers by the FH Acetyl-CoA α-ketoglutarate α-ketoglutarate α-ketoglutarate Nucleus activation of MYC that induces glutaminolysis. Glutamate NADPH Malate • The regulation of acetyl-CoA production from V NADPH IDH2 Fumarate glycolytic sources is also modulated by the NADP+ F IDH1 Succinyl-CoA PDH 0 • Increased glycolysis mitochondrial protein kinase Cδ signalosome, NADP+ (R)-2HG NADP+ • Increased vascularization Glycine SDH which is composed of PKCδ, p66SHC, cytochrome c • Induction of mitophagy HIF1α HIF1β MXI1 HIF1α HIF1β IV NADPH and retinol. This complex senses the redox status • Induction of COX4-2 (R)-2HG δALA Succinate of the ETC and ultimately modulates pyruvate • Inhibition of COX4-1 PKCδ Protein synthesis • Inhibition of PDH Effects αKG-dependent III Cyt c Retinol dehydrogenase activity to adjust the flow of enzymes, DNA methylation, I CoQ II p66SHC acetyl-CoA and reducing equivalents into the histone methylation and HIF1α ROS Pyruvate Lactate mitochondrion. ROS mTORC1 LDHA • The promyelocytic leukaemia (PML) protein interacts FOXO3A Haem with endoplasmic reticulum mitochondrially NRF2 KEAP1 2+ Glutaminolysis, ATP AMP associated membranes and can inhibit Ca release nucleotide synthesis, RHEB MYC HMOX1 PKM2 PKM2 PKM2 into the outer membrane cleft. This reduces LDHA expression and 2+ bioenergetic pathways mitochondrial uptake of Ca , which stabilizes PKM2 PKM2 PKM2 the mitochondrial permeability transition pore TSC2 Biliverdin Induction of the AKT P P AMPK inhibiting apoptosis, and increases cytosolic Ca2+ TSC1 AKT NRF2 stress- P levels. response pathway Phosphoenolpyruvate • Reduced mitochondrial DNA copy number and Mitochondrial biogenesis other types of mitochondrial stress can activate PGC1α LKB1 CREB FOXO3A and antioxidant defences the mitochondrial retrograde signalling pathway Bilirubin Macromolecular 3-phosphoglycerate PI3K through a reduction in the mitochondrial synthesis membrane potential. This results in increased Glycolysis cytosolic Ca2+ levels, activation of calcineurin and NF-κB, and activation of the nuclear NADPH Pentose phosphate PTEN enhanceosome, which upregulates proteins pathway and Glucose-6-phosphate TIGAR involved in Ca2+ regulation, tumorigenesis and nucleotide synthesis NADP+ invasive growth (not shown). Glutamine transporter, Glucose transporter, such as SLC1A5 such as GLUT1 Growth factor Glutamine Glucose receptor Allow your metabolism research to go further. • In-cell ELISA kits Why don’t you pair up these research tools with Abcam also offers a growing range of non-antibody products such as Author address Abbreviations transhydrogenase; NRF2, nuclear factor erythroid related Unique to Abcam, the MitoSciences range has over • Western blotting antibody cocktails antibodies to study cancer metabolism? proteins, peptide, lysates, immunoassays, immunohistochemistry kits, Douglas C. Wallace, Michael and Charles Barnett Endowed ANT; adenine nucleotide transporter; CHCHD4, coiled-coil- factor 2; PDH, pyruvate dehydrogenase; PGC1α, peroxisome proliferator-activated receptor-γ coactivator 1α; ROS, 200 products in the areas of mitochondria, • Cell fractionation kits We have over 25,000 antibodies in our cancer western blotting kits and kits for chromatin research. In total, our Chair in Pediatric Mitochondrial Medicine and Metabolic helix–coiled-coil-helix domain-containing protein 4; CoQ, • Cellular assay kits, such as ROS detection, ATP range: extensive catalog contains over 86, 000 quality products, each Disease and Director of the Center for Mitochondrial and coenzyme Q; COX, cyctochrome c oxidase; Cu–ZnSOD, reactive oxygen species; SCL1A5, solute carrier family 1 metabolism and apoptosis, offering a portfolio of (neutral amino acid transporter) member 5; SDH, succinate measurement and cell viability assays • Hypoxia accompanied by a comprehensive and up-to-date datasheet that Epigenomic Medicine (CMEM), Children's Hospital of copper–zinc superoxide dismutase; Cyt c, cytochrome c; ETC, tools in this highly evolving field of research. Philadelphia. Professor, Department of Pathology and electron transport chain; FH, Fumarate hydratase; G6P, dehydrogenase TIGAR, TP53-induced glycolysis and • Mitochondrial lysates from a range of tissues • Apoptosis includes customer reviews, frequently asked questions and scientific These include: Laboratory Medicine,
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