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The Multifaceted Contributions of Mitochondria to Cellular Metabolism

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The Multifaceted Contributions of Mitochondria to Cellular Metabolism FOCUS | REVIEW ARTICLE FOCUS | REVIEWhttps://doi.org/10.1038/s41556-018-0124-1 ARTICLE The multifaceted contributions of mitochondria to cellular metabolism Jessica B. Spinelli1,2 and Marcia C. Haigis 1,2* Although classically appreciated for their role as the powerhouse of the cell, the metabolic functions of mitochondria reach far beyond bioenergetics. In this Review, we discuss how mitochondria catabolize nutrients for energy, generate biosynthetic precursors for macromolecules, compartmentalize metabolites for the maintenance of redox homeostasis and function as hubs for metabolic waste management. We address the importance of these roles in both normal physiology and in disease. he transition to a highly oxidizing atmosphere in early Earth Pyruvate. Pyruvate is generated by a number of sources, depend- development created selective pressure that favoured organ- ing on nutrient availability and tissue, including glucose catabo- Tisms with respiratory capacity1,2, including heterotrophic lism (thought to be a major source) and lactate11–13. Pyruvate anaerobes, which consumed aerobic prokaryotic microorganisms utilization in the cytosol versus mitochondria is one of the clear- (protomitochondrion)3. Following endosymbiosis, mitochondrial est examples of how compartmentalization is a major determinant signals have been synchronized with the eukaryotic cell4. This of cellular bioenergetics. In healthy tissue, the fate of pyruvate is integral relationship is demonstrated by the compartmentalized dependent on oxygen availability and mitochondrial respiratory nature of cellular metabolism, in which mitochondrial reactions are capacity14. In normoxia, pyruvate is generated through glycolysis required components of metabolic pathways. and transported across the IMM through the mitochondrial pyru- Mitochondria coordinate cellular adaptation to stressors such as vate carrier (MPC)15,16. Pyruvate is further catabolized inside mito- nutrient deprivation, oxidative stress, DNA damage and endoplas- chondria through the TCA cycle. During hypoxia, mitochondrial mic reticulum (ER) stress5. Although long known to be critical for respiration is repressed, causing cells to adaptively sink electrons bioenergetics, emerging research shows that mitochondrial metab- onto pyruvate through lactate dehydrogenase (LDH), generating olism is multifaceted, mirroring their diverse functions. In addition lactate in the cytosol17. This pathway is engaged in muscle during to ATP, mitochondria produce metabolic precursors for macromol- exercise, the intestines and the renal medulla of the kidneys18–20. ecules such as lipids, proteins, DNA and RNA. Mitochondria also Otto Warburg observed that cancer cells rewire glucose metabo- generate metabolic by-products, such as reactive oxygen species lism for lactate synthesis even in normoxia, known as the Warburg (ROS) and ammonia, and possess mechanisms to clear or utilize effect14,21. Additional studies must be performed to determine the waste products. net catalytic activity of LDH in tumours, given that metabolic trac- In this Review, we discuss the metabolic functions of mitochon- ing studies in lung cancer patients have demonstrated that lactate dria as bioenergetic powerhouses, biosynthetic centres, balancers is a major source of TCA cycle intermediates13. The extent of LDH- of reducing equivalents and waste management hubs. Metabolic mediated pyruvate production may depend on in vitro versus in compartmentalization is instrumental for mitochondria to perform vivo models of tumour metabolism, emphasizing the need to test these functions. We highlight how mitochondrial metabolism sup- metabolic flux in vivo. ports their diverse functions in cell biology and how metabolism The critical role of pyruvate compartmentalization in bioener- is compartmentalized in normal physiology and disease. A deeper getics and metabolism is highlighted by recent elegant studies of understanding of mitochondrial contributions to metabolism will the MPC (refs 15,16). Pharmacological inhibition of MPC represses further elucidate their roles in disease and may reveal co-dependent mitochondrial pyruvate uptake, shifting reliance to glycolysis for pathways to target in therapies. ATP production. This shift is evident in cancer cells, which repress MPC1 to promote the Warburg effect, and in myocytes of diabetic Mitochondria are the powerhouses of the cell mice, which elevate glucose consumption in response to MPC Cells consume fuels such as sugars, amino acids and fatty acids to inhibition22,23. Suppression of MPC accelerates proliferation in generate energy in the form of ATP and GTP (ref. 6). Nutrients are intestinal stem cells24, suggesting that the role of MPC is context- metabolized and shuttled into the tricarboxylic acid (TCA) cycle, dependent and sensitive to mitochondrial respiratory capacity and/ and through iterative oxidations, electrons are stored in the reduc- or nutrient availability. 6 ing equivalents NADH and FADH2 (ref. ). These carriers deposit Within mitochondria, pyruvate may enter the TCA cycle through electrons into the electron transport chain (ETC) in the inner the activity of two distinct enzymes: pyruvate dehydrogenase com- mitochondrial membrane (IMM), and use electron flow to pump plex (PDC), which generates acetyl CoA, and pyruvate carboxylase protons into the intermembrane space7. Protons flow down their (PC), which generates oxaloacetate25. Although PDC and PC both electrochemical gradient through F1F0–ATP synthase to gener- catalyse the flux of pyruvate into the TCA cycle, their enzymatic ate ATP (ref. 8). Although oxidative phosphorylation is the largest activities can be distinguished by stable isotope tracing26,27, and their source of cellular ATP, the potential energy generated by the ETC is metabolic roles do not appear to be interchangeable. PDC deficiency also harnessed for biosynthetic purposes. Many diseases arise when is sufficient to rewire energy metabolism towards aerobic glycoly- the ETC is perturbed9,10. Here, we discuss how mitochondria inte- sis despite the potential adaptive node for TCA cycle anaplerosis grate fuel metabolism to generate energy for the cell, encompassing (a process to replenish TCA cycle intermediates), mediated by PC both classical and unconventional fuel sources (Fig. 1). (ref. 28). Many cancers favour PC-mediated anaplerosis, although 1Department of Cell Biology, Harvard Medical School, Boston, MA, USA. 2Ludwig Center, Harvard Medical School, Boston, MA, USA. *e-mail: [email protected] NATURE CELL BIOLOGY | VOL 20 | JULY 2018 | 745–754 | www.nature.com/naturecellbiology 745 © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. FOCUS | REVIEW ARTICLE REVIEWhttps://doi.org/10.1038/s41556-018-0124-1 ARTICLE | FOCUS NATURE CELL BIOLOGY Glucose TAG Glycolysis Lipolysis PEP NADH 2 ATP Fatty acids Lactate LDH Pyruvate Ca+2 Metabolites ACS (–) O2 (+) O2 + Fatty CoA NAD AMP/ATP VDAC Cytosol CPT1 Malonyl + CoA OMM H AMPK H+ 25A20 Acetyl MPC CoA P IMM H+ ACC Electron OH Pyruvate Acylcarnitine transport chain CPT2 PDC NADH Carnitine PHD3 I PC FADH + + NADH 2 NAD e- H NADH + e- Fatty CoA FADH2 H+ II Acetyl CoA β-oxidation FAD e- H+ Oxaloacetate e- MDH2 - H+ NADH CS e- III Malate e- H+ Methylbutyryl CoA e- Citrate H+ Fumarate Isovaleryl CoA O2 IV TCA cycle Isocitrate NADH NADH H2O SDH FADH2 ATP BCKDH IDH2 NAD+ ADP Succinate NADH Ketomethylvalerate α-KG Ketoisocaproate + H OGDH Succinyl CoA ATP synthase α-KG GDH BCAT2 NAD(P)H Glu Isoleucine Valine Glutamate Leucine GLS Glutamine Fig. 1 | Mitochondria are the powerhouse of the cell. Mitochondria integrate fuel metabolism to generate energy in the form of ATP. Mitochondria oxidize pyruvate (derived from glucose or lactate), fatty acids and amino acids to harness electrons onto the carriers NADH and FADH2. NADH and FADH2 transport these electrons to the electron transport chain, in which an electrochemical gradient is formed to facilitate ATP production through oxidative phosphorylation. VDAC, voltage-dependent anion channel; IDH2, isocitrate dehydrogenase 2; OGDH, α -ketoglutarate dehydrogenase; SDH, succinate dehydrogenase; BCAT2, branched-chain amino transferase 2; ACS, acyl CoA synthetase. Electrons and reducing equivalents are shown in yellow. the factors that dictate the choice for pyruvate-flux between PC elevation32,36,37. GLS inhibition suppresses proliferation, and GLS and PDC are little studied27,29,30. Therefore, these enzymes may have inhibitors are being evaluated in clinical studies for a number of important functions beyond TCA-cycle-flux for bioenergetics. cancers31,38,39. However, sensitivity to GLS inhibition in vitro is not always consistent in vivo, and is dependent on extracellular cystine Glutamine and branched-chain amino acids. Catabolism of glu- levels40. This emphasizes the need for investigators to study the tamine, the most abundant amino acid in plasma, often starts in effect of the microenvironment on metabolic dependencies and to the mitochondria, and its carbon and nitrogen atoms are distributed validate experiments in vivo. into macromolecules (DNA, RNA, protein and lipids) and other Although glutamine transporters at the plasma membrane have metabolites, such as TCA cycle intermediates (important in bioen- been identified41, the mitochondrial glutamine transporter has not ergetics), amino acids, nucleotides and glutathione31. been fully characterized42,43. This critical area of research is chal- In mitochondria, glutaminase (GLS) converts glutamine into
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