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CHAPTER 19 Mitochondria, Chloroplasts, Peroxisomes T his chapter considers three organelles formed by posttranslational import of proteins synthesized in the cytoplasm. Mitochondria and chloroplasts both arose from endosymbiotic bacteria, two singular events that occurred about one billion years apart. Both mitochondria and chloroplasts retain [besitzen noch] remnants of those prokaryotic genomes but depend largely on genes that were transferred to the nucleus of the host eukaryote. Both organelles brought biochemical mechanisms that allow their eukaryotic hosts to acquire and utilize energy more efficiently. In oxidative phosphorylation by mitochondria and photosynthesis by chloroplasts, energy from the breakdown of nutrients or from absorption of photons is used to energize electrons. As these electrons tunnel through transmembrane proteins, energy is partitioned off [wird aufgeteilt] to create proton gradients. These proton gradients drive the rotary [rotierend] ATP synthase (see Fig. 8-5) to make adenosine triphosphate (ATP), which is used as energy currency to power the cell. Peroxisomes contain no genes and depend entirely on nuclear genes to encode their proteins. Their evolutionary origins are obscure. Peroxisomes contain enzymes that catalyze oxidation reactions that are essential for normal human physiology. Patients who lack peroxisomes have severe neural defects. Mitochondria Evolution and Structure of Mitochondria Mitochondria (Fig. 19-1) arose about 2 billion years ago when a Bacterium fused with an archaeal cell or established a symbiotic relationship with a primitive eukaryotic cell (see Fig. 2-5 and associated text). The details are not preserved in the fossil record, but the bacterial origins of mitochondria are apparent in their many common features (Fig. 19-2). The closest extant [heute lebend] relatives of the Bacterium that gave rise to mitochondria are Rickettsia, aerobic α-proteobacteria with a genome of 1.1 megabase pairs. These intracellular pathogens cause typhus and Rocky Mountain spotted fever [amerikanisches Zeckenfieber]. However, some evidence argues that the actual progenitor [Vorfahre] bacterium had the genes required for both aerobic and anaerobic metabolism. As primitive eukaryotes diverged from each other, most of the bacterial genes were lost or moved to the nuclei of the host eukaryotes. The pace of the gene transfer to the nucleus varied considerably depending on the species, but all known mitochondria retain some bacterial genes. A very few eukaryotes, such as Entamoeba, that branched 331 332 SECTION VI — Cellular Organelles and Membrane Trafficking A B Figure 19-1 CELLULAR DISTRIBUTION AND STRUCTURE OF MITOCHONDRIA. A, Fluorescence light micrograph of a Cos-7 tissue culture cell with mitochondria labeled with green fluorescent antibody to the β-subunit of the F1-ATPase and microtubules labeled red with an antibody. B, Electron micrograph of a thin section of a mitochondrion. (A, Courtesy of Michael Yaffee, University of California, San Diego. B, Courtesy of Don Fawcett, Harvard Medical School, Boston, Massachusetts.) well after their ancestors [Vorfahren] acquired mitochondria lost the organelle, leaving behind a few mitochondrial genes in the nucleus. Chromosomes of contemporary [heutig] mitochondria vary in size from 366,924 base pairs (bp) in the plant Arabidopsis to only 5966 bp in Plasmodium. These small, usually circular genomes encode RNAs and proteins that are essential for mitochondrial function, including some subunits of proteins responsible for adenosine triphosphate (ATP) synthesis. The highly pared-down [verkleinert] human mitochondrial genome with 16,569 bp encodes only 13 mitochondrial membrane proteins, two ribosomal RNAs, and just enough tRNAs (22) to translate these genes. The number of proteins encoded by other mitochondrial genomes ranges from just 3 in Plasmodium to 97 in a protozoan. Nuclear genes encode the other 600 to 1000 mitochondria proteins, including those required to synthesize proteins in the matrix. All mitochondrial proteins that are encoded by nuclear genes are synthesized in the cytoplasm and subsequently imported into mitochondria (see Figs. 18-2 and 18-3). Mitochondria consist of two membrane-bounded compartments, one inside the other (Fig. 19-2). The outer membrane surrounds the intermembranous space. The inner membrane surrounds the matrix. Each membrane and compartment has a distinct protein composition and functions. Porins in the outer membrane provide channels for passage of molecules of less than 5000 D, including most metabolites required for ATP synthesis. The highly impermeable inner membrane is specialized for converting energy provided by breakdown of nutrients in the matrix into ATP. Four complexes (I to IV) of integral membrane proteins use the transport of energetic [energiereich] electrons to create a gradient of protons across the inner membrane. The F1F0 ATP synthase (see Fig. 8-5) utilizes the proton gradient to synthesize ATP. The area of inner membrane available for these reactions is increased by folds called cristae that vary in number and shape depending on the species, tissue, and metabolic state. Cristae may be tubular or flattened sacs. Contacts between the inner and outer membranes are sites of protein import (see Fig. 18-4). Proteins in the inter- A. Mitochondria Outer membrane Inner membrane DNA Book icon Cristae Matrix B INTERMEMBRANOUS SPACE C I I II III IV PERIPLASM II MATRIX III IV CYTOPLASM D. Bacterium DNA CYTOPLASM Periplasmic space Inner membrane Outer membrane Figure 19-2 The compartments of a mitochondrion (A–B) compared with a Bacterium (C–D). Respiratory chain complexes I to IV are labeled with roman numerals. CHAPTER 19 — Mitochondria, Chloroplasts, Peroxisomes membranous space participate in ATP synthesis but, when released into the cytoplasm, trigger [auslösen] programmed cell death (see Fig. 46-15). Biogenesis of Mitochondria Mitochondria grow by importing most of their proteins from the cytoplasm and by internal synthesis of some proteins and replication of the genome (Fig. 19-3). Targeting and sorting signals built into the mitochondrial proteins that are synthesized in the cytoplasm direct them to their destinations (see Fig. 18-4). Similar to cells, mitochondria divide, but unlike most cells, they also fuse with other mitochondria. These fusion and division reactions were first observed nearly one hundred years ago. Now it is appreciated that a balance between ongoing fusion and division determines the number of mitochondria within a cell. Both fusion and division depend on proteins with guanosine triphosphatase (GTPase) domains related to dynamin (see Fig. 22-11). In fact, eukaryotes might have acquired their dynamin genes from the bacterium that became mitochondria. One dynamin-related GTPase is required for division of mitochondria. This GTPase self-assembles into spirals that appear to pinch [abschnüren] mitochondria in two. During apoptosis (see Chapter 46), this GTPase also participates in the fragmentation of mitochondria. Fusion involves two GTPases, one anchored in the outer membrane and the other in the inner membrane, both linked by an adapter protein in the intermembrane space. Fusion of the outer membranes requires a proton gradient across the inner membrane, while fusion of the inner membranes depends on the electrical potential across the inner membrane. Loss of function mutations in fusion proteins lead to cells with numerous small mitochondria, some lacking a mtDNA molecule. Human Nuclear genes on nuclear DNA Over 600 mitochondrial proteins synthesized in cytoplasm Import into mitochondria Mitochondrial genes on mitochondrial DNA • 13 mitochondrial membrane proteins • 22 tRNAs • 2 rRNAs Figure 19-3 BIOGENESIS OF MITOCHONDRIA. The drawing shows the relative contributions of nuclear and mitochondrial genes to the protein composition. mutations in the genes for fusion proteins result in defects in the myelin sheath [Myelinscheide] that insulates axons (one form of Charcot-Marie-Tooth disease) and the atrophy [Schrumpfung] of the optic nerve. Mitochondrial fusion proteins are also required for apoptosis. Synthesis of ATP by Oxidative Phosphorylation Mitochondria use energy extracted from the chemical bonds of nutrients to generate a proton gradient across the inner membrane. This proton gradient drives the F1F0 ATP synthase to synthesize ATP from ADP and inorganic phosphate. Enzymes in the inner membrane and matrix cooperate with pumps, carriers, and electron transport proteins in the inner membrane to move electrons, protons, and other energetic intermediates across the impermeable inner membrane. This is a classic chemiosmotic process (see Fig. 11-1). Mitochondria receive energy-yielding [Energie freisetzend] chemical intermediates from two ancient metabolic pathways, glycolysis and fatty acid oxidation (Fig. 19-4), that evolved in the common ancestor of living things. Both pathways feed into the equally ancient citric acid cycle of energy-yielding reactions in the mitochondrial matrix: • The glycolytic pathway in cytoplasm converts the six-carbon sugar glucose into pyruvate, a three-carbon substrate for pyruvate dehydrogenase, a large, soluble, enzyme complex in the mitochondrial matrix. The products of pyruvate dehydrogenase (carbon dioxide, the reduced form of nicotinamide adenine dinucleotide [NADH], and acetyl coenzyme A [-CoA]) are released into the matrix. NADH is a high-energy electron carrier. Acetyl-CoA is a two-carbon metabolic intermediate that supplies the citric acid cycle with energyrich bonds. • Breakdown of lipids yields fatty acids linked to acetyl-CoA by a thioester bond. These intermediates are transported across the inner membrane of mitochondria, using carnitine in a shuttle system. In the matrix, acyl-carnitine is reconverted to acylCoA. Enzymes in the matrix degrade fatty acids two carbons at a time in a series of oxidative reactions that yield NADH, the reduced form of flavin adenine dinucleotide (FADH2, another energy-rich electron carrier associated with an integral membrane enzyme complex), and acetyl-CoA for the citric acid cycle. Breakdown of acetyl-CoA during one turn of the citric acid cycle produces three molecules of NADH, 333 334 SECTION VI — Cellular Organelles and Membrane Trafficking A. Glycolysis (in the cytoplasm) OPO32– HOH2C H2C O H ATP ADP H O H H H H HO OH H OH HO OH H OH Hexokinase H OH Glucose H OH Glucose 6-phosphate OPO32– O H2C OPO32– OH O CH2 ATP ADP H2C H H HO OH Phosphoglucose isomerase OH H Fructose 6-phosphate H H HO OH Phosphofructokinase OH H Fructose 1,6-biphosphate NADH + H+ NAD+ COO – HO C H Maltate CH2 COO – H2O COO – CH Fumarate CH COO – Phosphoglycerate kinase 2 ATP H H O 3-phosphoglycerate H C C C O– (2 molecules) O OH PO32– H2O COO – CH2 cis-Aconitate C COO – CH COO – Phosphoglyceromutase H H O 2-phosphoglycerate – (2 molecules) H C C C O HO OPO32– H2O COO – Isocitrate CH2 H C COO – HO C H COO – Enolase 2 H2O H H O Phosphoenolpyruvate – (2 molecules) H C C C O 2– OPO3 2 ADP Pyruvate NAD+ kinase CO2 + NADH + H+ FAD CH2 Succinate CH2 – COO GTP + HSCoA GDP + Pi COO – CH2 α-Keto- CH2 glutarate C O COO – Succinyl CoA O SCoA C CH2 CH2 COO – 2 NADH + 2 H+ H H O 1,3-bisphosphoglycerate H C C C OPO32– (2 molecules) O OH PO32– 2 ADP COO – CH2 HO C COO – Citrate CH2 COO – FADH2 COO – Triosephosphate isomerase 3-phosphate dehydrogenase HSCoA COO – C O Oxaloacetate CH2 COO – Aldolase HO O H H C C C OPO3H– H O H H O Glyceraldehyde H C C CH 3-phosphate O OH (2 molecules) PO32– 2 NAD + 2 Pi Glyceraldehyde B. Citric acid cycle (in the mitochondrial matrix) O H2O + CH3 C SCoA Acetyl CoA Dihydroxyacetone phosphate OPO32– CH2 2 ATP H O O Pyruvate – (2 molecules) H C C C O H C. Integration of metabolic pathways in mitochondrium ADP NAD+ + HSCoA CO2 + NADH + H+ ATP ADP O2 H2O + Pi ATP H+ H+ H+ e– FADH2 CO2 Pyruvate Fatty acids Pyruvate H+ Pi O2 Glycosis Lipid breakdown H+ FADH2 Acetyl CoA Citric acid cycle CO2 NADH NADH Figure 19-4 METABOLIC PATHWAYS SUPPLYING ENERGY FOR OXIDATIVE PHOSPHORYLATION. A, Glycolysis. B, Citric acid cycle. Production of acetylCoA by the glycolytic pathway in cytoplasm and fatty acid oxidation in the mitochondrial matrix drive the citric acid cycle in the mitochondrial matrix. This energy-yielding cycle is also called the Krebs cycle after the biochemist H. Krebs. NADH and FADH2 produced by these pathways supply high-energy electrons to the electron transport chain. C, Overview of metabolic pathways. Note energy-rich metabolites (yellow). 335 CHAPTER 19 — Mitochondria, Chloroplasts, Peroxisomes one molecule of FADH2, and two molecules of carbon dioxide. Energetic [energiereich] electrons donated by NADH and FADH2 drive an electron transport pathway in the inner mitochondrial membrane that powers a chemiosmotic cycle to produce ATP (Fig. 19-5). Electrons use two routes to pass through three protein complexes in the inner mitochondrial membrane. Starting with NADH, electrons pass through complex I to complex III to complex IV. Electrons from FADH2 pass through complex II to complex III to complex IV. Along both routes, energy is partitioned off [wird aufgeteilt] to transfer multiple protons (at least 10 electrons per NADH oxidized) across the Cytochrome c H+ INTERMEMBRANOUS SPACE + A inner mitochondrial membrane from the matrix to the inner membrane space. The resulting electrochemical gradient of protons drives ATP synthesis (see Fig. 8-5). This process is called oxidative phosphorylation, since molecular oxygen is the sink [Ausguss] for energybearing electrons at the end of the pathway and since the reactions add phosphate to ADP. Eukaryotes that live in environments with little or no oxygen use other acceptors for these electrons and produce nitrite, nitric oxide [Stickstoffmonoxid], or other reduced products rather than water. Oxidative phosphorylation is understood in remarkable detail, thanks to atomic structures H H+ ATP H+ Pi + + + Q e– – – + + + QH2 e– e- + O2 e- – – – H2O + – H+ H+ + – – ADP + + – – ADP + Pi FADH2 FAD Succinate Complex II NADH NAD+ Complex I B Complex III Complex IV Complex V Carriers MATRIX Rieske protein Cytochrome c1 ATP Subunit II INTERMEMBRANOUS SPACE F0 MATRIX Cytochrome b Subunit I Subunit III Cytochrome c oxidase Complex III Complex IV F1 Complex V Figure 19-5 CHEMIOSMOTIC CYCLE OF THE RESPIRATORY ELECTRON TRANSPORT CHAIN AND ATP SYNTHASE. A, left panel, A mitochondrion for orientation. Right panel, The electron transport system of the inner mitochondrial membrane. Note the pathway of electrons through the four complexes (red and yellow arrows) and the sites of proton translocation between the matrix to the intermembranous space (black arrows). The stoichiometry is not specified, but at the last step, four electrons are required to reduce oxygen to water. ATP synthase uses the electrochemical proton gradient produced by the electron transport reactions to drive ATP synthesis. B, The available atomic structures of the electron transport chain are shown. In the cytochrome bc1 complex III, the 3 of 11 mitochondrial subunits used by bacteria are shown as ribbon models. The supporting subunits found in mitochondria are shown as cylinders. The four subunits of complex IV encoded by the mitochondrial genome are shown as ribbon models. They form the functional core of the complex, which is supported by additional subunits shown as cylinders. See Figure 8-4 for further details of ATP synthase (complex V). (B, Images of complex III and complex IV courtesy of M. Saraste, European Molecular Biology Laboratory, Heidelberg, Germany. Reference: Zhang Z, Huang L, Schulmeister VM, et al: Electron transfer by domain movement in cytochrome bc1. Nature 392:677–684, 1998. PDB file: 1BCC. Reference: Yoshikawa S, Shinzawa-Itoh K, Nakashima R, et al: Redox-coupled crystal structural changes in bovine heart cytochrome c oxidase. Science 280:1723–1729, 1998. PDB file: 2OCC.) 336 SECTION VI — Cellular Organelles and Membrane Trafficking of ATP synthase and three of the four electron transfer complexes. Nuclear genes encode most of the protein subunits of these complexes, but mitochondrial genes are responsible for a few key subunits. Bacteria and mitochondria share homologous proteins for the key steps in oxidative phosphorylation (Fig. 19-2), but the machinery in mitochondria is usually more complex. Thus, bacteria are useful model systems with which to study the common mechanisms. Plasma membranes of bacteria and inner membranes of mitochondria have equivalent components, and the bacterial cytoplasm corresponds to the mitochondrial matrix (Fig. 19-2). Energy enters this pathway in the form of electrons that are produced when NADH is oxidized to NAD + , releasing one H + and two electrons (Fig. 19-5). If the proton and electrons were to combine immediately with oxygen, their energy would be lost as heat. Instead, these high-energy electrons are separated from the protons and then passed along the electron transport pathway before fi nally recombining to reduce molecular oxygen to form water. Along the pathway, electrons associate transiently [temporär] with a series of oxidation/reduction acceptors, generally metal ions associated with organic cofactors, such as hemes in cytochromes and iron-sulfur centers (2Fe2S) and copper centers in complex IV. Electrons move along the transport pathway at rates of up to 1000 s−1. To travel at this rate through a transmembrane protein complex spanning a 35-nm lipid bilayer, at least three redox cofactors are required in each complex, because the efficiency of quantum mechanical tunneling of electrons between redox cofactors falls off rapidly with distance. Two cofactors, even with optimal orientation, would be too slow. Step by step, electrons give up energy as they move along the transport pathway. In three complexes along the pathway, this energy is used to pump protons from the matrix to the inner membrane space. This establishes an electrochemical proton gradient across the inner mitochondrial membrane that is used by ATP synthase to drive ATP production. Direction is provided to the movements of electrons by progressive increases [fortschreitende Zunahme] in the electron affinity of the acceptors. The final acceptor, oxygen (at the end of the pathway), has the highest affi nity. The first component of the electron transport pathway is called complex I (or NADH:ubiquinone oxidoreductase). Vertebrate mitochondrial complex I with 46 different protein subunits is more complex than bacterial complex I with 14 subunits. NADH donates two electrons to flavin mononucleotide associated with protein subunits located on the matrix side of the inner membrane. A crystal structure of the cytoplasmic domain of the bacterial complex shows the path for the electrons from flavin mononucleotide through seven iron sulfur clusters to quinone in the lipid bilayer [Dop- pelschicht]. For each molecule of NADH oxidized, the transmembrane domains of complex I transfer four protons from the matrix into the inner membrane space. The second component of the electron transport pathway is complex II or succinate:ubiquinone reductase, a transmembrane enzyme that makes up part of the citric acid cycle. Complex II couples oxidation of succinate (a four-carbon intermediate in the citric acid cycle) to fumarate with reduction of flavin adenine dinucleotide (FAD) to FADH2. Complex II does not pump protons but transfers electrons from FADH2 to ubiquinone. Reduced ubiquinone carries these electrons to complex III. The third component of the electron transport pathway is complex III, also called cytochrome bc1. This well-characterized, transmembrane protein complex consists of 11 different subunits. The homologous bacterial complex has only three of these subunits, the ones that participate in energy transduction in mitochondria. Eight other subunits surround this core. Complex III couples the oxidation and reduction of ubiquinone to the transfer of protons from the matrix across the inner mitochondrial membrane. Energy is supplied by electrons that move through the cytochrome b subunit to a subunit with a 2Fe2S redox center. This subunit then rotates into position to transfer the electron to cytochrome c1, another subunit of the complex. Cytochrome c1 then transfers the electron to the watersoluble protein cytochrome c in the intermembranous space (or periplasm of bacteria). Cytochrome oxidase, complex IV, takes electrons from four cytochrome c molecules to reduce molecular oxygen to two waters as well as to pump four protons out of the matrix. Mitochondrial genes encode the three subunits that form the core of this enzyme, carry out electron transfer, and translocate protons. Nuclear genes encode the surrounding 10 subunits. The electrochemical proton gradient produced by the electron transport chain provides energy to synthesize ATP. Chapter 8 explained how the rotary [rotierend] ATP synthase (complex V) can either use ATP hydrolysis to pump protons or use the transit of protons down an electrochemical gradient to synthesize ATP (see Figs. 8-5 and 8-6). The proton gradient across the inner mitochondrial membrane drives rotation of the γsubunit. The rotating γ-subunit physically changes the conformations of the α- and β-subunits, bringing together ADP and inorganic phosphate to make ATP. An antiporter in the inner membrane exchanges cytoplasmic ADP for ATP synthesized in the matrix (see Fig. 9-2A). Mitochondria and Disease As expected from the central role of mitochondria in energy metabolism, mitochondrial dysfunction contrib- 337 CHAPTER 19 — Mitochondria, Chloroplasts, Peroxisomes utes to a remarkable diversity of human diseases (Fig. 19-6) including seizures [Krampfanfälle], strokes [Hirnschläge], optic atrophy [Sehnervenatrophie], neuropathy, myopathy, cardiomyopathy, hearing loss, and Type 2 diabetes mellitus. These disorders arise from mutations in genes for mitochondrial proteins encoded by both mitochondrial DNA (mtDNA) and nuclear DNA. More than half of the known disease-causing mutations are in genes for mitochondrial transfer RNAs. The existence of about 1000 copies of mtDNA per vertebrate cell influences the impact [Auswirkungen] of deleterious [schädlich] mutations. A mutation in one copy would be of no consequence, but segregation of mtDNAs may lead to cells in which mutant mtDNAs predominate, yielding defective proteins. For example, a recurring [wiederholt auftretend] point mutation in a subunit of complex I causes some patients to develop sudden onset of blindness in middle age owing to the death of neurons in the optic nerve. Patients with the same mutation in a larger fraction of mtDNA molecules suffer from muscle weakness and mental retardation [geistige Behinderung] as children. Mutations in the genes for subunits of ATP synthase cause muscle weakness and degeneration of the retina. Slow accumulation of mutations in mtDNA may contribute to some symptoms of aging. Mutations in nuclear genes for mitochondrial proteins cause similar diseases (Fig. 19-6A). A mutation in one subunit of the protein import machinery (see Fig. 18-5), Tim8, causes a type of deafness. Chloroplasts Structure and Evolution of Photosynthesis Systems Photosynthetic Bacteria and chloroplasts of algae and plants (Fig. 19-7) use chlorophyll to capture the remarkable amount of energy carried by single photons to boost electrons to an excited state. These high-energy electrons drive a chemiosmotic cycle to make NADPH and ATP, energy currency [Währung] that is used by all cells. Photosynthetic organisms use ATP and the reducing power of NADPH to synthesize three-carbon sugar phosphates from carbon dioxide. Glycolytic reactions (Fig. 19-4) running backward use this three-carbon sugar phosphate to make six-carbon sugars and more complex carbohydrates for use as metabolic energy sources and structural components. Some Archaea, such as Halobacteria halobium, and some recently discovered Bacteria use a completely different light-driven pump lacking chlorophyll to generate a proton gradient to synthesize ATP. Retinol associated with bacteriorhodopsin absorbs light to drive proton transport (see Fig. 8-3). Photosynthesis originated approximately 3.5 billion years ago in a Bacterium, most likely a gram-negative purple bacterium (see Fig. 2-4). These bacteria evolved A. Disorders secondary to mutations in nuclear DNA–encoded proteins Complex II Complex III Number of subunits Complex I nDNA-encoded ~35 4 10 Leigh syndrome Leigh syndrome Leukodystrophy Paraganglioma SPACE Complex IV Complex V 10 ~14 Leigh syndrome Cardioencephalomyopathy Leukodystrophy/tubulopathy Cytochrome C H+ H+ INTERMEMBRANOUS H+ ATP H+ Pi + + – – Q + e– + + + + – – – QH2 e– e- O2 e- H2O + – H+ + – – H+ ADP + + – – ADP + Pi NADH NAD+ FADH2 FAD Succinate ATP B. Disorders secondary to mutations in mitochondrial DNA–encoded proteins Complex II Number of subunits Complex I 7 0 mtDNA-encoded LHON LHON + Dystonia Sporadic myopathy Complex III 1 Sporadic myopathy Complex IV 3 Sporadic anemia Sporadic myopathy Encephalomyopathy Complex V 2 NARP MILS FBSN MATRIX Figure 19-6 Mutations in both mitochondrial and nuclear genes for mitochondrial proteins cause a variety of diseases by compromising [Beeinträchtigung] the function of particular mitochondrial subsystems. FBSN, familial bilateral striatal necrosis; LHON, Leber hereditary optic neuropathy; MILS, maternally inherited Leigh syndrome; NARP, neurogenic muscle weakness, ataxia, retinitis pigmentosa. (Adapted from Schon EA: Mitochondrial genetics and disease. Trends Biochem Sci 25:555–560, 2000.) 338 SECTION VI — Cellular Organelles and Membrane Trafficking A Grana Thylakoid space Thylakoid membrane Stroma Outer membrane Inner membrane B. Chloroplast Outer membrane Inner membrane Stroma Thylakoid space Thylakoid membrane Grana Grana Starch granule DNA Ribosomes C THYLAKOID SPACE STROMA D PERIPLASM CYTOPLASM E. Cyanobacterium Cell wall Plasma membrane Thylakoid membrane Thylakoid space Cytoplasm DNA Ribosomes Figure 19-7 MORPHOLOGY OF CHLOROPLASTS AND CYANOBACTERIA. A, Electron micrograph of a thin section of a spinach chloroplast. B, Chloroplast. C–D, Comparison of the machinery in the photosynthetic membranes of chloroplasts and cyanobacteria. E, Drawing of a cyanobacterium illustrating the internal folds of the plasma membrane to form photosynthetic thylakoids. (A, Courtesy of K. Miller, Brown University, Providence, Rhode Island.) components to assemble a transmembrane complex of proteins, pigments, and oxidation/reduction cofactors called a reaction center (Fig. 19-8). Reaction centers absorb light and initiate an electron transport pathway that pumps protons out of the cell. Such photosystems turn sunlight into electrical and chemical energy with 40% efficiency, better than any human-made photovoltaic cell. Given their alarming complexity and physical perfection, it is remarkable that photosystems emerged only a few hundred million years after the origin of life itself. Broadly speaking, photosynthetic reaction centers of contemporary organisms can be divided into two different groups (Fig. 19-8). The reaction centers of purple bacteria and green fi lamentous bacteria utilize the pigment pheophytin and a quinone as the electron acceptor, similar to photosystem II of cyanobacteria and chloroplasts. The reaction centers of green sulfur bacteria and heliobacteria have iron-sulfur centers as electron acceptors, similar to photosystem I of cyanobacteria and chloroplasts. Cyanobacteria are unique among Bacteria in that they have both types of photosystems as well as a manganese [Mangan] enzyme that splits water, releasing from two water molecules four electrons, four protons, and oxygen (Fig. 19-7E). Coupling this enzyme to photosynthesis was a pivotal [entscheidend] event in the history of the earth, as this reaction is the source of most of the oxygen in the earth’s atmosphere. Chloroplasts of eukaryotic cells arose from a symbiotic cyanobacterium (see Fig. 2-8). Much evidence indicates that this event occurred just once, giving all chloroplasts a common origin. However, to account for chloroplasts in organisms that diverged prior to the acquisition of chloroplasts, one must also postulate lateral transfer of chloroplasts from, for example, a green alga to Euglena. Less likely, but not ruled out conclusively, cyanobacteria may have colonized eukaryotic cells on up to three different occasions, giving rise to organelles that evolved into chloroplasts. Chloroplasts have retained [behalten] up to 250 original bacterial genes on circular genomes, whereas many bacterial genes were lost or moved to the nucleus of host eukaryotes. Chloroplast genomes encode subunits of many proteins responsible for photosynthesis and chloroplast division, ribosomal RNAs and proteins, and a complete set of tRNAs. Chloroplast proteins encoded by nuclear genes are transported posttranslationally into chloroplasts (Fig. 18-6) after their synthesis in cytoplasm. The organization of cyanobacterial membranes explains the architecture of chloroplasts (Fig. 19-7C–E). In cyanobacteria, light-absorbing pigments, as well as protein complexes involved with electron transport and ATP synthesis, are concentrated in invaginations of the CHAPTER 19 — Mitochondria, Chloroplasts, Peroxisomes A. Purple bacteria, green filamentous bacteria PERIPLASM -1.0 H+ 3 H+ + QB e- QH2 ADP + Pi H+ Light PERIPLASM H+ Light Fes Fes Purple bacteria D. Electron energy BChl2* – – NAD reductase ATP synthase 0 BChl2 0.5 Green sulfur bacteria F. Electron energy LUMEN Plastocyanin Chl2* H+ -1.0 + Fes H+ Fes 2 H+ H Light-harvesting complexes FX FA/B NAD -0.5 CYTOPLASM e- QH2 Chl 1.0 Light e- BChl2 + + PERIPLASM/ Light Mn2+ QB QB Cytochrome bc1 Cytochrome c2 ATP E. Cyanobacteria, algae, plants QA 0.5 ADP + Pi eNAD NADH + H+ Cytochrome bc Type I complex photosystem H+ – H+ Ferridoxin 2 QA 0 -1.0 Light-harvesting complex 2 H2O BChl BPhe 1.0 H+ 3 H+ -0.5 ATP synthase CYTOPLASM + 4 H+ + O BChl2* ATP C. Green sulfur bacteria Heliobacteria Cytochrome c2 H+ – – – 2 H+ H Light-harvesting complex Type II Cytochrome bc1 photosystem complex + + eFerridoxin Photosystem II Cytochrome b6-f Photosystem I complex NADP NADPH + H+ NADP reductase H+ + + – – – ADP + Pi ATP ATP synthase STROMA/ CYTOPLASM Energy (volts) QA H+ Energy (volts) Light B. Electron energy Cytochrome c2 Energy (volts) Cytochrome Chl2* -0.5 QA QB 0.5 H2O 1.0 FX FA/B NAD Phe 0 Chl2 Chl Q Chl2 YZ Chloroplasts and cyanobacteria Photosystem II Photosystem I Figure 19-8 COMPARISON OF PHOTOSYNTHETIC COMPONENTS, ELECTRON TRANSPORT PATHWAYS, AND CHEMIOSMOTIC CYCLES TO MAKE ATP. A–B, Type II photosystem only. C–D, Type I photosystem only. E–F, Both photosystem II and photosystem I. Right diagrams, The energy levels of electrons in the three types of photosynthetic organisms, showing excitation of an electron by an absorbed photon (vertical arrows), electron transfer pathways through each reaction center (arrows sloping right), and electron transfer steps outside the reaction centers (arrows sloping left). (A, C, and E, Reference: Kramer DM, Schoepp B, Liebl U, Nitschke W: Cyclic electron transfer in Heliobacillus mobilis. Biochemistry 36:4203–4211, 1997. B, D, and F, Reference: Allen JP, Williams JC: Photosynthetic reaction centers. FEBS Lett 438:5–9, 1998.) plasma membrane. The F1 domain of ATP synthase faces the cytoplasm, and the lumen of this membrane system is periplasmic. This internal membrane system remains in chloroplasts but is separated from the inner membrane (the former plasma membrane). These thylakoid membranes contain photosynthetic hardware and enclose the thylakoid membrane space. Like the bacterial plasma membrane, the chloroplast “inner membrane” is a permeability barrier, containing carriers for metabolites. The inner membrane surrounds the 339 340 SECTION VI — Cellular Organelles and Membrane Trafficking stroma, the cytoplasm of the original symbiotic bacterium, a protein-rich compartment devoted to synthesis of three-carbon sugar phosphates, chloroplast proteins, and all plant fatty acids. The stroma also houses the genomes and stores starch [Stärke]. The outer membrane, like the comparable bacterial and mitochondrial membranes, has large pore channels that allow free passage of metabolites. Light and Dark Reactions Photosynthetic mechanisms capture energy from photons to drive two types of reactions: • Light reactions depend on continuous absorption of photons. These reactions occur in or on the surface of thylakoid membranes. They include generation of high-energy electrons, electron transport to make NADPH, creation of a proton gradient across the thylakoid membrane for the chemiosmotic synthesis of ATP, and generation of oxygen. • Dark reactions convert carbon dioxide into threecarbon sugar phosphates. These reactions continue for some time in the dark. However, they depend on ATP and NADPH produced by light reactions, so they eventually stop when ATP and NADPH are exhausted in the dark. These reactions account for most of the carbon dioxide converted to carbohydrates on earth. (Alternatively specialized prokaryotes drive carbon fi xation by oxidation of hydrogen sulfide and other inorganic compounds.) All photosynthetic systems use similar mechanisms to capture energy from photons (Fig. 19-8). Pigments associated with transmembrane proteins in photosynthetic reaction centers absorb photons and use the energy to boost electrons to a high-energy, excited state. Subsequent electron transfer reactions partition this energy in several steps to generate a proton gradient across the membrane. Generation of this proton electrochemical gradient and chemiosmotic production of ATP are similar to oxidative phosphorylation (Fig. 19-5). Specific photosynthetic systems differ in the complexity of the hardware, the source of electrons, and the products (Fig. 19-8). Most photosynthetic bacteria use either a type I photosystem or a type II photosystem to create a proton gradient to synthesize ATP. Cyanobacteria and green plants use both types of reaction centers in series to raise electrons to an energy sufficient to make NADPH in addition to ATP. These advanced systems also use water as the electron donor and produce molecular oxygen as a byproduct. Energy Capture and Transduction by Type II Photosystems and Photosystem II The reaction center from the purple bacterium Rhodopseudomonas viridis (Fig. 19-9A) is a model for the more complex photosystem II of cyanobacteria and chloroplasts. This bacterial reaction center consists of just four subunits. A cytochrome subunit on the periplasmic side of the membrane donates electrons. Two core subunits form a rigid [starr] transmembrane framework to bind 10 cofactors in orientations that favor transfer of high-energy electrons from two “special” bacteriochlorophylls through chlorophyll b and bacteriopheophytin b. Photosynthesis begins with absorption of a photon by the special pair bacteriochlorophylls. Photons in the visible part of the spectrum are quite energetic [energiereich], 40 to 80 kcal mol−1, enough to make several ATPs. The purple bacterium reaction center absorbs relatively low-energy, 870-nm red light. The energy elevates an electron in the special pair bacteriochlorophylls to an excited state (Fig. 19-8B). In an organic solvent, the excited state would decay [abnehmen] rapidly (109 s −1), and the energy would dissipate [vergeuden] as heat or emission of a less energetic photon by fluorescence or phosphorescence. However, reaction centers are optimized to transfer excited-state electrons rapidly and efficiently from the special pair bacteriochlorophylls to bacteriopheophytin (3 × 10−12 s) and then to tightly bound quinone A (200 × 10−12 s). Transfer is by quantum mechanical tunneling right through the protein molecule. Because the tunneling rate falls off quickly with distance, four redox centers must be spaced close together to allow an energetic electron to transfer across the lipid bilayer faster than spontaneous decay of the excited state. On the cytoplasmic side of the membrane, two electrons transfer from quinone A to loosely bound quinone B (100 × 10−9 s), where they combine with two protons to make a high-energy reduced quinone, QH2 (Fig. 19-8A). In purple bacteria, these cytoplasmic protons are taken up through water-filled channels in the reaction center, contributing to the proton gradient. QH2 has a low affinity for the reaction center and diffuses in the hydrophobic core of the bilayer to the next component in the pathway, the chloroplast equivalent of the mitochondrial cytochrome bc1 complex III (Fig. 19-8A). As in mitochondria, passage of energetic electrons through this complex releases protons from QH2 on the periplasmic side of the membrane, adding to the electrochemical gradient. The electron circuit is completed by transfer of low-energy electrons from complex bc1 to a soluble periplasmic protein, cytochrome c2. Electrons then move to the cytochrome subunit of the reaction center, which supplies special CHAPTER 19 — Mitochondria, Chloroplasts, Peroxisomes A. Purple bacterium type II photosystem reaction center B. Cyanobacterium type I photosystem Cytochrome Hemes L Electron pathway PsaM PsaA/B PsaK PsaF/J Clb eC1 Car eC2 eC3 Phb QB Fe QA M FX PsaE PsaL/I PsaD H PsaC CYTOPLASM Figure 19-9 STRUCTURES OF PHOTOSYSTEM HARDWARE. A, Ribbon diagram of type II photosystem from the purple bacterium Rhodopseudomonas viridis, with ball and stick models of bacteriochlorophyll and other cofactors to the right in their natural orientations. Similar core subunits L and M each consists of five transmembrane helices. This pair of subunits binds four molecules of chlorophyll b (Clb), two molecules of bacteriopheophytin b (Phb), one nonheme iron (Fe), two quinones (QA, QB), and one carotenoid (Car) in a rigid framework. A cytochrome with four heme groups binds to the periplasmic side of the core subunits. Subunit H associates with the core subunits via one transmembrane helix and with their cytoplasmic surfaces. The atomic structure of this photosynthetic reaction center was the Nobel Prize work of J. Deisenhoffer, R. Huber, and H. Michel. B, Ribbon diagram of photosystem I of Synechococcus elongatus, with ball and stick models of chlorophyll and other cofactors to the right in their natural orientations. This trimeric complex consists of three identical units, each composed of 11 polypeptide chains. Within each of these units, this 4-Å resolution structure includes 43 α-helices, 89 chlorophylls, a quinone, and three iron-sulfur centers, but other details (e.g., amino acid side chains) are not resolved. The photosynthetic reaction center consists of the C-terminal halves of the two central subunits (PsaA/PsaB, red-brown) associated with six chlorophylls, one or two quinones, and a shared iron-sulfur cluster. Plastocyanin or cytochrome c6 on the lumen side donates electrons to reduce the P700 special pair chlorophylls (eC1) of the reaction center. Light energizes an electron, which passes successively through two other chlorophylls, a quinone, and the shared iron-sulfur cluster (red), Fx. The electron then transfers to the iron-sulfur clusters of the accessory subunit PsaC on the stromal side of the membrane. The surrounding eight subunits (red, gray), associated with about 80 chlorophylls, compose the core antenna system, forming a nearly continuous ring of α-helices around the reaction center. Absorption of light by additional light-harvesting complexes [Lichtsammelkomplexe] and these antenna subunits puts chloroplast electrons into an excited state. This energy passes from one pigment to the next until it eventually reaches the reaction center. (A, Copyright of Deisenhoffer & Michel, Nobel Foundation, 1988. Reference: Deisenhoffer J, Michel H: The photosynthetic reaction center from the purple bacterium Rhodopseudomonas viridis. Science 245:1463–1473, 1989. PDB file: 1PRC. A 3.5 Å crystal structure [PDB file: 1IZL] of the PSII complex from the cyanobacterium Thermosynechococcus elongatus including 19 subunits is now available. Reference: Ferreira KN, Iverson TM, Maghlaoui K, et al: Architecture of the photosynthetic oxygen-evolving center. Science 303:1831–1838, 2004. B, PDB file: 2PPS. Reference: Schubert W-D, Klukas O, Krauss N, et al: Photosystem I of Synechococcus elongatus at 4 Å resolution: Comprehensive structure analysis. J Mol Biol 272:741–769, 1997.) pair chlorophylls with electrons for the photosynthetic reaction cycle. The net result of this cycle is the conversion of the energy of two photons into transport of three protons to the periplasm. A diagram of the energy levels of the various intermediates in the cycle (Fig. 19-8B) shows how energy is partitioned after an electron is excited by a photon and then moves, step by step, through protein-associated redox centers back to the ground state. The proton electrochemical gradient established by photosynthetic electron transfer reactions is used to drive an ATP synthase (see Fig. 8-5) similar to those of nonphotosynthetic prokaryotes and mitochondria. Light Harvesting Reaction center chlorophylls absorb light themselves, but both chloroplasts and bacteria increase the efficiency of light collection with proteins that absorb light 341 342 SECTION VI — Cellular Organelles and Membrane Trafficking and transfer the energy to a reaction center. Most of these light-harvesting complexes are small, transmembrane proteins that cluster around a reaction center, although some bacteria and algae also have soluble lightharvesting proteins. Transmembrane, light-harvesting proteins consist of a few α-helices associated with multiple chlorophyll and carotenoid pigments (Figs. 19-8A and C and 19-9B). The use of different pigments broadens the range of wavelengths absorbed. Multiple pigments increase the efficiency of photon capture. Leaves are green because chlorophylls and carotenoids absorb purple and blue wavelengths (<530 nm) as well as red wavelengths (>620 nm), reflecting only yellow-green wavelengths in between. Light that is absorbed by light-harvesting proteins boosts pigment electrons to an excited state. This energy (but not the electrons) moves without dissipation [Verlust] by fluorescence resonance energy transfer from one closely spaced pigment molecule to another and eventually to the special pair chlorophylls of a reaction center. This rapid (10−12 s), efficient process transfers energy captured over a wide area to a reaction center to initiate a cycle of electron transfer and energy transduction. Energy Capture and Transduction by Photosystem I The reaction centers of green sulfur bacteria and heliobacteria are similar to photosystem I of cyanobacteria and chloroplasts. Generation of a proton gradient by photosystem I has many parallels with photosystem II. Direct absorption of light or resonance energy transfer from surrounding light-harvesting complexes excites special pair chlorophylls in photosystem I (Fig. 19-8C– D). Excited-state electrons move rapidly within the reaction center from these chlorophylls through two accessory chlorophylls and to an iron-sulfur center. The pathway includes a quinone in cyanobacteria and chloroplasts. Electrons then move to the iron-sulfur center of a subunit on the cytoplasmic side of the membrane. The subsequent events in green sulfur bacteria and heliobacteria are still under investigation but are thought to include electron transfer by the soluble protein ferridoxin to an NAD reductase, followed by transfer by a lipid intermediate to cytochrome bc complex, and then back to the reaction center via a cytochrome c. Oxygen-Producing Synthesis of NADPH and ATP by Dual Photosystems Chloroplasts and cyanobacteria combine photosystem II and photosystem I in the same membrane to form a system capable of accepting low-energy electrons from the oxidation of water and producing both a proton gradient to drive ATP synthesis and reducing equiva- lents in the form of NADPH (Fig. 19-8E–F). Both photosystems are more elaborate in dual systems than in single systems. Although plant photosystem II, with more than 25 protein subunits, is much more complicated than is the homologous reaction center of purple bacteria, the arrangement of transmembrane helices and chlorophyll cofactors in the core of the plant reaction center is similar to the simple reaction center of purple bacteria. Photosynthesis involves a tortuous [gewunden] electron transfer pathway powered at two way stations by absorption of photons. This process begins when the special pair chlorophylls of photosystem II are excited by direct absorption of light or by resonance energy transfer from surrounding light-harvesting complexes (Fig. 19-8E–F). Electrons come from splitting two waters into molecular oxygen and four protons. Excited-state electrons tunnel through the redox cofactors and combine with protons from the stroma (or cytoplasm in bacteria) to reduce quinone QB to QH2, a high-energy electron donor. QH2 diffuses to complex b6-f, the chloroplast equivalent of the mitochondrial bc1 complex. Passage of electrons through complex b6-f releases protons from QH2 into the thylakoid lumen (or bacterial periplasm), contributing to the proton gradient across the membrane. Complex b6-f donates [abgeben] electrons from QH2 to photosystem I. Direct absorption of 680-nm light or resonance energy transfer from surrounding light-harvesting complexes boosts special pair chlorophyll electrons to a very high-energy, excited state (Fig. 19-8F). Excited-state electrons pass through chlorophyll and iron-sulfur centers of photosystem I to the iron-sulfur center of the redox protein, ferridoxin, on the cytoplasmic/stromal surface of the membrane. The enzyme NADP reductase combines electrons from ferridoxin with a proton to form NADPH, the final product of this tortuous electron transfer pathway powered at two way stations by absorption of photons. Uptake of stromal protons during NADPH formation contributes to the transmembrane proton gradient for the synthesis of ATP. Antiporters in the inner membrane exchange ATP for ADP, as in mitochondria. Synthesis of Carbohydrates ATP and NADPH produced by light reactions drive the unfavorable conversion of carbon dioxide into sugars. This is the first step in the earth’s annual production of about 1010 tons of carbohydrates by photosynthetic organisms. This process is very expensive, consuming three ATPs and two NADPHs for each carbon dioxide added to the five-carbon sugar ribulose 1,5-bisphosphate. The responsible enzyme, ribulose phosphate carboxylase (called RUBISCO), is the most abundant protein in the stroma and might be the CHAPTER 19 — Mitochondria, Chloroplasts, Peroxisomes most abundant protein on the earth. The products of combining the five-carbon sugar with carbon dioxide are two molecules of the three-carbon sugar 3-phosphoglycerate. An antiporter in the inner chloroplast membrane exchanges 3-phosphoglycerate for inorganic phosphate, so 3-phosphoglycerate can join the glycolytic pathway in the cytoplasm (Fig. 19-4). Driven by this abundant supply of 3-phosphoglycerate, the glycolytic pathway runs backward to make six-carbon sugars, which are used to make disaccharides such as sucrose [Saccharose] to nourish [mit Nährstoff versorgen] nonphotosynthetic parts of the plant, the glucose polymer starch to store carbohydrate, and cellulose for the extracellular matrix (see Figs. 3-25A and 32-12). Peroxisomes Peroxisomes are organelles bounded by a single membrane (Fig. 19-10), named for their content of enzymes that produce and degrade hydrogen peroxide, H2O2. Oxidases produce H2O2 and peroxidases such as catalase break it down. Peroxisomes also contain diverse enzymes for the metabolism of lipids and other metabolites, including the β-oxidation of fatty acids and oxidation of bile acids [Abschnüren] and cholesterol. Peroxisomes lack nucleic acids, and there is no evidence that they arose from a bacterial ancestor. All peroxisomal proteins are encoded by nuclear genes, translated on cytoplasmic ribosomes, and then subsequently incorporated into peroxisomes (see Fig. 18-8). Peroxisomes form in two different ways: de novo synthesis by budding from the endoplasmic reticulum and growth and division of preexisting peroxisomes (see Fig. 18-8). Cells that lack preexisting peroxisomes can form peroxisomes without a template by differentiation and budding of ER membranes. PEX3 and PEX16 target to the ER, where they recruit other peroxins to form a specialized domain that pinches off [schürt sich ab] to form a nascent peroxisome. In addition to arising by outgrowth from the ER, new peroxisomes can form by fission [Teilung] of preexisting peroxisomes. Defects in peroxisomal biogenesis cause a spectrum of lethal human diseases known as the peroxisomal biogenesis disorders (see Appendix 18-1). These diseases include Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum’s disease, and rhizomelic chondrodysplasia punctata. They are moderately rare, occurring in approximately 1 in 50,000 live births. Most patients with peroxisomal biogenesis disorders display no defect in peroxisome membrane synthesis or import of peroxisomal membrane proteins, but they do have mild-to-severe defects in matrix protein import. However, in rare cases, patients lack peroxisome membranes altogether. Studies of both yeast pex mutants and cells from patients with peroxisomal biogenesis disor- A B Figure 19-10 PEROXISOMES. A, Fluorescence micrographs of a CV1 cell expressing green fluorescent protein fused to PTS1, which labels peroxisomes green. Microtubules are stained red with labeled antibodies, and nuclear DNA is stained blue with propidium iodide. B, Electron micrograph of a thin section of a tissue culture cell showing three peroxisomes. Peroxisomes have a single bilayer membrane and a dense matrix, including a crystal (in some species) of the enzyme urate oxidase. (A, Courtesy of S. Subramani, University of California, San Diego. Reference: Wiemer EAC, Wenzel T, Deernick TJ, et al: Visualization of the peroxisomal compartment in living mammalian cells. J Cell Biol 136:71–80, 1997. B, Courtesy of Don W. Fawcett, Harvard Medical School, Boston, Massachusetts.) ders have provided clues regarding peroxisome biogenesis (see Fig. 18-7). ACKNOWLEDGMENT Thanks go to Gary Brudvig for his suggestions on revisions to this chapter. SELECTED READINGS Blankenship RE, Hartman H: The origin and evolution of oxygenic photosynthesis. Trends Biochem Sci 23:94–97, 1998. 343 344 SECTION VI — Cellular Organelles and Membrane Trafficking Cecchini G: Function and structure of complex II of the respiratory chain. Annu Rev Biochem 72:77–109, 2003. Deisenhofer J, Michel H: The photosynthetic reaction center from the purple bacterium Rhodopseudomonas viridis. Science 245:1463–1473, 1989. Frey TG, Mannella CA: The internal structure of mitochondria. Trends Biochem Sci 25:319–324, 2000. Gray MW, Burger G, Lang BF: Mitochondrial evolution. Science 283:1476–1481, 1999. Hosler JP, Ferguson-Miller S, Mills DA: Energy transduction: Proton transfer through the respiratory complexes. Annu Rev Biochem 75:165–187, 2006. Iwata S, Barber J: Structure of photosystem II and molecular architecture of the oxygen-evolving centre. Curr Opin Struct Biol 14:447–453, 2004. Lazarow PB: Peroxisome biogenesis: Advances and conundrums. Curr Opin Cell Biol 15:489–497, 2003. Lowell BB, Shulman, GI: Mitochondrial dysfunction and type 2 diabetes. Science 307:384–387, 2004. Meeusen SL, Nunnari J: How mitochondria fuse. Curr Opin Cell Biol 17:389–394, 2005. Moser CC, Keske JM, Warncke K, et al: Nature of biological electron transfer. Nature 355:796–802, 1992. Osteryoung KW, Nunnari J: The division of endosymbiotic organelles. Science 302:1698–1704, 2003. Rhee K-H: Photosystem II: The solid structural era. Annu Rev Biophys Biomol Struct 30:307–328, 2001. Rhee K-H, Morris EP, Barber J, Kuhlbrandt W: Three-dimensional structure of the plant photosystem II reaction centre at 8 Å resolution. Nature 396:283–286, 1998. Rutherford AW, Boussac A: Water photolysis in biology. Science 303:1782–1784, 2004. Scheffler IE: Mitochondria. New York, Wiley & Sons, 1999. Schubert W-D, Klukas O, Krauss N, et al: Photosystem I of Synechococcus elongatus at 4 Å resolution: Comprehensive structure analysis. J Mol Biol 272:741–769, 1997. Schultz BE, Chan SI: Structures and proton-pumping strategies of mitochondrial respiratory enzymes. Annu Rev Biophys Biomol Struct 30:23–65, 2001. Smith JL, Zhang H, Yan J, et al: Cytochrome bc complexes: A common core of structure and function surrounded by diversity in the outlying provinces. Curr Opin Struct Biol 14:432–439, 2004. Tielens AGM, Rotte C, van Hellemond JJ, Martin W: Mitochondria as we don’t know them. Trends Biochem Sci 27:564–572, 2002. Wallace DC: Mitochondrial diseases in man and mouse. Science 283:1482–1488, 1999. Wanders RJ, Waterham HR: Biochemistry of mammalian peroxisomes revisited. Annu Rev Biochem 75:295–332, 2006. Wittenhagen LM, Kelley SO: Impact of disease-related mitochondrial mutations on tRNA structure and function. Trends Biochem Sci 28:605–611, 2003.