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ScienceWeek
CELL BIOLOGY: ON THE DIVISION OF ENDOSYMBIOTIC ORGANELLES
The following points are made by K.W. Osteryoung and J. Nunnari (Science 2003 302:1698):
1) Chloroplasts and mitochondria power eukaryotic cells (1). Chloroplasts fix carbon from CO2 into organic molecules that constitute the base of the global food chain. Mitochondria convert the energy stored in these compounds into adenosine triphosphate, the form of cellular energy used to power most of the processes required for growth and development. These organelles (2) also have many other metabolic functions essential to eukaryotic organisms (3). Mitochondria also play a key role in programmed cell death, a process essential to the development of multicellular organisms (4).
2) Mitochondria and chloroplasts are the descendants of serial endosymbiotic events (5). Mitochondria arose first from an alpha-proteobacterial ancestor that was acquired by either an archaeal or primitive eukaryotic host, and the transition from autonomous bacterium to host (nuclear)-controlled organelle was pivotal in the evolution of eukaryotic cells (5). Chloroplasts later arose from a cyanobacterial ancestor acquired by a eukaryote in which mitochondria were already established. Most of the bacterial genes were transferred to the nuclear genome or lost as the endosymbionts were subjugated by the host cell, but both organelles in present-day eukaryotes retain genes, metabolic activities, genetic mechanisms, and protein import complexes that clearly reflect their prokaryotic origins.
3) Like their free-living ancestors, both chloroplasts and mitochondria divide. Organelle division, segregation, and growth are often uncoupled from the cell division cycle, indicating that organelle and cell division are independent processes. Division of mitochondria and chloroplasts is orchestrated by multicomponent protein machines that assemble and drive the constriction and fission of the organellar membranes. Because both organelles are surrounded by inner and outer membranes that differ in composition, their division machines must accomplish the synchronized constriction of both membranes, the subsequent fusion of the four lipid bilayers, the final separation of the two daughter organelles, and possibly the resolution of the fused membranes back into two discrete bilayers.
4) In summary: Mitochondria and chloroplasts are essential eukaryotic organelles of endosymbiotic origin. Dynamic cellular machineries divide these organelles. The mechanisms by which mitochondria and chloroplasts divide were thought to be fundamentally different because chloroplasts use proteins derived from the ancestral prokaryotic cell division machinery, whereas mitochondria have largely evolved a division apparatus that lacks bacterial cell division components. Recent findings indicate, however, that both types of organelles universally require dynamin-related guanosine triphosphatases to divide. This mechanistic link provides fundamental insights into the molecular events driving the division, and possibly the evolution, of organelles in eukaryotes.
References (abridged):
1. J. F. Allen, Philos. Trans. R. Soc. London Ser. B 358, 19 (2003)
2. All subsequent references to organelles refer specifically to mitochondria and chloroplasts.
3. B. B. Buchanan, W. Gruissem, R. L. Jones, Biochemistry & Molecular Biology of Plants (American Society of Plant Physiologists, Rockville, MD, 2002)
4. D. D. Newmeyer, S. Ferguson-Miller, Cell 112, 481 (2003)
5. M. W. Gray, G. Burger, B. F. Lang, Science 283, 1476 (1999)
Science http://www.sciencemag.org
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CHLOROPLASTS AND GENES
The following points are made by Paul Jarvis (Current Biology 2003 13:R314):
1) Chloroplasts, like mitochondria, evolved from a free-living prokaryotic organism that entered the eukaryotic lineage through endosymbiosis. During the course of their evolution, chloroplasts relinquished most of their genes to the nucleus, and so became subservient to the eukaryotic host. Today, more than 90% of the 3000 or so proteins present in chloroplasts are encoded in the nucleus, translated in the cytosol and imported into the organelle post-translationally. The remainder are encoded and synthesized within the organelle itself by an endogenous genetic system.
2) One of the consequences of this partitioning of genetic information is that processes which take place inside chloroplasts necessarily require input from two different compartments. For example, the photosynthetic complexes of the thylakoid membranes comprise core subunits encoded by the chloroplast genome, and peripheral subunits encoded by the nuclear genome. To ensure that these complexes are assembled in stoichiometric fashion, and to enable their rapid reorganization in response to changing environmental cues, the activities of the nuclear and chloroplast genomes must be closely coordinated through intracellular signalling.
Current Biology http://www.current-biology.com
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Notes:
The term "thylakoid" refers to a sac-like vesicle containing the photosynthetic pigments in photosynthetic organisms. In prokaryotes, the thylakoids are of various shapes and are attached to the plasma membrane; in eukaryotes, the thylakoids are flattened and located in chloroplasts; in the chloroplasts of higher plants, the thylakoids form dense stacks called "grana". Isolated thylakoids preparations can carry out photosynthetic electron transport and associated phosphorylation.
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ON MITOCHONDRIAL DNA AND DISEASE
The following points are made by R.E. Broughton et al (Genome Research 2001 11:1958):
1) Mitochondria provide the primary source of cellular ATP in eukaryotes via the process of oxidative phosphorylation. In animals, extranuclear mitochondrial genomes are typically circular, and with few exceptions code for 13 subunits of the oxidative phosphorylation machinery as well as for genes for 2 ribosomal RNA subunits and 22 transfer RNAs.
2) Mutations in mitochondrial DNA have a number of known deleterious effects. At least 50 base substitutions and hundreds of insertion/deletion mutations have been identified in human mitochondrial DNA, with effects ranging from degenerative diseases to aging to cancer. In addition to their role as the powerhouse of the cell, mitochondria are also involved in regulating programmed cell death (apoptosis), and mutagenic reactive oxygen species are generated in the process of energy production. Pathologies can result directly from the loss of ATP production in affected tissues, the buildup of oxygen radicals due to downstream blockage of the oxidative phosphorylation pathway, or unregulated apoptosis.
3) Hundreds of mitochondria and thousands of mitochondrial DNAs are inherited maternally through the cytoplasm of the oocyte. If a zygote receives more than one form of mitochondrial DNA (heteroplasmy), different forms can be randomly distributed to daughter cells during cell division, and over many cell generations these different forms can drift to high or low frequency in various cell lineages. Thus, if one of the mutant forms is deleterious, disease may affect lineages where it reaches sufficiently high frequency.
Genome Research http://www.genome.org
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MEDICAL BIOLOGY: MITOCHONDRIA IN HUMAN DISEASE
Mitochondria are double-membrane enclosed organelles of cells that are involved with several important biochemical pathways, including *electron transport and *oxidative metabolism. Various types of eukaryotic cells (i.e., cells containing membrane-bound organelles) may contain from a few to several thousand mitochondria in each cell type. The mitochondria are relatively large cylindrical structures up to 10 microns long and up to 2 microns in diameter, and they are believed to have originated as organisms that became *symbiotic with eukaryotic cells.
In general, the term "apoptosis" refers to programmed cell death, whether as a part of normal tissue differentiation and development, or as a program activated in a defective cell. In the molecular biology of cancer, apoptosis is the name given to the programmed cell death provoked by certain proteins expressed by *tumor suppressor genes. Thus, malignant cells are defective cells with a deactivated apoptosis program, and this allows malignant cells to survive and replicate. In most tissues within the body, a delicate balance is maintained between cell proliferation and cell death. Aging or damaged cells are replaced with new cells, ensuring that tissues are maintained in prime condition. If this balance is disturbed in either direction, the consequences can be severe. Tissue degeneration will occur if cell death predominates over cell proliferation, and when cell proliferation outstrips cell death, the result is the development of tumors.
In recent years, it has been discovered that mitochondria play a central role in the apoptosis process, this in addition to their well-established role of providing *adenosine triphosphate (ATP) to drive the energy-requiring processes within the cell.
The following points are made by Anne Murphy (The Biochemist April 2000):
1) Mitochondrial dysfunction is an apparent underlying contributor to many diseases. It has long been known that the lack of mitochondrial ATP production can lead to necrotic death in many pathologies, including *ischemia/reperfusion injury and *toxin exposure. More recently, it has become apparent that apoptosis can be induced by a wide variety of events, many of which involve the release of "apoptogens" (e.g., *cytochrome c and *caspases) from mitochondria. Often these stimuli initiate a caspase-dependent cascade of *proteolysis from which cells generally do not recover.
2) Forms of apoptosis exist that may not be dependent on mitochondrial apoptogen release. These forms of apoptosis appear to involve responses to certain *inflammatory mediators that bind specific death receptors. The extent to which mitochondria play a role in these varieties of cell death may be dependent upon cell type and the level of expression of specific caspases.
3) There are numerous diseases with components of apoptosis, but notable among these are certain neurodegenerative diseases, ischemic/reperfusion injury, autoimmune disorders and inflammatory diseases (including arthritis), and viral infection (including human immunodeficiency virus [HIV])). Also, the development of certain cancers is apparently associated with the loss of appropriate levels of apoptosis. Furthermore, in cancer, resistance of malignant cells to chemotherapeutic agents is associated with the expression of proteins, localized to mitochondria, that inhibit apoptosis.
4) Clinical studies have implicated mitochondrial dysfunction in certain chronic diseases, including *Alzheimer's, *Huntington's, and *Parkinson's diseases. There is evidence of metabolic abnormalities in the rates of *glucose utilization and *lactate production in the affected brain regions of patients with these diseases. There is also evidence of a decrease in the maximal activity of *electron-transport-chain complexes in the brains or peripheral tissues of patients with these diseases. The question is whether these defects are sufficient to compromise normal neuronal function, and whether they are the cause or the result of the respective disease.
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Notes:
electron transport: This refers to a sequence of steps in the final stage of the aerobic respiration biochemical pathway in which high energy electrons are effectively passed through a series of membrane-bound carrier molecules to support a proton gradient involved in energy storage. The term "transport" here refers essentially to a chemical flow diagram and not necessarily to an actual spatial translocation of electrons.
oxidative metabolism: In general, a set of biochemical pathways dependent on the utilization of supplied oxygen.
symbiotic: In biology, "symbiosis" is an intimate and protracted association of individuals of different species.
tumor suppressor genes: In general, cancer genes have been divided into 2 classes, proto-oncogenes and tumor suppressor genes. Proto-oncogenes are genes that sustain activating changes in human cancer. These changes may take the form of point mutations or gene rearrangements that lead to increased or uncontrolled activity of the encoded protein, or they make take the form of gene amplification, which results in increased levels of protein expression. In contrast, tumor suppressor genes are characterized by inactivating changes in human cancer, typically point mutations that result in truncation or functional inactivation of the encoded protein, or gross deletions of chromosomal fragments carrying these genes.
adenosine triphosphate (ATP): ATP is the most important chemical energy source in all living cells, intimately involved in various cell functions and cell metabolism, and an entity in numerous cyclic chemical pathways involved in the synthesis of various cell components.
ischemia/reperfusion injury: In general, "ischemia" is a sudden loss of blood supply to a tissue caused by blockage of a blood vessel. The term "ischemia/reperfusion injury" refers to the damage that can occur to a tissue when it is reperfused after a prolonged period of ischemia. The phenomenon is of considerable clinical importance, especially in connection with heart attacks and strokes.
toxin: In general, any noxious or poisonous substance, especially substances produced by living systems.
cytochrome c: The cytochromes, categorized as hemoproteins with differing porphyrin groups, are widely distributed respiratory (oxygen-utilizing) catalysts involved in the electron transport chain of living cells. They do not combine with substrates, but alternate between Fe(2+) and Fe(3+) states. There are various cytochromes, with cytochrome c present in the greatest amounts, and most importantly in the mitochondria of eukaryotic cells.
caspases: Proteases are a class of enzymes that hydrolyze proteins, splitting them into various groups of subunits, with the sites of hydrolysis dependent on the particular enzyme and the protein substrate, and a caspase is a type of protease implicated in apoptosis.
proteolysis: In general, hydrolysis (breakdown) of proteins.
inflammatory mediators: In general, an "inflammatory change" is a response of tissues to irritation or injury. The response involves a dynamic complex of cellular and chemical reactions that occur in the affected blood vessels and adjacent tissues.
Alzheimer's, *Huntington's, and *Parkinson's diseases: All three of these neurodegenerative diseases involve considerable loss of nerve cells in certain areas of the brain.
glucose utilization: In biological systems, glycolysis (also known as Embden-Meyerhof pathway), involving the breakdown of glucose, is one of the main energy producing pathways in the cell.
lactate production: Lactate is a salt or ester of lactic acid, and lactic acid is a common end product of glycolysis in biological systems.
electron-transport-chain complexes: The term "electron-transport chain" (respiratory chain) refers to the sequence of reactions involving enzymes and other proteins within the mitochondrion by which substrates are oxidized.
ScienceWeek http://www.scienceweek.com
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