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PLoS Comput Biol, Vol. 5, No. 4. (24 April 2009), e1000374.
Abstract
Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study ...
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Molecular Systems Biology, Vol. 6 (16 February 2010)
by Joao F. Passos, Glyn Nelson, Chunfang Wang, et al.Torsten Richter, Cedric Simillion, Carole J. Proctor, Satomi Miwa, Sharon Olijslagers, Jennifer Hallinan, Anil Wipat, Gabriele Saretzki, Karl L. Rudolph, Tom B. L. Kirkwood, Thomas von Zglinicki
Abstract
Cellular senescence—the permanent arrest of cycling in normally proliferating cells such as fibroblasts—contributes both to age-related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which ...
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Nature, Vol. 463, No. 7282. (11 February 2010), pp. 744-745.
Abstract
Defects in mitochondria are implicated in Parkinson's disease. Study of a quality-control pathway involving the proteins PINK1 and Parkin provides further clues about the mechanism involved. The pursuit of a unifying mechanism for Parkinson's disease has been refuelled by the identification of genetic mutations that underlie inherited variants of the disorder1. For instance, mutants of a particular enzyme — the mitochondrial PTEN-induced kinase-1 (PINK1) — cause a rare, early-onset form of Parkinson's2, directly implicating altered mitochondrial regulation in the disease process. ...
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Am J Physiol Cell Physiol, Vol. 288, No. 5. (May 2005)
Abstract
We present a computational model of mitochondrial deoxynucleotide metabolism and mitochondrial DNA (mtDNA) synthesis. The model includes the transport of deoxynucleosides and deoxynucleotides into the mitochondrial matrix space, as well as their phosphorylation and polymerization into mtDNA. Different simulated cell types (cancer, rapidly dividing, slowly dividing, and postmitotic cells) are represented in this model by different cytoplasmic deoxynucleotide concentrations. We calculated the changes in deoxynucleotide concentrations within the mitochondrion during the course of a mtDNA replication event and the time required ...
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PLoS Genetics, Vol. 2, No. 7. (1 July 2006), e115.
Abstract
We analyzed expression of 81 normal muscle samples from humans of varying ages, and have identified a molecular profile for aging consisting of 250 age-regulated genes. This molecular profile correlates not only with chronological age but also with a measure of physiological age. We compared the transcriptional profile of muscle aging to previous transcriptional profiles of aging in the kidney and the brain, and found a common signature for aging in these diverse human tissues. The common aging signature consists of ...
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Sci. Aging Knowl. Environ., Vol. 2005, No. 45. (9 November 2005), re5.
Abstract
Mitochondria are the organelles of aerobic respiration. They consume the oxygen we breathe to stay alive and generate energy for cells to function. But oxygen can be dangerous. Indeed, mitochondria generate the majority of reactive oxygen species that are prime suspects among the causes of aging. Mitochondria have been influential elements of evolving eukaryotic cells for perhaps 2 billion years, since a eubacterium fused with an archaebacterium. The picture that has emerged from this long history of genomic fusion is that ...
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Am J Physiol Cell Physiol, Vol. 292, No. 2. (1 February 2007), pp. C698-707.
Abstract
Potential functional consequences of the differences in protein distribution between the mitochondria of the rat liver, heart, brain, and kidney, as determined in the companion paper in this issue (Johnson DT, French S, Blair PV, You JS, Bemis KG, Wang M, Harris RA, and Balaban RS. The tissue heterogeneity of the mammalian mitochondrial proteome. Am J Physiol Cell Physiol292: C689-C697, 2006), were analyzed using a canonical metabolic pathway approach as well as a functional domain homology analysis. These data were inserted ...
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Am J Physiol Cell Physiol, Vol. 292, No. 2. (1 February 2007), pp. C689-697.
Abstract
The functionality of the mitochondrion is primarily determined by nuclear encoded proteins. The mitochondrial functional requirements of different tissues vary from a significant biosynthetic role (liver) to a primarily energy metabolism-oriented organelle (heart). The purpose of this study was to compare the mitochondrial proteome from four different tissues of the rat, brain, liver, heart, and kidney, to provide insight into the extent of mitochondrial heterogeneity and to further characterize the overall mitochondrial proteome. Mitochondria were isolated, solubilized, digested, and subjected to ...
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J Biol Chem, Vol. 279, No. 38. (17 September 2004), pp. 39532-39540.
Abstract
Diverse datasets including genomic, proteomic, isotopomer, and DNA sequence variation are becoming available for human mitochondria. Thus there is a need to integrate these data within an in silico modeling framework where mitochondrial biology and related disorders can be studied and analyzed. This paper reports a reconstruction and characterization of the human mitochondrial metabolic network based on proteomic and biochemical data. The 189 reactions included in this reconstruction are both elementally and charge-balanced and are assigned to their respective cellular compartments ...
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PLoS Genetics, Vol. 2, No. 10. (1 October 2006), e170.
Abstract
Mitochondria carry out specialized functions; compartmentalized, yet integrated into the metabolic and signaling processes of the cell. Although many mitochondrial proteins have been identified, understanding their functional interrelationships has been a challenge. Here we construct a comprehensive network of the mitochondrial system. We integrated genome-wide datasets to generate an accurate and inclusive mitochondrial parts list. Together with benchmarked measures of protein interactions, a network of mitochondria was constructed in their cellular context, including extra-mitochondrial proteins. This network also integrates data from ...
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Am J Physiol Cell Physiol, Vol. 292, No. 1. (January 2007)
Abstract
The emerging field of systems biology seeks to develop novel approaches to integrate heterogeneous data sources for effective analysis of complex living systems. Systemic studies of mitochondria have generated a large number of proteomic data sets in numerous species, including yeast, plant, mouse, rat, and human. Beyond component identification, mitochondrial proteomics is recognized as a powerful tool for diagnosing and characterizing complex diseases associated with these organelles. Various proteomic techniques for isolation and purification of proteins have been developed; each tailored ...
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Critical Reviews in Clinical Laboratory Sciences, Vol. 42, No. 5-6. (October 2005), pp. 453-472.
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Circ Res, Vol. 90, No. 4. (8 March 2002), pp. 380-389.
Abstract
The identification of a majority of the polypeptides in mitochondria would be invaluable because they play crucial and diverse roles in many cellular processes and diseases. The endogenous production of reactive oxygen species (ROS) is a major limiter of life as illustrated by studies in which the transgenic overexpression in invertebrates of catalytic antioxidant enzymes results in increased lifespans. Mitochondria have received considerable attention as a principal source---and target---of ROS. Mitochondrial oxidative stress has been implicated in heart disease including myocardial ...
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Nat Rev Cancer, Vol. 3, No. 10. (October 2003), pp. 789-795.
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Mechanisms of ageing and development, Vol. 128, No. 7-8. (g 2007), pp. 456-459.
Abstract
Since Szilard's seminal 1959 article, the role of accumulating nuclear DNA (nDNA) damage -- whether as mutations, i.e. changes to sequence, or as epimutations, i.e. adventitious but persistent alterations to methylation and other decorations of nDNA and histones -- has been widely touted as likely to contribute substantially to the aging process throughout the animal kingdom. Such damage certainly accumulates with age and is central to one of the most prevalent age-related causes of death in mammals, namely cancer. However, its ...
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Genome biology, Vol. 6, No. 5. (2005)
Abstract
Mitochondria and plastids (including chloroplasts) have a small but vital genetic coding capacity, but what are the properties of some genes that dictate that they must remain encoded in organelles? ...
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Exp Gerontol, Vol. 41, No. 1. (January 2006), pp. 11-24.
Abstract
The accumulation of mitochondria containing mutated genomes was proposed to be an important factor involved in aging. Although the level of mutated mtDNA has shown to increase over time, it is currently not possible to directly measure the mtDNA mutation rate within living cells. The combination of mathematical modeling and controlled experiments is an alternative approach to obtain an estimate for the mutation rate in a well-defined system. In order to judge the relevance of mitochondrial mutations for the aging process, ...
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Genome Biology, Vol. 8, No. 2. (23 February 2007), 203.
Abstract
The integration of information on different aspects of the composition and function of mitochondria is defining a more comprehensive mitochondrial interactome and elucidating its role in a multitude of cellular processes and human disease. ...
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Biochemistry (Moscow), Vol. 70, No. 2. (1 February 2005), pp. 200-214.
Abstract
Oxidative stress is considered a major contributor to etiology of both “normal” senescence and severe pathologies with serious public health implications. Mitochondria generate reactive oxygen species (ROS) that are thought to augment intracellular oxidative stress. Mitochondria possess at least nine known sites that are capable of generating superoxide anion, a progenitor ROS. Mitochondria also possess numerous ROS defense systems that are much less studied. Studies of the last three decades shed light on many important mechanistic details of mitochondrial ROS production, ...
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Molecular Cancer, Vol. 1, No. 1. (2002)
Abstract
Mitochondria play important roles in cellular energy metabolism, free radical generation, and apoptosis. Defects in mitochondrial function have long been suspected to contribute to the development and progression of cancer. In this review article, we aim to provide a brief summary of our current understanding of mitochondrial genetics and biology, review the mtDNA alterations reported in various types of cancer, and offer some perspective as to the emergence of mtDNA mutations, their functional consequences in cancer development, and therapeutic implications. ...
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