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See detailA Conserved Mito-Cytosolic Translational Balance Links Two Longevity Pathways.
Molenaars, Marte; Janssens, Georges E.; Williams, Evan UL et al

in Cell metabolism (2020), 31(3), 549-5637

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal ... [more ▼]

Slowing down translation in either the cytosol or the mitochondria is a conserved longevity mechanism. Here, we found a non-interventional natural correlation of mitochondrial and cytosolic ribosomal proteins (RPs) in mouse population genetics, suggesting a translational balance. Inhibiting mitochondrial translation in C. elegans through mrps-5 RNAi repressed cytosolic translation. Transcriptomics integrated with proteomics revealed that this inhibition specifically reduced translational efficiency of mRNAs required in growth pathways while increasing stress response mRNAs. The repression of cytosolic translation and extension of lifespan from mrps-5 RNAi were dependent on atf-5/ATF4 and independent from metabolic phenotypes. We found the translational balance to be conserved in mammalian cells upon inhibiting mitochondrial translation pharmacologically with doxycycline. Lastly, extending this in vivo, doxycycline repressed cytosolic translation in the livers of germ-free mice. These data demonstrate that inhibiting mitochondrial translation initiates an atf-5/ATF4-dependent cascade leading to coordinated repression of cytosolic translation, which could be targeted to promote longevity. [less ▲]

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See detailDiet modulates cecum bacterial diversity and physiological phenotypes across the BXD mouse genetic reference population.
Perez-Munoz, Maria Elisa; McKnite, Autumn M.; Williams, Evan UL et al

in PloS one (2019), 14(10), 0224100

The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different ... [more ▼]

The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different levels of fat in the diet using both chow diet (CD, 13-18% fat) and a high-fat diet (HFD, 45-60% fat). We studied cohorts of BXD strains, both inbred parents C57BL/6J and DBA/2J (commonly known as B6 and D2, respectively), as well as B6D2 and D2B6 reciprocal F1 hybrids. The comparative impact of genetic and dietary factors was analyzed by profiling a range of phenotypes, most prominently their cecum bacterial composition. The parents of the BXDs and F1 hybrids express limited differences in terms of weight and body fat gain on CD. In contrast, the strain differences on HFD are substantial for percent body fat, with DBA/2J accumulating 12.5% more fat than C57BL/6J (P < 0.0001). The F1 hybrids born to DBA/2J dams (D2B6F1) have 10.6% more body fat (P < 0.001) than those born to C57BL/6J dams. Sequence analysis of the cecum microbiota reveals important differences in bacterial composition among BXD family members with a substantial shift in composition caused by HFD. Relative to CD, the HFD induces a decline in diversity at the phylum level with a substantial increase in Firmicutes (+13.8%) and a reduction in Actinobacteria (-7.9%). In the majority of BXD strains, the HFD also increases cecal sIgA (P < 0.0001)-an important component of the adaptive immunity response against microbial pathogens. Host genetics modulates variation in cecum bacterial composition at the genus level in CD, with significant quantitative trait loci (QTLs) for Oscillibacter mapped to Chr 3 (18.7-19.2 Mb, LRS = 21.4) and for Bifidobacterium mapped to Chr 6 (89.21-89.37 Mb, LRS = 19.4). Introduction of HFD served as an environmental suppressor of these QTLs due to a reduction in the contribution of both genera (P < 0.001). Relations among liver metabolites and cecum bacterial composition were predominant in CD cohort, but these correlations do not persist following the shift to HFD. Overall, these findings demonstrate the important impact of environmental/dietary manipulation on the relationships between host genetics, gastrointestinal bacterial composition, immunological parameters, and metabolites-knowledge that will help in the understanding of the causal sources of metabolic disorders. [less ▲]

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See detailJCAD: from systems genetics identification to the experimental validation of a coronary artery disease risk locus.
Williams, Evan UL; Stein, Sokrates

in European heart journal (2019), 40(29), 2409-2412

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See detailA new class of protein biomarkers based on subcellular distribution: application to a mouse liver cancer model.
Sajic, Tatjana; Ciuffa, Rodolfo; Lemos, Vera et al

in Scientific reports (2019), 9(1), 6913

To-date, most proteomic studies aimed at discovering tissue-based cancer biomarkers have compared the quantity of selected proteins between case and control groups. However, proteins generally function in ... [more ▼]

To-date, most proteomic studies aimed at discovering tissue-based cancer biomarkers have compared the quantity of selected proteins between case and control groups. However, proteins generally function in association with other proteins to form modules localized in particular subcellular compartments in specialized cell types and tissues. Sub-cellular mislocalization of proteins has in fact been detected as a key feature in a variety of cancer cells. Here, we describe a strategy for tissue-biomarker detection based on a mitochondrial fold enrichment (mtFE) score, which is sensitive to protein abundance changes as well as changes in subcellular distribution between mitochondria and cytosol. The mtFE score integrates protein abundance data from total cellular lysates and mitochondria-enriched fractions, and provides novel information for the classification of cancer samples that is not necessarily apparent from conventional abundance measurements alone. We apply this new strategy to a panel of wild-type and mutant mice with a liver-specific gene deletion of Liver receptor homolog 1 (Lrh-1(hep-/-)), with both lines containing control individuals as well as individuals with liver cancer induced by diethylnitrosamine (DEN). Lrh-1 gene deletion attenuates cancer cell metabolism in hepatocytes through mitochondrial glutamine processing. We show that proteome changes based on mtFE scores outperform protein abundance measurements in discriminating DEN-induced liver cancer from healthy liver tissue, and are uniquely robust against genetic perturbation. We validate the capacity of selected proteins with informative mtFE scores to indicate hepatic malignant changes in two independent mouse models of hepatocellular carcinoma (HCC), thus demonstrating the robustness of this new approach to biomarker research. Overall, the method provides a novel, sensitive approach to cancer biomarker discovery that considers contextual information of tested proteins. [less ▲]

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See detailMild inborn errors of metabolism in commonly used inbred mouse strains.
Leandro, Joao; Violante, Sara; Argmann, Carmen A. et al

in Molecular genetics and metabolism (2019), 126(4), 388-396

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, alpha-aminoadipic acidemia and branched-chain ketoacid ... [more ▼]

Inbred mouse strains are a cornerstone of translational research but paradoxically many strains carry mild inborn errors of metabolism. For example, alpha-aminoadipic acidemia and branched-chain ketoacid dehydrogenase deficiency are known in C57BL/6J mice. Using RNA sequencing, we now reveal the causal variants in Dhtkd1 and Bckdhb, and the molecular mechanism underlying these metabolic defects. C57BL/6J mice have decreased Dhtkd1 mRNA expression due to a solitary long terminal repeat (LTR) in intron 4 of Dhtkd1. This LTR harbors an alternate splice donor site leading to a partial splicing defect and as a consequence decreased total and functional Dhtkd1 mRNA, decreased DHTKD1 protein and alpha-aminoadipic acidemia. Similarly, C57BL/6J mice have decreased Bckdhb mRNA expression due to an LTR retrotransposon in intron 1 of Bckdhb. This transposable element encodes an alternative exon 1 causing aberrant splicing, decreased total and functional Bckdhb mRNA and decreased BCKDHB protein. Using a targeted metabolomics screen, we also reveal elevated plasma C5-carnitine in 129 substrains. This biochemical phenotype resembles isovaleric acidemia and is caused by an exonic splice mutation in Ivd leading to partial skipping of exon 10 and IVD protein deficiency. In summary, this study identifies three causal variants underlying mild inborn errors of metabolism in commonly used inbred mouse strains. [less ▲]

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See detailMulti-omic measurements of heterogeneity in HeLa cells across laboratories.
Liu, Yansheng; Mi, Yang; Mueller, Torsten et al

in Nature biotechnology (2019), 37(3), 314-322

Reproducibility in research can be compromised by both biological and technical variation, but most of the focus is on removing the latter. Here we investigate the effects of biological variation in HeLa ... [more ▼]

Reproducibility in research can be compromised by both biological and technical variation, but most of the focus is on removing the latter. Here we investigate the effects of biological variation in HeLa cell lines using a systems-wide approach. We determine the degree of molecular and phenotypic variability across 14 stock HeLa samples from 13 international laboratories. We cultured cells in uniform conditions and profiled genome-wide copy numbers, mRNAs, proteins and protein turnover rates in each cell line. We discovered substantial heterogeneity between HeLa variants, especially between lines of the CCL2 and Kyoto varieties, and observed progressive divergence within a specific cell line over 50 successive passages. Genomic variability has a complex, nonlinear effect on transcriptome, proteome and protein turnover profiles, and proteotype patterns explain the varying phenotypic response of different cell lines to Salmonella infection. These findings have implications for the interpretation and reproducibility of research results obtained from human cultured cells. [less ▲]

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See detailQuantifying and Localizing the Mitochondrial Proteome Across Five Tissues in A Mouse Population.
Williams, Evan UL; Wu, Yibo; Wolski, Witold et al

in Molecular and Cellular Proteomics (2018), 17(9), 1766-1777

We have used SWATH mass spectrometry to quantify 3648 proteins across 76 proteomes collected from genetically diverse BXD mouse strains in two fractions (mitochondria and total cell) from five tissues ... [more ▼]

We have used SWATH mass spectrometry to quantify 3648 proteins across 76 proteomes collected from genetically diverse BXD mouse strains in two fractions (mitochondria and total cell) from five tissues: liver, quadriceps, heart, brain, and brown adipose (BAT). Across tissues, expression covariation between genes' proteins and transcripts-measured in the same individuals-broadly aligned. Covariation was however far stronger in certain subsets than others: only 8% of transcripts in the lowest expression and variance quintile covaried with their protein, in contrast to 65% of transcripts in the highest quintiles. Key functional differences among the 3648 genes were also observed across tissues, with electron transport chain (ETC) genes particularly investigated. ETC complex proteins covary and form strong gene networks according to tissue, but their equivalent transcripts do not. Certain physiological consequences, such as the depletion of ATP synthase in BAT, are thus obscured in transcript data. Lastly, we compared the quantitative proteomic measurements between the total cell and mitochondrial fractions for the five tissues. The resulting enrichment score highlighted several hundred proteins which were strongly enriched in mitochondria, which included several dozen proteins were not reported in literature to be mitochondrially localized. Four of these candidates were selected for biochemical validation, where we found MTAP, SOAT2, and IMPDH2 to be localized inside the mitochondria, whereas ABCC6 was in the mitochondria-associated membrane. These findings demonstrate the synergies of a multi-omics approach to study complex metabolic processes, and this provides a resource for further discovery and analysis of proteoforms, modified proteins, and protein localization. [less ▲]

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See detailGenetic cartography of longevity in humans and mice: Current landscape and horizons.
Hook, Michael; Roy, Suheeta; Williams, Evan UL et al

in Biochimica et biophysica acta. Molecular basis of disease (2018), 1864(9 Pt A), 2718-2732

Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this finding has given rise to the idea that it may be futile to search for DNA ... [more ▼]

Aging is a complex and highly variable process. Heritability of longevity among humans and other species is low, and this finding has given rise to the idea that it may be futile to search for DNA variants that modulate aging. We argue that the problem in mapping longevity genes is mainly one of low power and the genetic and environmental complexity of aging. In this review we highlight progress made in mapping genes and molecular networks associated with longevity, paying special attention to work in mice and humans. We summarize 40years of linkage studies using murine cohorts and 15years of studies in human populations that have exploited candidate gene and genome-wide association methods. A small but growing number of gene variants contribute to known longevity mechanisms, but a much larger set have unknown functions. We outline these and other challenges and suggest some possible solutions, including more intense collaboration between research communities that use model organisms and human cohorts. Once hundreds of gene variants have been linked to differences in longevity in mammals, it will become feasible to systematically explore gene-by-environmental interactions, dissect mechanisms with more assurance, and evaluate the roles of epistasis and epigenetics in aging. A deeper understanding of complex networks-genetic, cellular, physiological, and social-should position us well to improve healthspan. [less ▲]

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See detailGenetic Regulation of Plasma Lipid Species and Their Association with Metabolic Phenotypes.
Jha, Pooja; McDevitt, Molly T.; Halilbasic, Emina et al

in Cell systems (2018), 6(6), 709-7216

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either ... [more ▼]

The genetic regulation and physiological impact of most lipid species are unexplored. Here, we profiled 129 plasma lipid species across 49 strains of the BXD mouse genetic reference population fed either chow or a high-fat diet. By integrating these data with genomics and phenomics datasets, we elucidated genes by environment (diet) interactions that regulate systemic metabolism. We found quantitative trait loci (QTLs) for approximately 94% of the lipids measured. Several QTLs harbored genes associated with blood lipid levels and abnormal lipid metabolism in human genome-wide association studies. Lipid species from different classes provided signatures of metabolic health, including seven plasma triglyceride species that associated with either healthy or fatty liver. This observation was further validated in an independent mouse model of non-alcoholic fatty liver disease (NAFLD) and in plasma from NAFLD patients. This work provides a resource to identify plausible genes regulating the measured lipid species and their association with metabolic traits. [less ▲]

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See detailSimilarities and Differences of Blood N-Glycoproteins in Five Solid Carcinomas at Localized Clinical Stage Analyzed by SWATH-MS.
Sajic, Tatjana; Liu, Yansheng; Arvaniti, Eirini et al

in Cell reports (2018), 23(9), 2819-28315

Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes ... [more ▼]

Cancer is mostly incurable when diagnosed at a metastatic stage, making its early detection via blood proteins of immense clinical interest. Proteomic changes in tumor tissue may lead to changes detectable in the protein composition of circulating blood plasma. Using a proteomic workflow combining N-glycosite enrichment and SWATH mass spectrometry, we generate a data resource of 284 blood samples derived from patients with different types of localized-stage carcinomas and from matched controls. We observe whether the changes in the patient's plasma are specific to a particular carcinoma or represent a generic signature of proteins modified uniformly in a common, systemic response to many cancers. A quantitative comparison of the resulting N-glycosite profiles discovers that proteins related to blood platelets are common to several cancers (e.g., THBS1), whereas others are highly cancer-type specific. Available proteomics data, including a SWATH library to study N-glycoproteins, will facilitate follow-up biomarker research into early cancer detection. [less ▲]

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See detailSystems Analyses Reveal Physiological Roles and Genetic Regulators of Liver Lipid Species.
Jha, Pooja; McDevitt, Molly T.; Gupta, Rahul et al

in Cell systems (2018), 6(6), 722-7336

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 ... [more ▼]

The genetics of individual lipid species and their relevance in disease is largely unresolved. We profiled a subset of storage, signaling, membrane, and mitochondrial liver lipids across 385 mice from 47 strains of the BXD mouse population fed chow or high-fat diet and integrated these data with complementary multi-omics datasets. We identified several lipid species and lipid clusters with specific phenotypic and molecular signatures and, in particular, cardiolipin species with signatures of healthy and fatty liver. Genetic analyses revealed quantitative trait loci for 68% of the lipids (lQTL). By multi-layered omics analyses, we show the reliability of lQTLs to uncover candidate genes that can regulate the levels of lipid species. Additionally, we identified lQTLs that mapped to genes associated with abnormal lipid metabolism in human GWASs. This work provides a foundation and resource for understanding the genetic regulation and physiological significance of lipid species. [less ▲]

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See detailResources for Systems Genetics.
Williams, Robert W.; Williams, Evan UL

in Methods in molecular biology (Clifton, N.J.) (2017), 1488

A key characteristic of systems genetics is its reliance on populations that vary to a greater or lesser degree in genetic complexity-from highly admixed populations such as the Collaborative Cross and ... [more ▼]

A key characteristic of systems genetics is its reliance on populations that vary to a greater or lesser degree in genetic complexity-from highly admixed populations such as the Collaborative Cross and Diversity Outcross to relatively simple crosses such as sets of consomic strains and reduced complexity crosses. This protocol is intended to help investigators make more informed decisions about choices of resources given different types of questions. We consider factors such as costs, availability, and ease of breeding for common scenarios. In general, we recommend using complementary resources and minimizing depth of resampling of any given genome or strain. [less ▲]

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See detailApplication of SWATH Proteomics to Mouse Biology.
Wu, Yibo; Williams, Evan UL; Aebersold, Ruedi

in Current protocols in mouse biology (2017), 7(2), 130-143

The quantitative measurement of the proteome has been shown to yield new insights into physiology and cell biology that cannot be determined from the genome and transcriptome because the quantitative ... [more ▼]

The quantitative measurement of the proteome has been shown to yield new insights into physiology and cell biology that cannot be determined from the genome and transcriptome because the quantitative relationship between transcriptome and proteome is complex. MS-based proteomics techniques, such as SWATH-MS, have recently advanced to the point at which they may be reliably applied by biologists who are not specialists in mass spectrometry. Here we provide standard protocols for preparation of tissue samples for input into the SWATH-MS analytical pipeline. These protocols are designed for high-throughput processing of tissues with >/=5 mg of sample available for analysis. Studies with extremely limited amounts of tissue should consider PCT-SWATH. An experienced single user should be able to process 48 samples per day for injection into the mass spectrometer, or up to 144 samples a week. The machine time necessary for running these samples with SWATH is approximately 1.5 hr per sample. Data acquisition protocols are also provided. (c) 2017 by John Wiley & Sons, Inc. [less ▲]

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See detailSystematic proteome and proteostasis profiling in human Trisomy 21 fibroblast cells.
Liu, Yansheng; Borel, Christelle; Li, Li et al

in Nature communications (2017), 8(1), 1212

Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from ... [more ▼]

Down syndrome (DS) is mostly caused by a trisomy of the entire Chromosome 21 (Trisomy 21, T21). Here, we use SWATH mass spectrometry to quantify protein abundance and protein turnover in fibroblasts from a monozygotic twin pair discordant for T21, and to profile protein expression in 11 unrelated DS individuals and matched controls. The integration of the steady-state and turnover proteomic data indicates that protein-specific degradation of members of stoichiometric complexes is a major determinant of T21 gene dosage outcome, both within and between individuals. This effect is not apparent from genomic and transcriptomic data. The data also reveal that T21 results in extensive proteome remodeling, affecting proteins encoded by all chromosomes. Finally, we find broad, organelle-specific post-transcriptional effects such as significant downregulation of the mitochondrial proteome contributing to T21 hallmarks. Overall, we provide a valuable proteomic resource to understand the origin of DS phenotypic manifestations. [less ▲]

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See detailUrolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents.
Ryu, Dongryeol; Mouchiroud, Laurent; Andreux, Penelope A. et al

in Nature medicine (2016), 22(8), 879-88

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the ... [more ▼]

The biological effects of urolithins remain poorly characterized, despite wide-spread human exposure via the dietary consumption of their metabolic precursors, the ellagitannins, which are found in the pomegranate fruit, as well as in nuts and berries. We identified urolithin A (UA) as a first-in-class natural compound that induces mitophagy both in vitro and in vivo following oral consumption. In C. elegans, UA prevented the accumulation of dysfunctional mitochondria with age and extended lifespan. Likewise, UA prolonged normal activity during aging in C. elegans, including mobility and pharyngeal pumping, while maintaining mitochondrial respiratory capacity. These effects translated to rodents, where UA improved exercise capacity in two different mouse models of age-related decline of muscle function, as well as in young rats. Our findings highlight the health benefits of urolithin A and its potential application in strategies to improve mitochondrial and muscle function. [less ▲]

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See detailThe Movement Tracker: A Flexible System for Automated Movement Analysis in Invertebrate Model Organisms.
Mouchiroud, Laurent; Sorrentino, Vincenzo; Williams, Evan UL et al

in Current protocols in neuroscience (2016), 77

Phenotyping strategies in simple model organisms such as D. melanogaster and C. elegans are often broadly limited to growth, aging, and fitness. Recently, a number of physical setups and video tracking ... [more ▼]

Phenotyping strategies in simple model organisms such as D. melanogaster and C. elegans are often broadly limited to growth, aging, and fitness. Recently, a number of physical setups and video tracking software suites have been developed to allow for accurate, quantitative, and high-throughput analysis of movement in flies and worms. However, many of these systems require precise experimental setups and/or fixed recording formats. We report here an update to the Parallel Worm Tracker software, which we termed the Movement Tracker. The Movement Tracker allows variable experimental setups to provide cross-platform automated processing of a variety of movement characteristics in both worms and flies and permits the use of simple physical setups that can be readily implemented in any laboratory. This software allows high-throughput processing capabilities and high levels of flexibility in video analysis, providing quantitative movement data on C. elegans and D. melanogaster in a variety of different conditions. (c) 2016 by John Wiley & Sons, Inc. [less ▲]

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See detailJoint mouse-human phenome-wide association to test gene function and disease risk.
Wang, Xusheng; Pandey, Ashutosh K.; Mulligan, Megan K. et al

in Nature communications (2016), 7

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for ... [more ▼]

Phenome-wide association is a novel reverse genetic strategy to analyze genome-to-phenome relations in human clinical cohorts. Here we test this approach using a large murine population segregating for approximately 5 million sequence variants, and we compare our results to those extracted from a matched analysis of gene variants in a large human cohort. For the mouse cohort, we amassed a deep and broad open-access phenome consisting of approximately 4,500 metabolic, physiological, pharmacological and behavioural traits, and more than 90 independent expression quantitative trait locus (QTL), transcriptome, proteome, metagenome and metabolome data sets--by far the largest coherent phenome for any experimental cohort (www.genenetwork.org). We tested downstream effects of subsets of variants and discovered several novel associations, including a missense mutation in fumarate hydratase that controls variation in the mitochondrial unfolded protein response in both mouse and Caenorhabditis elegans, and missense mutations in Col6a5 that underlies variation in bone mineral density in both mouse and human. [less ▲]

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See detailTwo Conserved Histone Demethylases Regulate Mitochondrial Stress-Induced Longevity.
Merkwirth, Carsten; Jovaisaite, Virginija; Durieux, Jenni et al

in Cell (2016), 165(5), 1209-1223

Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress ... [more ▼]

Across eukaryotic species, mild mitochondrial stress can have beneficial effects on the lifespan of organisms. Mitochondrial dysfunction activates an unfolded protein response (UPR(mt)), a stress signaling mechanism designed to ensure mitochondrial homeostasis. Perturbation of mitochondria during larval development in C. elegans not only delays aging but also maintains UPR(mt) signaling, suggesting an epigenetic mechanism that modulates both longevity and mitochondrial proteostasis throughout life. We identify the conserved histone lysine demethylases jmjd-1.2/PHF8 and jmjd-3.1/JMJD3 as positive regulators of lifespan in response to mitochondrial dysfunction across species. Reduction of function of the demethylases potently suppresses longevity and UPR(mt) induction, while gain of function is sufficient to extend lifespan in a UPR(mt)-dependent manner. A systems genetics approach in the BXD mouse reference population further indicates conserved roles of the mammalian orthologs in longevity and UPR(mt) signaling. These findings illustrate an evolutionary conserved epigenetic mechanism that determines the rate of aging downstream of mitochondrial perturbations. [less ▲]

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See detailSystems proteomics of liver mitochondria function.
Williams, Evan UL; Wu, Yibo; Jha, Pooja et al

in Science (New York, N.Y.) (2016), 352(6291), 0189

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across ... [more ▼]

Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis. [less ▲]

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See detailTetracyclines Disturb Mitochondrial Function across Eukaryotic Models: A Call for Caution in Biomedical Research.
Moullan, Norman; Mouchiroud, Laurent; Wang, Xu et al

in Cell reports (2015), 10(10), 1681-1691

In recent years, tetracyclines, such as doxycycline, have become broadly used to control gene expression by virtue of the Tet-on/Tet-off systems. However, the wide range of direct effects of tetracycline ... [more ▼]

In recent years, tetracyclines, such as doxycycline, have become broadly used to control gene expression by virtue of the Tet-on/Tet-off systems. However, the wide range of direct effects of tetracycline use has not been fully appreciated. We show here that these antibiotics induce a mitonuclear protein imbalance through their effects on mitochondrial translation, an effect that likely reflects the evolutionary relationship between mitochondria and proteobacteria. Even at low concentrations, tetracyclines induce mitochondrial proteotoxic stress, leading to changes in nuclear gene expression and altered mitochondrial dynamics and function in commonly used cell types, as well as worms, flies, mice, and plants. Given that tetracyclines are so widely applied in research, scientists should be aware of their potentially confounding effects on experimental results. Furthermore, these results caution against extensive use of tetracyclines in livestock due to potential downstream impacts on the environment and human health. [less ▲]

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