Manipulating mtDNA in vivo reprograms metabolism via novel response mechanisms.

Abstract:

:Mitochondria have been increasingly recognized as a central regulatory nexus for multiple metabolic pathways, in addition to ATP production via oxidative phosphorylation (OXPHOS). Here we show that inducing mitochondrial DNA (mtDNA) stress in Drosophila using a mitochondrially-targeted Type I restriction endonuclease (mtEcoBI) results in unexpected metabolic reprogramming in adult flies, distinct from effects on OXPHOS. Carbohydrate utilization was repressed, with catabolism shifted towards lipid oxidation, accompanied by elevated serine synthesis. Cleavage and translocation, the two modes of mtEcoBI action, repressed carbohydrate rmetabolism via two different mechanisms. DNA cleavage activity induced a type II diabetes-like phenotype involving deactivation of Akt kinase and inhibition of pyruvate dehydrogenase, whilst translocation decreased post-translational protein acetylation by cytonuclear depletion of acetyl-CoA (AcCoA). The associated decrease in the concentrations of ketogenic amino acids also produced downstream effects on physiology and behavior, attributable to decreased neurotransmitter levels. We thus provide evidence for novel signaling pathways connecting mtDNA to metabolism, distinct from its role in supporting OXPHOS.

journal_name

PLoS Genet

journal_title

PLoS genetics

authors

Bahhir D,Yalgin C,Ots L,Järvinen S,George J,Naudí A,Krama T,Krams I,Tamm M,Andjelković A,Dufour E,González de Cózar JM,Gerards M,Parhiala M,Pamplona R,Jacobs HT,Jõers P

doi

10.1371/journal.pgen.1008410

subject

Has Abstract

pub_date

2019-10-04 00:00:00

pages

e1008410

issue

10

eissn

1553-7390

issn

1553-7404

pii

PGENETICS-D-19-00109

journal_volume

15

pub_type

杂志文章
  • Autoimmune disease classification by inverse association with SNP alleles.

    abstract::With multiple genome-wide association studies (GWAS) performed across autoimmune diseases, there is a great opportunity to study the homogeneity of genetic architectures across autoimmune disease. Previous approaches have been limited in the scope of their analysis and have failed to properly incorporate the direction...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000792

    authors: Sirota M,Schaub MA,Batzoglou S,Robinson WH,Butte AJ

    更新日期:2009-12-01 00:00:00

  • Genome-wide analysis of KAP1 binding suggests autoregulation of KRAB-ZNFs.

    abstract::We performed a genome-scale chromatin immunoprecipitation (ChIP)-chip comparison of two modifications (trimethylation of lysine 9 [H3me3K9] and trimethylation of lysine 27 [H3me3K27]) of histone H3 in Ntera2 testicular carcinoma cells and in three different anatomical sources of primary human fibroblasts. We found tha...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.0030089

    authors: O'Geen H,Squazzo SL,Iyengar S,Blahnik K,Rinn JL,Chang HY,Green R,Farnham PJ

    更新日期:2007-06-01 00:00:00

  • A polycomb group protein is retained at specific sites on chromatin in mitosis.

    abstract::Epigenetic regulation of gene expression, including by Polycomb Group (PcG) proteins, may depend on heritable chromatin states, but how these states can be propagated through mitosis is unclear. Using immunofluorescence and biochemical fractionation, we find PcG proteins associated with mitotic chromosomes in Drosophi...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003135

    authors: Follmer NE,Wani AH,Francis NJ

    更新日期:2012-01-01 00:00:00

  • Coevolution of interacting fertilization proteins.

    abstract::Reproductive proteins are among the fastest evolving in the proteome, often due to the consequences of positive selection, and their rapid evolution is frequently attributed to a coevolutionary process between interacting female and male proteins. Such a process could leave characteristic signatures at coevolving gene...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000570

    authors: Clark NL,Gasper J,Sekino M,Springer SA,Aquadro CF,Swanson WJ

    更新日期:2009-07-01 00:00:00

  • A positive feedback loop links opposing functions of P-TEFb/Cdk9 and histone H2B ubiquitylation to regulate transcript elongation in fission yeast.

    abstract::Transcript elongation by RNA polymerase II (RNAPII) is accompanied by conserved patterns of histone modification. Whereas histone modifications have established roles in transcription initiation, their functions during elongation are not understood. Mono-ubiquitylation of histone H2B (H2Bub1) plays a key role in coord...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002822

    authors: Sansó M,Lee KM,Viladevall L,Jacques PÉ,Pagé V,Nagy S,Racine A,St Amour CV,Zhang C,Shokat KM,Schwer B,Robert F,Fisher RP,Tanny JC

    更新日期:2012-01-01 00:00:00

  • Control of metabolic homeostasis by stress signaling is mediated by the lipocalin NLaz.

    abstract::Metabolic homeostasis in metazoans is regulated by endocrine control of insulin/IGF signaling (IIS) activity. Stress and inflammatory signaling pathways--such as Jun-N-terminal Kinase (JNK) signaling--repress IIS, curtailing anabolic processes to promote stress tolerance and extend lifespan. While this interaction con...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000460

    authors: Hull-Thompson J,Muffat J,Sanchez D,Walker DW,Benzer S,Ganfornina MD,Jasper H

    更新日期:2009-04-01 00:00:00

  • Evolution of Social Insect Polyphenism Facilitated by the Sex Differentiation Cascade.

    abstract::The major transition to eusociality required the evolution of a switch to canalize development into either a reproductive or a helper, the nature of which is currently unknown. Following predictions from the 'theory of facilitated variation', we identify sex differentiation pathways as promising candidates because of ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005952

    authors: Klein A,Schultner E,Lowak H,Schrader L,Heinze J,Holman L,Oettler J

    更新日期:2016-03-31 00:00:00

  • Compensatory interactions between Sir3p and the nucleosomal LRS surface imply their direct interaction.

    abstract::The previously identified LRS (Loss of rDNA Silencing) domain of the nucleosome is critically important for silencing at both ribosomal DNA and telomeres. To understand the function of the LRS surface in silencing, we performed an EMS mutagenesis screen to identify suppressors of the H3 A75V LRS allele. We identified ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000301

    authors: Norris A,Bianchet MA,Boeke JD

    更新日期:2008-12-01 00:00:00

  • PCNA ubiquitylation ensures timely completion of unperturbed DNA replication in fission yeast.

    abstract::PCNA ubiquitylation on lysine 164 is required for DNA damage tolerance. In many organisms PCNA is also ubiquitylated in unchallenged S phase but the significance of this has not been established. Using Schizosaccharomyces pombe, we demonstrate that lysine 164 ubiquitylation of PCNA contributes to efficient DNA replica...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1006789

    authors: Daigaku Y,Etheridge TJ,Nakazawa Y,Nakayama M,Watson AT,Miyabe I,Ogi T,Osborne MA,Carr AM

    更新日期:2017-05-08 00:00:00

  • Genomic variation in rice: genesis of highly polymorphic linkage blocks during domestication.

    abstract::Genomic regions that are unusually divergent between closely related species or racial groups can be particularly informative about the process of speciation or the operation of natural selection. The two sequenced genomes of cultivated Asian rice, Oryza sativa, reveal that at least 6% of the genomes are unusually div...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.0020199

    authors: Tang T,Lu J,Huang J,He J,McCouch SR,Shen Y,Kai Z,Purugganan MD,Shi S,Wu CI

    更新日期:2006-11-17 00:00:00

  • Regulation of transcription elongation in response to osmostress.

    abstract::Cells trigger massive changes in gene expression upon environmental fluctuations. The Hog1 stress-activated protein kinase (SAPK) is an important regulator of the transcriptional activation program that maximizes cell fitness when yeast cells are exposed to osmostress. Besides being associated with transcription facto...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1007090

    authors: Silva A,Cavero S,Begley V,Solé C,Böttcher R,Chávez S,Posas F,de Nadal E

    更新日期:2017-11-20 00:00:00

  • Deconstructing cerebellar development cell by cell.

    abstract::The cerebellum is a pivotal centre for the integration and processing of motor and sensory information. Its extended development into the postnatal period makes this structure vulnerable to a variety of pathologies, including neoplasia. These properties have prompted intensive investigations that reveal not only devel...

    journal_title:PLoS genetics

    pub_type: 杂志文章,评审

    doi:10.1371/journal.pgen.1008630

    authors: van Essen MJ,Nayler S,Becker EBE,Jacob J

    更新日期:2020-04-16 00:00:00

  • Extensive DNA end processing by exo1 and sgs1 inhibits break-induced replication.

    abstract::Homology-dependent repair of DNA double-strand breaks (DSBs) by gene conversion involves short tracts of DNA synthesis and limited loss of heterozygosity (LOH). For DSBs that present only one end, repair occurs by invasion into a homologous sequence followed by replication to the end of the chromosome resulting in ext...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1001007

    authors: Marrero VA,Symington LS

    更新日期:2010-07-08 00:00:00

  • H3K27me3 profiling of the endosperm implies exclusion of polycomb group protein targeting by DNA methylation.

    abstract::Polycomb group (PcG) proteins act as evolutionary conserved epigenetic mediators of cell identity because they repress transcriptional programs that are not required at particular developmental stages. Each tissue is likely to have a specific epigenetic profile, which acts as a blueprint for its developmental fate. A ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1001152

    authors: Weinhofer I,Hehenberger E,Roszak P,Hennig L,Köhler C

    更新日期:2010-10-07 00:00:00

  • A Parent-of-Origin Effect Impacts the Phenotype in Low Penetrance Retinoblastoma Families Segregating the c.1981C>T/p.Arg661Trp Mutation of RB1.

    abstract::Retinoblastoma (Rb), the most common pediatric intraocular neoplasm, results from inactivation of both alleles of the RB1 tumor suppressor gene. The second allele is most commonly lost, as demonstrated by loss of heterozygosity studies. RB1 germline carriers usually develop bilateral tumors, but some Rb families displ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1005888

    authors: Eloy P,Dehainault C,Sefta M,Aerts I,Doz F,Cassoux N,Lumbroso le Rouic L,Stoppa-Lyonnet D,Radvanyi F,Millot GA,Gauthier-Villars M,Houdayer C

    更新日期:2016-02-29 00:00:00

  • Heritable transmission of stress resistance by high dietary glucose in Caenorhabditis elegans.

    abstract::Glucose is a major energy source and is a key regulator of metabolism but excessive dietary glucose is linked to several disorders including type 2 diabetes, obesity and cardiac dysfunction. Dietary intake greatly influences organismal survival but whether the effects of nutritional status are transmitted to the offsp...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004346

    authors: Tauffenberger A,Parker JA

    更新日期:2014-05-01 00:00:00

  • Polycomb group gene OsFIE2 regulates rice (Oryza sativa) seed development and grain filling via a mechanism distinct from Arabidopsis.

    abstract::Cereal endosperm represents 60% of the calories consumed by human beings worldwide. In addition, cereals also serve as the primary feedstock for livestock. However, the regulatory mechanism of cereal endosperm and seed development is largely unknown. Polycomb complex has been shown to play a key role in the regulation...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1003322

    authors: Nallamilli BR,Zhang J,Mujahid H,Malone BM,Bridges SM,Peng Z

    更新日期:2013-01-01 00:00:00

  • Variants in myelin regulatory factor (MYRF) cause autosomal dominant and syndromic nanophthalmos in humans and retinal degeneration in mice.

    abstract::Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive e...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1008130

    authors: Garnai SJ,Brinkmeier ML,Emery B,Aleman TS,Pyle LC,Veleva-Rotse B,Sisk RA,Rozsa FW,Ozel AB,Li JZ,Moroi SE,Archer SM,Lin CM,Sheskey S,Wiinikka-Buesser L,Eadie J,Urquhart JE,Black GCM,Othman MI,Boehnke M,Sullivan SA

    更新日期:2019-05-02 00:00:00

  • Repeated, selection-driven genome reduction of accessory genes in experimental populations.

    abstract::Genome reduction has been observed in many bacterial lineages that have adapted to specialized environments. The extreme genome degradation seen for obligate pathogens and symbionts appears to be dominated by genetic drift. In contrast, for free-living organisms with reduced genomes, the dominant force is proposed to ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002651

    authors: Lee MC,Marx CJ

    更新日期:2012-01-01 00:00:00

  • Direct Keap1-Nrf2 disruption as a potential therapeutic target for Alzheimer's disease.

    abstract::Nrf2, a transcriptional activator of cell protection genes, is an attractive therapeutic target for the prevention of neurodegenerative diseases, including Alzheimer's disease (AD). Current Nrf2 activators, however, may exert toxicity and pathway over-activation can induce detrimental effects. An understanding of the ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1006593

    authors: Kerr F,Sofola-Adesakin O,Ivanov DK,Gatliff J,Gomez Perez-Nievas B,Bertrand HC,Martinez P,Callard R,Snoeren I,Cochemé HM,Adcott J,Khericha M,Castillo-Quan JI,Wells G,Noble W,Thornton J,Partridge L

    更新日期:2017-03-02 00:00:00

  • Recovery of novel association loci in Arabidopsis thaliana and Drosophila melanogaster through leveraging INDELs association and integrated burden test.

    abstract::Short insertions, deletions (INDELs) and larger structural variants have been increasingly employed in genetic association studies, but few improvements over SNP-based association have been reported. In order to understand why this might be the case, we analysed two publicly available datasets and observed that 63% of...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1007699

    authors: Song B,Mott R,Gan X

    更新日期:2018-10-16 00:00:00

  • Myoinhibitory peptide signaling modulates aversive gustatory learning in Caenorhabditis elegans.

    abstract::Aversive learning and memories are crucial for animals to avoid previously encountered stressful stimuli and thereby increase their chance of survival. Neuropeptides are essential signaling molecules in the brain and are emerging as important modulators of learned behaviors, but their precise role is not well understo...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1007945

    authors: Peymen K,Watteyne J,Borghgraef C,Van Sinay E,Beets I,Schoofs L

    更新日期:2019-02-19 00:00:00

  • Multiple regulatory mechanisms to inhibit untimely initiation of DNA replication are important for stable genome maintenance.

    abstract::Genomic instability is a hallmark of human cancer cells. To prevent genomic instability, chromosomal DNA is faithfully duplicated in every cell division cycle, and eukaryotic cells have complex regulatory mechanisms to achieve this goal. Here, we show that untimely activation of replication origins during the G1 phase...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002136

    authors: Tanaka S,Araki H

    更新日期:2011-06-01 00:00:00

  • Pervasive antagonistic interactions among hybrid incompatibility loci.

    abstract::Species barriers, expressed as hybrid inviability and sterility, are often due to epistatic interactions between divergent loci from two lineages. Theoretical models indicate that the strength, direction, and complexity of these genetic interactions can strongly affect the expression of interspecific reproductive isol...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1006817

    authors: Guerrero RF,Muir CD,Josway S,Moyle LC

    更新日期:2017-06-12 00:00:00

  • Specificity of the STAT4 genetic association for severe disease manifestations of systemic lupus erythematosus.

    abstract::Systemic lupus erythematosus (SLE) is a genetically complex disease with heterogeneous clinical manifestations. A polymorphism in the STAT4 gene has recently been established as a risk factor for SLE, but the relationship with specific SLE subphenotypes has not been studied. We studied 137 SNPs in the STAT4 region gen...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1000084

    authors: Taylor KE,Remmers EF,Lee AT,Ortmann WA,Plenge RM,Tian C,Chung SA,Nititham J,Hom G,Kao AH,Demirci FY,Kamboh MI,Petri M,Manzi S,Kastner DL,Seldin MF,Gregersen PK,Behrens TW,Criswell LA

    更新日期:2008-05-30 00:00:00

  • Mapping the fitness landscape of gene expression uncovers the cause of antagonism and sign epistasis between adaptive mutations.

    abstract::How do adapting populations navigate the tensions between the costs of gene expression and the benefits of gene products to optimize the levels of many genes at once? Here we combined independently-arising beneficial mutations that altered enzyme levels in the central metabolism of Methylobacterium extorquens to uncov...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1004149

    authors: Chou HH,Delaney NF,Draghi JA,Marx CJ

    更新日期:2014-02-27 00:00:00

  • Whole-exome sequencing and homozygosity analysis implicate depolarization-regulated neuronal genes in autism.

    abstract::Although autism has a clear genetic component, the high genetic heterogeneity of the disorder has been a challenge for the identification of causative genes. We used homozygosity analysis to identify probands from nonconsanguineous families that showed evidence of distant shared ancestry, suggesting potentially recess...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.1002635

    authors: Chahrour MH,Yu TW,Lim ET,Ataman B,Coulter ME,Hill RS,Stevens CR,Schubert CR,ARRA Autism Sequencing Collaboration.,Greenberg ME,Gabriel SB,Walsh CA

    更新日期:2012-01-01 00:00:00

  • Discovery and analysis of evolutionarily conserved intronic splicing regulatory elements.

    abstract::Knowledge of the functional cis-regulatory elements that regulate constitutive and alternative pre-mRNA splicing is fundamental for biology and medicine. Here we undertook a genome-wide comparative genomics approach using available mammalian genomes to identify conserved intronic splicing regulatory elements (ISREs). ...

    journal_title:PLoS genetics

    pub_type: 杂志文章

    doi:10.1371/journal.pgen.0030085

    authors: Yeo GW,Van Nostrand EL,Liang TY

    更新日期:2007-05-25 00:00:00

  • What Is the Tree of Life?

    abstract::A universal Tree of Life (TOL) has long been a goal of molecular phylogeneticists, but reticulation at the level of genes and possibly at the levels of cells and species renders any simple interpretation of such a TOL, especially as applied to prokaryotes, problematic. ...

    journal_title:PLoS genetics

    pub_type: 杂志文章,评审

    doi:10.1371/journal.pgen.1005912

    authors: Doolittle WF,Brunet TD

    更新日期:2016-04-14 00:00:00

  • Human social genomics.

    abstract::A growing literature in human social genomics has begun to analyze how everyday life circumstances influence human gene expression. Social-environmental conditions such as urbanity, low socioeconomic status, social isolation, social threat, and low or unstable social status have been found to associate with differenti...

    journal_title:PLoS genetics

    pub_type: 杂志文章,评审

    doi:10.1371/journal.pgen.1004601

    authors: Cole SW

    更新日期:2014-08-28 00:00:00