Search

Author(s): Marco Tigano [sup.1] [sup.2] , Danielle C. Vargas [sup.1] , Samuel Tremblay-Belzile [sup.1] [sup.2] , Yi Fu [sup.1] [sup.2] , Agnel Sfeir [sup.1] [sup.2] Author Affiliations: (1) Skirball Institute [...], Mitochondrial DNA double-strand breaks (mtDSBs) are toxic lesions that compromise the integrity of mitochondrial DNA (mtDNA) and alter mitochondrial function.sup.1. Communication between mitochondria and the nucleus is essential to maintain cellular homeostasis; however, the nuclear response to mtDSBs remains unknown.sup.2. Here, using mitochondrial-targeted transcription activator-like effector nucleases (TALENs).sup.1,3,4, we show that mtDSBs activate a type-I interferon response that involves the phosphorylation of STAT1 and activation of interferon-stimulated genes. After the formation of breaks in the mtDNA, herniation.sup.5 mediated by BAX and BAK releases mitochondrial RNA into the cytoplasm and triggers a RIG-I-MAVS-dependent immune response. We further investigated the effect of mtDSBs on interferon signalling after treatment with ionizing radiation and found a reduction in the activation of interferon-stimulated genes when cells that lack mtDNA are exposed to gamma irradiation. We also show that mtDNA breaks synergize with nuclear DNA damage to mount a robust cellular immune response. Taken together, we conclude that cytoplasmic accumulation of mitochondrial RNA is an intrinsic immune surveillance mechanism for cells to cope with mtDSBs, including breaks produced by genotoxic agents. Breaks in mitochondrial DNA cause leakage of mitochondrial RNA into the cytoplasm, enhancing immune surveillance and synergizing with nuclear DNA damage to mount a robust type-I interferon immune response.

Author(s): Nina A. Bonekamp [sup.1] , Bradley Peter [sup.2] , Hauke S. Hillen [sup.3] , Andrea Felser [sup.4] , Tim Bergbrede [sup.5] , Axel Choidas [sup.5] , Moritz Horn [sup.6] [...], Altered expression of mitochondrial DNA (mtDNA) occurs in ageing and a range of human pathologies (for example, inborn errors of metabolism, neurodegeneration and cancer). Here we describe first-in-class specific inhibitors of mitochondrial transcription (IMTs) that target the human mitochondrial RNA polymerase (POLRMT), which is essential for biogenesis of the oxidative phosphorylation (OXPHOS) system.sup.1-6. The IMTs efficiently impair mtDNA transcription in a reconstituted recombinant system and cause a dose-dependent inhibition of mtDNA expression and OXPHOS in cell lines. To verify the cellular target, we performed exome sequencing of mutagenized cells and identified a cluster of amino acid substitutions in POLRMT that cause resistance to IMTs. We obtained a cryo-electron microscopy (cryo-EM) structure of POLRMT bound to an IMT, which further defined the allosteric binding site near the active centre cleft of POLRMT. The growth of cancer cells and the persistence of therapy-resistant cancer stem cells has previously been reported to depend on OXPHOS.sup.7-17, and we therefore investigated whether IMTs have anti-tumour effects. Four weeks of oral treatment with an IMT is well-tolerated in mice and does not cause OXPHOS dysfunction or toxicity in normal tissues, despite inducing a strong anti-tumour response in xenografts of human cancer cells. In summary, IMTs provide a potent and specific chemical biology tool to study the role of mtDNA expression in physiology and disease. Inhibitors of mitochondrial transcription that target human mitochondrial RNA polymerase provide a chemical biology tool for studying the role of mitochondrial DNA expression in a wide range of pathologies.

Introduction Retinopathy of prematurity (ROP) is a complication of treating preterm infants with [O.sub.2]. It is estimated that as many as 10% of very premature infants become blind as a [...], Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide hydrolase (sEH) enzymes affects retinal angiogenesis and vascular stability, we investigated the role of sEH in a mouse model of ROP. In WT mice, hyperoxia elicited tyrosine nitration and inhibition of sEH and decreased generation of the DHA-derived diol 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP). Correspondingly, in a murine model of ROP, [sEH.sup.-/-] mice developed a larger central a vascular zone and peripheral pathological vascular tuft formation than did their WT littermates. Astrocytes were the cells most affected by Seh deletion, and hyperoxia increased astrocyte apoptosis. In rescue experiments, 19,20-DHDP prevented astrocyte loss by targeting the mitochondrial membrane to prevent the hyperoxia-induced dissociation of presenilin-1 and presenilin-1-associated protein to attenuate poly ADP-ribose polymerase activation and mitochondrial DNA damage. Therapeutic intravitreal administration of 19,20-DHDP not only suppressed astrocyte loss, but also reduced pathological vascular tuft formation in [sEH.sup.-/-] mice. Our data indicate that sEH activity is required for mitochondrial integrity and retinal astrocyte survival in ROP. Moreover, 19,20-DHDP may be more effective than DHA as a nutritional supplement for preventing retinopathy in preterm infants.

Author(s): Toby Lieber [sup.1] , Swathi P. Jeedigunta [sup.2] , Jonathan M. Palozzi [sup.2] , Ruth Lehmann [sup.1] , Thomas R. Hurd [sup.2] Author Affiliations: (1) HHMI and Kimmel Center [...], Mitochondria contain their own genomes that, unlike nuclear genomes, are inherited only in the maternal line. Owing to a high mutation rate and low levels of recombination of mitrochondrial DNA (mtDNA), special selection mechanisms exist in the female germline to prevent the accumulation of deleterious mutations.sup.1-5. However, the molecular mechanisms that underpin selection are poorly understood.sup.6. Here we visualize germline selection in Drosophila using an allele-specific fluorescent in situ-hybridization approach to distinguish wild-type from mutant mtDNA. Selection first manifests in the early stages of Drosophila oogenesis, triggered by reduction of the pro-fusion protein Mitofusin. This leads to the physical separation of mitochondrial genomes into different mitochondrial fragments, which prevents the mixing of genomes and their products and thereby reduces complementation. Once fragmented, mitochondria that contain mutant genomes are less able to produce ATP, which marks them for selection through a process that requires the mitophagy proteins Atg1 and BNIP3. A reduction in Atg1 or BNIP3 decreases the amount of wild-type mtDNA, which suggests a link between mitochondrial turnover and mtDNA replication. Fragmentation is not only necessary for selection in germline tissues, but is also sufficient to induce selection in somatic tissues in which selection is normally absent. We postulate that there is a generalizable mechanism for selection against deleterious mtDNA mutations, which may enable the development of strategies for the treatment of mtDNA disorders. An in situ hybridization approach is used to visualize mitochondrial DNA germline selection in Drosophila, revealing the role of mitochondrial fragmentation in the selection against deleterious mutations.

Patterns in the genetic variation of species can be used to infer their specific demographic and evolutionary history and provide insight into the general mechanisms underlying population divergence and speciation. The Macoun's Arctic (Oeneis macounii (W.H. Edwards, 1885); MA) butterfly occurs across Canada and parts of the northern United States in association with jack pine (Pinus banksiana Lamb.) and lodgepole pine (Pinus contorta Douglas ex Loudon). MA's current distribution is highly fragmented, and the extent of reproductive isolation among allopatric populations is unknown. Furthermore, although MA is biennial, adults emerge every year in some populations. These populations presumably consist of two alternate-year cohorts, providing the opportunity for sympatric divergence via allochronic isolation. Using mitochondrial DNA (mtDNA) and amplified fragment length polymorphism (AFLP) markers, we analyzed MA's genetic structure to determine the current and historical role of allopatric and allochronic isolation in MA population divergence. Both markers revealed high diversity and a low, but significant, degree of spatial structure and pattern of isolation by distance. Phylogeographic structure was generally absent, with low divergence among mtDNA haplotypes. MA likely exhibits low dispersal and gene flow among most allopatric populations; however, there was no evidence of differentiation resulting from allochronic isolation for sympatric cohorts. Key words: Macoun's Arctic butterfly, Oeneis macounii, AFLP, allochronic, biennialism, COI, population structure. Les motifs de variation genetique d'une espece peuvent etre utilises pour inferer son histoire demographique et evolutive particuliere et fournir de l'information sur les mecanismes generaux qui sous-tendent la divergence et la speciation des populations. Le nordique de Macoun (Oeneis macounii (W.H. Edwards, 1885); MA) est present a la grandeur du Canada et dans des regions du nord des Etats-Unis en association avec de pin gris (Pinus banksiana Lamb.) et de pin tordu (Pinus contorta Douglas ex Loudon). Son aire de repartition actuelle est tres fragmentee, et l'ampleur de l'isolement reproductif de populations allopatriques n'est pas connue. En outre, bien que le MA soit biennal, des adultes emergent chaque annee dans certaines populations. Ces populations sont probablement composees de deux cohortes d'annees alternantes, de sorte qu'une divergence sympatrique par isolement allochronique pourrait etre possible. A l'aide de marqueurs d'ADN mitochondrial (ADNmt) et de polymorphisme de longueur de fragments amplifies (AFLP), nous avons analyse la structure genetique des MA afin de determiner le role actuel et passe de l'isolement allopatrique et allochronique dans la divergence des populations de MA. Les deux marqueurs revelent une grande diversite et un degre faible, mais significatif de structure spatiale et d'isolement par la distance. Il y a generalement absence de structure phylogeographique et une faible divergence entre les haplotypes d'ADNmt. Les MA presentent vraisemblablement une faible dispersion et un flux genetique faible dans la plupart des populations allopatriques; aucun indice de differenciation decoulant de l'isolement allochronique de cohortes sympatriques n'est toutefois note. [Traduit par la Redaction] Mots-cles : nordique de Macoun, Oeneis macounii, AFLP, allochronique, biennialisme, COI, structure de la population., Introduction Patterns of genetic variation within species are a consequence of both historical events and contemporary gene flow. At the last glacial maximum (LGM) in North America (15-20 ka), Canada [...]

Abstract--The population structure of the ocellate spot skate (Okamejei kenojei), distributed in the western North Pacific, was assessed on the basis of genetic variations in the mitochondrial DNA control region [...]

Introduction Populations of woodland caribou (Rangifer tarandus subsp.) have declined across most of Canada, and most Canadian subspecies and (or) populations have been formally designated to be at some risk [...], Post-glacial origins of woodland caribou (Rangifer tarandus subsp.) on the island of Newfoundland and their relationship to mainland populations have been uncertain. Sequence analysis of 2223 bp of the mitochondrial DNA control region and cytochrome b gene from 233 Newfoundland caribou identified 32 haplotypes in four major clades. Comparison with other Nearctic caribou confirms a closer affinity of the basal Clade A with animals from the mainland, and as an outgroup to Clades B, C, and D that are endemic to the island. This indicates re-entry of caribou to post-glacial Newfoundland across the Strait of Belle Isle from Labrador, rather than from southern coastal refugia. Newfoundland caribou are a distinct subspecies, Rangifer tarandus terranovae (Bangs, 1896). Hierarchical AMOVA shows significant clinal differentiation of the major clades from northwest to southeast across the island. The isolated Avalon Peninsula population in the extreme southeast is genetically depauperate. Founder effects are evident in herds introduced to previously unoccupied areas by wildlife managers over the past 40-50 years. Reindeer introduced in the early 20th century have not contributed to mtDNA diversity in Newfoundland caribou. Key words: Rangifer, insular subspecies, post-glacial recolonization, founder and bottleneck effects. Les origines postglaciaires du caribou forestier (Rangifer tarandus subsp.) sur l'île de Terre-Neuve et sa relation avec les populations continentales demeurent incertaines. Le séquençage et l'analyse d'un segment de 2223 pb de la région de contrôle mitochondriale et du gène codant pour le cytochrome b chez 233 caribous de Terre-Neuve a permis d'identifier 32 haplotypes formant quatre clades majeurs. Une comparaison avec d'autres caribous néarctiques a confirmé une parenté plus grande entre les animaux appartenant au Clade A (basal) et ceux du continent, et le fait que ceux-ci forment un groupe extérieur par rapport aux Clades B, C et D qui regroupent des animaux endémiques de l'île. Ceci indique une réintroduction postglaciaire du caribou à Terre-Neuve via une traversée du détroit de Belle-Isle à partir du Labrador, plutôt qu'en provenance de refuges côtiers méridionaux. Les caribous de Terre-Neuve sont ainsi une sous-espèce distincte, Rangifer tarandus terranovae (Bangs, 1896). Une AMOVA hiérarchique a montré une différenciation significative des clades principaux le long d'un cline qui traverse l'île du nord-ouest au sud-est. La population isolée de la péninsule d'Avalon dans l'extrémité sud-est est appauvrie sur le plan génétique. Des effets fondateurs sont évidents au sein des hardes introduites au cours des 40-50 dernières par des gestionnaires de la faune dans des régions inoccupées jusqu'alors. Les rennes introduits au début du [20.sup.ième] siècle n'ont pas contribué à la diversité de l'ADN mitochondrial chez les caribous de Terre-Neuve. [Traduit par la Rédaction] Mots-clés: Rangifer, sous-espèces insulaires, phylogéographie postglaciaire, effets fondateurs et de goulot.

Introduction Mitochondrial transcription factor A (TFAM) is a promoter-specific enhancer of mitochondrial DNA (mtDNA), regulator of mitochondrial genes and mtDNA copy number, and a physical protector of mtDNA (Ekstrand et [...], Although mitochondrial transcription factor A (TFAM) is a protective component of mitochondrial DNA and a regulator of calcium and reactive oxygen species (ROS) production, the mechanism remains unclear. In heart failure, TFAM is significantly decreased and cardiomyocyte instability ensues. TFAM inhibits nuclear factor of activated T cells (NFAT), which reduces ROS production; additionally, TFAM transcriptionally activates SERCA2a to decrease free calcium. Therefore, decreasing TFAM vastly increases protease expression and hypertrophic factors, leading to cardiomyocyte functional decline. To examine this hypothesis, treatments of 1.0 [micro]g of a TFAM vector and 1.0 [micro]g of a CRISPR-Cas9 TFAM plasmid were administered to HL-1 cardiomyocytes via lipofectamine transfection. Western blotting and confocal microscopy analysis show that CRISPR-Cas9 knockdown of TFAM significantly increased proteases Calpain1, MMP9, and regulators Serca2a, and NFAT4 protein expression. CRISPR knockdown of TFAM in HL-1 cardiomyocytes upregulates degradation factors, leading to cardiomyocyte instability. Hydrogen peroxide oxidative stress decreased TFAM expression and increased Calpain1, MMP9, and NFAT4 protein expression. TFAM overexpression normalizes pathological hypertrophic factor NFAT4 in the presence of oxidative stress. Key words: TFAM, Calpain1, MMP9, Serca2a, [H.sub.2][O.sub.2], NFAT. Bien que le facteur A de transcription mitochondriale (ou TFAM pour<>) soit une composante de la protection de l&apos;ADN mitochondrial, ainsi qu&apos;un agent de regulation du calcium et de la production de derives reactifs de l&apos;oxygene (ROS), son mode d&apos;action demeure a eclaircir. Dans l&apos;insuffisance cardiaque, les taux de TFAM diminuent de facon marquee, ce qui entrame une instabilite des cardiomyocytes. Le TFAM entrame une inhibition du facteur nucleaire des lymphocytes T (NFAT pour<< nuclear factor of activated T cells>>), ce qui reduit la production de ROS; de plus, le TFAM entrame l&apos;activation du SERCA2a par un mecanisme de transcription, ce qui fait diminuer les concentrations de calcium libre. Par consequent, l&apos;abaissement des taux de TFAM entrame une augmentation considerable de l&apos;expression de proteases et de facteurs de l&apos;hypertrophie, ce qui mene au declin fonctionnel des cardiomyocytes. En vue de verifier cette hypothese, nous avons transfecte par la lipofectamine 1,0 [micro]g de vecteurs du TFAM ainsi que 1,0 [micro]g d&apos;un plasmide du gene TFAM couple a la CRISPR-Cas9 dans des cardiomyocytes HL-1. L&apos;immunobuvardage de Western et l&apos;etude par microscopie confocale montraient que le << knockdown >> du gene TFAM par la CRISPR-Cas9 entrame une augmentation notable des taux des proteases calpaine 1, MMP9 et des regulateurs Serca2a, ainsi que l&apos;expression proteique du NFAT4. Le knock-down du TFAM par la CRISPR dans les cardiomyocytes HL-1 entrame une regulation a la hausse de facteurs de degradation, ce qui mene a l&apos;instabilite des cardiomyocytes. Le stress oxydatif provoque par le peroxyde d&apos;hydrogene a entraine une diminution de l&apos;expression du TFAM avec une augmentation de l&apos;expression des proteines suivantes : calpaine 1, MMP9 et NFAT4. La surexpression du TFAM permet le retour a la normale de NFAT4, un facteur de l&apos;hypertrophie pathologique, en presence de stress oxydatif. [Traduit par la Redaction] Mots-cles: TFAM, calpaine 1, MMP9, Serca2a, [H.sub.2][O.sub.2], NFAT.

Introduction The methyl methanesulfonate sensitivity gene 19 (MMS19)isa highly conserved HEAT repeat protein that was first identified in Saccharomyces cerevisiae as being required for the removal of ultraviolet radiation (UV)-induced [...], MMS19 localizes to the cytoplasmic and nuclear compartments involved in transcription and nucleotide excision repair (NER). However, whether MMS19 localizes to mitochondria, where it plays a role in maintaining mitochondrial genome stability, remains unknown. In this study, we provide the first evidence that MMS19 is localized in the inner membrane of mitochondria and participates in mtDNA oxidative damage repair. MMS19 knockdown led to mitochondrial dysfunctions including decreased mtDNA copy number, diminished mtDNA repair capacity, and elevated levels of mtDNA common deletion after oxidative stress. Immunoprecipitation--mass spectrometry analysis identified that MMS19 interacts with ANT2, a protein associated with mitochondrial ATP metabolism. ANT2 knockdown also resulted in a decreased mtDNA repair capacity after oxidative damage. Our findings suggest that MMS19 plays an essential role in maintaining mitochondrial genome stability. Key words: MMS19, mitochondria, ANT2, ROS, oxidative stress. La protéine MMS19 se trouve dans les compartiments cytoplasmique et cellulaire impliqués dans la transcription et la réparation par excision de nucléotides (NER, << nucleotide excision repair >>). Toutefois, la localisation de MMS19 dans la mitochondrie, où elle jouerait un rôle dans le maintien de l&apos;intégrité du génome mitochondrial, reste à clarifier. Dans cette étude, les auteurs présentent les premières indications que MMS19 se trouve dans la membrane interne de la mitochondrie et participe à la réparation du dommage oxydant de l&apos;ADNmt. L&apos;inactivation de MMS19 menait à des dysfonctionnements mitochondriaux, dont une diminution du nombre de copies d&apos;ADNmt, une diminution de la capacité de réparation de l&apos;ADNmt, et un accroissement du niveau de délétions communes de l&apos;ADNmt après un dommage oxydant. Une analyse par immunoprécipitation et spectrométrie de masse a révélé que MMS19 interagit avec ANT2, une protéine associée au métabolisme de l&apos;ATP mitochondrial. L&apos;inactivation d&apos;ANT2 résultait aussi en une diminution de la capacité de réparation d&apos;ADNmt après un dommage oxydant. Les résultats des auteurs suggèrent que MMS19 joue un rôle essentiel dans le maintien de l&apos;intégrité de génome mitochondrial. [Traduit par la Rédaction] Mots-clés : MMS19, mitochondrie, ANT2, DRO, stress oxydant.

Author(s): Jason E. Lee [1]; Laura M. Westrate [1]; Haoxi Wu [1]; Cynthia Page [1]; Gia K. Voeltz (corresponding author) [1] Mitochondria cannot be generated de novo ; they must [...]

ABSTRACT Spatial and temporal genetic structure of the eastern oyster Crassostrea virginica was examined along the coast of North Carolina (NC); utilizing a fragment of the mitochondrial large (16S) ribosomal [...]

Mitochondrial genomes (mitochondrial DNA, mtDNA) encode essential oxidative phosphorylation (OXPHOS) components. Because hundreds of mtDNAs exist per cell, a deletion in a single mtDNA has little impact. However, if the [...]

Neutrophils contribute to inflammation by interacting with innate and adaptive immune cells (1) and by releasing proteolytic enzymes and reactive intermediates (2). NET formation, a cell death pathway characterized by [...], Neutrophil extracellular traps (NETs) are implicated in autoimmunity, but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes (RNP ICs), inducers of NETosis, require mitochondrial reactive oxygen species (ROS) for maximal NET stimulation. After RNP IC stimulation of neutrophils, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro, and when this DNA is injected into mice, it stimulates type I interferon (IFN) signaling through a pathway dependent on the DNA sensor STING. Mitochondrial ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus. This was also observed in individuals with chronic granulomatous disease, who lack NADPH oxidase activity but still develop autoimmunity and type I IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type I IFN responses in a mouse model of lupus. Together, these findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases.

Author(s): Tiago Branco Fonseca [sup.1] [sup.2] [sup.3] , Ángela Sánchez-Guerrero [sup.1] [sup.2] , Ira Milosevic [sup.2] , Nuno Raimundo [sup.1] Author Affiliations: (1) Institute of Cellular Biochemistry, University Medical Center [...]

Introduction The mitochondrial DNA (mtDNA) codes for some of the genes necessary to produce the proteins required in the oxidative phosphorylation (OXPHOS) reaction that produces ATP. In contrast to the [...], Mitochondrial DNA (mtDNA) is predominantly maternally inherited in eukaryotes. Diverse molecular mechanisms underlying the phenomenon of strict maternal inheritance (SMI) of mtDNA have been described, but the evolutionary forces responsible for its predominance in eukaryotes remain to be elucidated. Exceptions to SMI have been reported in diverse eukaryotic taxa, leading to the prediction that several distinct molecular mechanisms controlling mtDNA transmission are present among the eukaryotes. We propose that these mechanisms will be better understood by studying the deviations from the predominating pattern of SMI. This minireview summarizes studies on eukaryote species with unusual or rare mitochondrial inheritance patterns, i.e., other than the predominant SMI pattern, such as maternal inheritance of stable heteroplasmy, paternal leakage of mtDNA, biparental and strictly paternal inheritance, and doubly uniparental inheritance of mtDNA. The potential genes and mechanisms involved in controlling mitochondrial inheritance in these organisms are discussed. The linkage between mitochondrial inheritance and sex determination is also discussed, given that the atypical systems of mtDNA inheritance examined in this minireview are frequently found in organisms with uncommon sexual systems such as gynodioecy, monoecy, or andromonoecy. The potential of deviations from SMI for facilitating a better understanding of a number of fundamental questions in biology, such as the evolution of mtDNA inheritance, the coevolution of nuclear and mitochondrial genomes, and, perhaps, the role of mitochondria in sex determination, is considerable. Keywords: mitochondrial DNA, mitochondrial inheritance, sex determination, paternal leakage, heteroplasmy. L&apos;ADN mitochondrial (l&apos;ADNmt) est principalement herite de la meire chez les eucaryotes. Divers mecanismes moleculaires sous-jacents au phenomeine ont ete decrits, mais les forces evolutives responsables de sa predominance chez les eucaryotes restent encore ai etre elucidees. Des exceptions ai la transmission strictement maternelle de l&apos;ADNmt (<< strict maternal inheritance >> ou SMI) ont ete signalees chez divers taxons eucaryotes, laissant penser que plusieurs nouveaux mecanismes moleculaires de transmission de l&apos;ADNmt existent chez les eucaryotes. Nous proposons que ces mecanismes seront mieux compris en etudiant les exceptions au type predominant de transmission mitochondrial SMI. Cette mini-revue resume les etudes sur les espeices eucaryotes avec des systeimes de transmission mitochondriale inhabituels ou rares, c&apos;est- ai-dire autres que la SMI, tels que la transmission maternelle stable d&apos;une heteroplasmie, la transmission occasionnelle de l&apos;ADNmt paternel (<< paternal leakage >>), la transmission biparentale ou encore strictement paternelle de l&apos;ADNmt et la transmission doublement uniparentale de l&apos;ADNmt. Les geines et les mecanismes impliques dans le controle de la transmission mitochondriale chez ces organismes << deviants >> sont discutes. Le lien etroit entre la transmission mitochondriale et la determination du sexe est egalement aborde, puisque les systeimes atypiques d&apos;heritabilite de l&apos;ADNmt examines dans cette etude sont surtout presents chez des organismes avec des systeimes sexuels rares comme la gynodioecie, la monoecie et l&apos;andromonoecie. L&apos;etude de ces exceptions permettra incontestablement une meilleure comprehension d&apos;un certain nombre de questions fondamentales en biologie, comme l&apos;evolution des mecanismes de transmission de l&apos;ADNmt, la coevolution des genomes nucleaires et mitochondriaux et, peut-etre, le roie des mitochondries dans la determination du sexe. [Traduit par la Redaction] Mots-cles : ADN mitochondrial, transmission mitochondriale, determination du sexe, transmission paternelle occasionnelle, heteroplasmie.

Globally, sharks are under enormous pressure from fishing efforts. One such species is the silky shark, Carcharhinus falciformis, which occurs in all the Earth's tropical oceans and is captured in large numbers in pelagic fisheries. Regionally, the silky shark is listed as Vulnerable to Near Threatened by the International Union for the Conservation of Nature due to high levels of direct and bycatch exploitation. Despite major conservation concerns about this species, little is known about its genetic status and level of demographic or evolutionary connectivity among its regional distributions. We report a genetic assessment of silky sharks sampled across a major portion of the species' global range. We sequenced the complete mitochondrial DNA control region from 276 individuals taken from the western Atlantic and Indo-Pacific Oceans and the Red Sea. Overall, haplotype and nucleotide diversities were relatively large (0.93 ± 0.01 and 0.61 ± 0.32 %, respectively). Nucleotide diversity in Indo-Pacific sharks, however, was significantly lower and about half that in Atlantic sharks. Strong phylogeographic partitioning occurred between ocean basins. Furthermore, shallow but significant pairwise statistical differentiation occurred among most regional samples within the Indo-Pacific, but not the western Atlantic. Overall, at least five mitochondrial DNA populations of silky sharks were identified globally. Despite historically large population sizes, silky sharks appear to be isolated on relatively small spatial scales, at least in the Indo-Pacific, indicating that conservation and management efforts will need to be exerted at relatively small scales in a pelagic and highly vagile species. Electronic supplementary material The online version of this article (doi:10.1007/s00227-015-2636-6) contains supplementary material, which is available to authorized users., Author(s): Christopher R. Clarke[sup.1] , Stephen A. Karl[sup.2] , Rebekah L. Horn[sup.3] , Andrea M. Bernard[sup.3] , James S. Lea[sup.1] , Fabio H. Hazin[sup.5] , Paulo A. Prodohl[sup.6] , Mahmood [...]

Although laboratory experiments allow greater control of environmental conditions than field studies, they have several drawbacks. To analyze physiological responses to forcing environmental variables, experimental conditions should mimic natural conditions as closely as possible. For filter-feeding organisms in particular, diet quality and quantity is one of the environmental parameters that can differ markedly between experimental and field conditions. In the hatchery, Pacific oysters, Crassostrea gigas, commonly show good physiological performance and growth on a mixed algal diet of Tisochrysis lutea, formerly Isochrysis aff. galbana clone Tahiti (T-Iso), and Chaetoceros calcitrans, presumably as it provides a good supply of essential polyunsaturated fatty acids (PUFA) as 20:4n-6, 20:5n-3 and 22:6n-3. The present study tests whether the fluctuating biotic and abiotic conditions in the field modify the structure and function of oyster mitochondria. One group of oysters was maintained in the intertidal zone, and the other group was fed the mixed diet in a nearby experimental hatchery under salinity and temperature conditions equivalent to those in the field. After 4 weeks of conditioning, the functional capacities and membrane lipid composition of gill mitochondria were measured. For essential polyunsaturated fatty acids, only the proportion of 20:5n-3 differed between field and laboratory oysters, and confirmed the capacity of the mixed diet T-Iso + C. gracilis, to provide the essential PUFA. Nevertheless, proportions of other FA (e.g., 22:5n-6 and non-methylene-interrupted FA) differed markedly between laboratory and field-conditioned oysters. Mitochondrial oxygen uptake, cytochrome c oxidase activity, content of cardiolipin and concentration of cytochrome b were significantly lower in laboratory-conditioned than in field-conditioned oysters. These results indicate that laboratory conditioning, although allowing similar growth and gonad maturation, only partially mimics conditions that allow C. gigas to maintain mitochondrial function. Although our experimental design cannot ascertain what difference between experimental laboratory and field conditions led to changes in membrane composition and mitochondrial function, differences in nutritional quality (other than known essential PUFA) and abiotic factors (e.g., oxygen availability, emersion or daily temperature fluctuations) had a major impact on mitochondrial properties in oysters., Author(s): Tony Dudognon[sup.1] , Helga Guderley[sup.4] , Claudie Quere[sup.2] , Philippe Soudant[sup.1] , Ilie S. Racotta[sup.3] , Edouard Kraffe[sup.1] [sup.5] Author Affiliations: (1) Laboratoire des Sciences de l'Environnement Marin, Institut [...]

Author(s): A. Phillip West [sup.1] , William Khoury-Hanold [sup.2] , Matthew Staron [sup.2] , Michal C. Tal [sup.2] [sup.7] , Cristiana M. Pineda [sup.1] , Sabine M. Lang [sup.1] , [...], Mitochondrial DNA stress potentiates type I interferon responses via activation of the cGAS-STING-IRF3 pathway. Mitochondria trigger innate immunity Accumulating evidence suggests that mitochondria, the organelles primarily responsible for cellular respiration and energy production, are also critical centres for antibacterial and antiviral innate immune responses. This study describes a link between mitochondrial stress and antiviral innate immunity. Specifically, mitochondrial DNA stress in herpes virus infected mice is shown to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance through activation of the DNA sensor cGAS and the STING-IRF3 stress pathway. Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids.sup.1. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation.sup.2. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses.sup.3. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined.sup.4. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.

Author(s): Nandhitha Uma Naresh, Cole M. Haynes Author Affiliations: Breaks in mitochondrial DNA rig the immune response Mitochondria are membrane-bound organelles that act as hubs of metabolism and of innate [...], Damage to DNA in a cellular organelle called the mitochondrion triggers an immune response in the nucleus. Mechanistic insights into this process shed light on how organelles communicate. Mitochondrial DNA cleavage leads to a nuclear interferon response.

Author(s): Zhenyu Zhong [sup.1] [sup.2] , Shuang Liang [sup.3] [sup.4] , Elsa Sanchez-Lopez [sup.1] [sup.2] , Feng He [sup.1] [sup.2] , Shabnam Shalapour [sup.1] [sup.2] , Xue-jia Lin [sup.1] [sup.2] [...], Dysregulated NLRP3 inflammasome activity results in uncontrolled inflammation, which underlies many chronic diseases. Although mitochondrial damage is needed for the assembly and activation of the NLRP3 inflammasome, it is unclear how macrophages are able to respond to structurally diverse inflammasome-activating stimuli. Here we show that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signalling. Toll-like receptors signal via the MyD88 and TRIF adaptors to trigger IRF1-dependent transcription of CMPK2, a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation. The dependence on CMPK2 catalytic activity provides opportunities for more effective control of NLRP3 inflammasome-associated diseases.New mitochondrial DNA synthesis links the priming and activation of the NLRP3 inflammasome.