Browsing by Subject "mtDNA"

Sort by: Order: Results:

Now showing items 1-8 of 8
  • Esterhuizen, Karien; Lindeque, J. Zander; Mason, Shayne; van der Westhuizen, Francois H.; Suomalainen, Anu; Hakonen, Anna H.; Carroll, Christopher J.; Rodenburg, Richard J.; de Laat, Paul B.; Janssen, Mirian C. H.; Smeitink, Jan A. M.; Louw, Roan (2019)
    We used a comprehensive metabolomics approach to study the altered urinary metabolome of two mitochondrial myopathy, encephalopathy lactic acidosis and stroke like episodes (MELAS) cohorts carrying the m.3243A > G mutation. The first cohort were used in an exploratory phase, identifying 36 metabolites that were significantly perturbed by the disease. During the second phase, the 36 selected metabolites were able to separate a validation cohort of MELAS patients completely from their respective control group, suggesting usefulness of these 36 markers as a diagnostic set. Many of the 36 perturbed metabolites could be linked to an altered redox state, fatty acid catabolism and one-carbon metabolism. However, our evidence indicates that, of all the metabolic perturbations caused by MELAS, stalled fatty acid oxidation prevailed as being particularly disturbed. The strength of our study was the utilization of five different analytical platforms to generate the robust metabolomics data reported here. We show that urine may be a useful source for disease-specific metabolomics data, linking, amongst others, altered one-carbon metabolism to MELAS. The results reported here are important in our understanding of MELAS and might lead to better treatment options for the disease.
  • Hanninen, Reetta L.; Ahonen, Saija; Marquez, Merce; Myohanen, Maarit J.; Hytonen, Marjo K.; Lohi, Hannes (2015)
    Mitochondrial DNA depletion syndromes (MDS) are often serious autosomal recessively inherited disorders characterized by tissue-specific mtDNA copy number reduction. Many genes, including MPV17, are associated with the hepatocerebral form of MDS. MPV17 encodes for a mitochondrial inner membrane protein with a poorly characterized function. Several MPV17 mutations have been reported in association with a heterogeneous group of early-onset manifestations, including liver disease and neurological problems. Mpv17-deficient mice present renal and hearing defects. We describe here a MPV17 truncation mutation in dogs. We found a 1-bp insertion in exon 4 of the MPV17 gene, resulting in a frameshift and early truncation of the encoded protein. The mutation halves MPV17 expression in the lymphocytes of the homozygous dogs and the truncated protein is not translated in transfected cells. The insertion mutation is recurrent and exists in many unrelated breeds, although is highly enriched in the Boxer breed. Unexpectedly, despite the truncation of MPV17, we could not find any common phenotypes in the genetically affected dogs. The lack of observable phenotype could be due to a late onset, mild symptoms or potential tissue-specific compensatory mechanisms. This study suggests species-specific differences in the manifestation of the MPV17 defects and establishes a novel large animal model to further study MPV17 function and role in mitochondrial biology.
  • Kinkar, Liina; Laurimae, Teivi; Simsek, Sami; Balkaya, Ibrahim; Casulli, Adriano; Manfredi, Maria Teresa; Ponce-Gordo, Francisco; Varcasia, Antonio; Lavikainen, Antti; Miguel Gonzalez, Luis; Rehbein, Steffen; Van der Giessen, Joke; Sprong, Hein; Saarma, Urmas (2016)
    Echinococcus granulosus is the causative agent of cystic echinococcosis. The disease is a significant global public health concern and human infections are most commonly associated with E. granulosus sensu stricto (s. s.) genotype G1. The objectives of this study were to: (i) analyse the genetic variation and phylogeography of E. granulosus s. s. G1 in part of its main distribution range in Europe using 8274 bp of mtDNA; (ii) compare the results with those derived from previously used shorter mtDNA sequences and highlight the major differences. We sequenced a total of 91 E. granulosus s. s. G1 isolates from six different intermediate host species, including humans. The isolates originated from seven countries representing primarily Turkey, Italy and Spain. Few samples were also from Albania, Greece, Romania and from a patient originating from Algeria, but diagnosed in Finland. The analysed 91 sequences were divided into 83 haplotypes, revealing complex phylogeography and high genetic variation of E. granulosus s. s. G1 in Europe, particularly in the high-diversity domestication centre of western Asia. Comparisons with shorter mtDNA datasets revealed that 8274 bp sequences provided significantly higher phylogenetic resolution and thus more power to reveal the genetic relations between different haplotypes.
  • Gonzalez de Cozar, Jose M.; Gerards, Mike; Teeri, Eveliina; George, Jack; Dufour, Eric; Jacobs, Howard T.; Joers, Priit (2019)
    Mitochondrial DNA (mtDNA) replication uses a simple core machinery similar to those of bacterial viruses and plasmids, but its components are challenging to unravel. Here, we found that, as in mammals, the single Drosophila gene for RNase H1 (rnh1) has alternative translational start sites, resulting in two polypeptides, targeted to either mitochondria or the nucleus. RNAi-mediated rnh1 knockdown did not influence growth or viability of S2 cells, but compromised mtDNA integrity and copy number. rnh1 knockdown in intact flies also produced a phenotype of impaired mitochondrial function, characterized by respiratory chain deficiency, locomotor dysfunction, and decreased lifespan. Its overexpression in S2 cells resulted in cell lethality after 5-9 days, attributable to the nuclearly localized isoform. rnh1 knockdown and overexpression produced opposite effects on mtDNA replication intermediates. The most pronounced effects were seen in genome regions beyond the major replication pauses where the replication fork needs to progress through a gene cluster that is transcribed in the opposite direction. RNase H1 deficiency led to an accumulation of replication intermediates in these zones, abundant mtDNA molecules joined by four-way junctions, and species consistent with fork regression from the origin. These findings indicate replication stalling due to the presence of unprocessed RNA/DNA heteroduplexes, potentially leading to the degradation of collapsed forks or to replication restart by a mechanism involving strand invasion. Both mitochondrial RNA and DNA syntheses were affected by rnh1 knockdown, suggesting that RNase H1 also plays a role in integrating or coregulating these processes in Drosophila mitochondria.
  • Seppä, Perttu; Bonelli, Mariaelena; Dupont, Simon; Hakala, Sanja Maria; Bagnères, Anne-Geneviève; Lorenzi, M. Cristina (2020)
    Simple Summary The co-evolution of hosts and parasites depends on their ability to adapt to each other's defense and counter-defense mechanisms. The strength of selection on those mechanisms may vary among populations, resulting in a geographical mosaic of co-evolution. The boreo-montane paper wasp Polistes biglumis and its parasite Polistes atrimandibularis exemplify this type of co-evolutionary system. Here, we used genetic markers to examine the genetic population structures of these wasps in the western Alps. We found that both host and parasite populations displayed similar levels of genetic variation. In the host species, populations located near to each other were genetically similar; in both the host and the parasite species populations farther apart were significantly different. Thus, apparent dispersal barriers (i.e., high mountains) did not seem to restrict gene flow across populations as expected. Furthermore, there were no major differences in gene flow between the two species, perhaps because P. atrimandibularis parasitizes both alpine and lowland host species and annually migrates between alpine and lowland populations. The presence of strong gene flow in a system where local populations experience variable levels of selection pressure challenges the classical hypothesis that restricted gene flow is required for local adaptations to evolve. The co-evolutionary pathways followed by hosts and parasites strongly depend on the adaptive potential of antagonists and its underlying genetic architecture. Geographically structured populations of interacting species often experience local differences in the strength of reciprocal selection pressures, which can result in a geographic mosaic of co-evolution. One example of such a system is the boreo-montane social wasp Polistes biglumis and its social parasite Polistes atrimandibularis, which have evolved local defense and counter-defense mechanisms to match their antagonist. In this work, we study spatial genetic structure of P. biglumis and P. atrimandibularis populations at local and regional scales in the Alps, by using nuclear markers (DNA microsatellites, AFLP) and mitochondrial sequences. Both the host and the parasite populations harbored similar amounts of genetic variation. Host populations were not genetically structured at the local scale, but geographic regions were significantly differentiated from each other in both the host and the parasite in all markers. The net dispersal inferred from genetic differentiation was similar in the host and the parasite, which may be due to the annual migration pattern of the parasites between alpine and lowland populations. Thus, the apparent dispersal barriers (i.e., high mountains) do not restrict gene flow as expected and there are no important gene flow differences between the species, which contradict the hypothesis that restricted gene flow is required for local adaptations to evolve.
  • Junnelius, Maarit (University of Helsinki, 1999)
  • Nikula, Raisa (University of Helsinki, 2000)