A5074546907- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- RNA modifications and cancer
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- RNA Research and Splicing
- Adipose Tissue and Metabolism
- Genomics and Rare Diseases
- Metabolomics and Mass Spectrometry Studies
- Autophagy in Disease and Therapy
- Amino Acid Enzymes and Metabolism
- Genetic factors in colorectal cancer
- Advanced Proteomics Techniques and Applications
- Biochemical Acid Research Studies
- Genomic variations and chromosomal abnormalities
- Muscle metabolism and nutrition
- Biochemical and Molecular Research
- CRISPR and Genetic Engineering
- Coenzyme Q10 studies and effects
- Lipid metabolism and biosynthesis
- Metalloenzymes and iron-sulfur proteins
- Evolution and Genetic Dynamics
- DNA Repair Mechanisms
- Epigenetics and DNA Methylation
Karolinska University Hospital
2014-2024
Karolinska Institutet
2014-2024
Science for Life Laboratory
2021
Icahn School of Medicine at Mount Sinai
2018
James J. Peters VA Medical Center
2018
Max Planck Institute for Biology of Ageing
2008-2013
University of Helsinki
2013
Federal Foreign Office
2006
University of Göttingen
1991
There is an intense debate concerning whether selection or demographics has been most important in shaping the sequence variation observed modern human mitochondrial DNA (mtDNA). Purifying thought to be mtDNA evolution, but strength of this debated, mainly due threshold effect pathogenic mutations and excess new population data. We experimentally addressed issue by studying maternal transmission random mutator mice expressing a proofreading-deficient polymerase. report rapid strong...
Abstract Background We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital Science for Life Laboratory to establish advanced, genomics-based diagnostics in Stockholm healthcare setting. Methods Our analysis covers detection interpretation of...
Somatic mutations of mtDNA are implicated in the aging process, but there is no universally accepted method for their accurate quantification. We have used ultra-deep sequencing to study genome-wide mutation load liver normally- and prematurely-aging mice. Mice that homozygous an allele expressing a proof-reading–deficient polymerase (mtDNA mutator mice) 10-times-higher point loads than wildtype siblings. In addition, mice increased levels truncated linear molecule, resulting decreased...
Replication of the mammalian mitochondrial DNA (mtDNA) is dependent on minimal replisome, consisting heterotrimeric mtDNA polymerase (POLG), hexameric helicase TWINKLE and tetrameric single-stranded DNA-binding protein (mtSSB). has been shown to unwind during replication process many disease-causing mutations have mapped its gene. Patients carrying Twinkle develop multiple deletions mtDNA, deficient respiratory chain function neuromuscular symptoms. Despite importance in human disease, it...
The severity of mitochondrial disease caused by mutations mtDNA does depend on the absolute amount wild-type mtDNA.
Mutations of mtDNA are an important cause human disease, but few animal models exist. Because mammalian mitochondria cannot be transfected, the development mice with pathogenic mutations has been challenging, and main strategy therefore to introduce found in cell lines into mouse embryos. Here, we describe a phenotype-driven that is based on detecting clonal expansion colonic crypts founder derived from heterozygous mutator mice. As proof concept, report generation line transmitting...
Variants of mitochondrial DNA (mtDNA) are commonly used as markers to track human evolution because the high sequence divergence and exclusive maternal inheritance. It is assumed that inheritance clonal, i.e. mtDNA transmitted between generations without germline recombination. In contrast this assumption, a number studies have reported presence recombinant molecules in cell lines animal tissues, including humans. If recombination frequent, it would strongly impact phylogenetic population by...
The majority of mitochondrial DNA replication events are terminated prematurely. nascent remains stably associated with the template, forming a triple-stranded displacement loop (D-loop) structure. However, function D-loop region genome poorly understood. Using comparative genomics approach we here identify two closely related 15 nt sequence motifs D-loop, strongly conserved among vertebrates. One motif is at 5′-end and part block 1 (CSB1). other motif, denoted coreTAS, 3′-end. Both these...
<h3>Background</h3> Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. deficiency has been associated with range metabolic diseases, as well some drug treatments ageing. <h3>Methods</h3> We used whole exome sequencing (WES) to investigate patients inherited diseases applied novel ultra-pressure liquid chromatography—mass spectrometry approach measure coenzyme patient samples. <h3>Results</h3> identified...
Regulation of mitochondrial DNA (mtDNA) expression is critical for the control oxidative phosphorylation in response to physiological demand, and this regulation often impaired disease aging. We have previously shown that transcription termination factor 3 (MTERF3) a key regulator represses mtDNA mouse, but its molecular mode action has remained elusive. Based on hypothesis regulatory mechanisms are conserved metazoans, we analyzed Mterf3 knockout knockdown flies. demonstrate here decreased...
The sleep-inducing mechanisms of L-Tryptophan (L-Trp) are generally thought to be mediated by a central serotonergic activation. Evidence is presented that some effects L-Trp on sleep may melatonin, Trp-metabolite with sedative properties. Trp vigilance, sleep, and plasma-melatonin concentrations were measured after double-blind application 0, I, 3, 5 g in nine five healthy probands during daytime nighttime, respectively. - A significant effect was observed administration nighttime....
Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group disorders with highly variable clinical presentation, often acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation specific treatment, provided that correct molecular diagnosis rapidly obtained. MPS thus significantly improve both diagnostics and outcome affected...
Polyadenylation has well characterised roles in RNA turnover and translation a variety of biological systems. While polyadenylation on mitochondrial transcripts been suggested to be two-step process required complete translational stop codons, its involvement is less understood. We studied knockdown knockout models the poly(A) polymerase (MTPAP) Drosophila melanogaster demonstrate that mRNAs exclusively performed by MTPAP. Further, our results show does not regulate mRNA stability but...
The RNA helicase SUV3 and the polynucleotide phosphorylase PNPase are involved in degradation of mitochondrial mRNAs but their roles vivo not fully understood. Additionally, upstream processes, such as transcript maturation, have been linked to some these factors, suggesting either dual or tightly interconnected mechanisms metabolism. To get a better understanding turn-over RNAs vivo, we manipulated mRNA degrading complex Drosophila melanogaster models studied molecular consequences....
Induction of the one-carbon cycle is an early hallmark mitochondrial dysfunction and cancer metabolism. Vital intermediary steps are localized to mitochondria, but it remains unclear how availability connects function. Here, we show that metabolite methyl group donor
Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the aging population, but their etiology disease mechanisms poorly understood. Studying monogenic neurodegenerative diseases with known genetic cause provides opportunity to understand cellular also affected in more complex disorders. We recently reported that loss-of-function mutations autophagy adaptor protein SQSTM1/p62 lead a slowly progressive presenting childhood. To further...