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The Wredenberg Lab

Stockholm

About the lab

We are a young research group at the Division of Molecular Metabolism at the Karolinska Institute, working on various aspects of mitochondrial biology. Mitochondria form an integral part of cellular metabolism with many metabolic pathways relying on or passing through mitochondria. Dysfunction of any of these metabolic pathways can have significant affects on human health. We are interested in understanding the connections between energy metabolism and cell function and how disturbances in this network affects an individual’s health. For this, we use a combination of model systems, ranging from the fruit fly, Drosophila melanogaster, to patient-derived iPS cells, for detailed molecular and metabolic characterisation.

Anna Wredenberg recently received an ERC start-up grant. She is a Ragnar Söderberg fellow in Medicine and an MD at the Centre for inherited metabolic diseases at the Karolinska University Hospital. The centre is a specialised clinic for the diagnosis of inherited metabolic diseases and performs a range of molecular, bioenergetic and metabolic investigations on patients from all over Sweden. Modern diagnostic tools have dramatically increased our understanding of these diseases, and provide a unique opportunity to identify the molecular mechanisms of metabolic derangements. We work in close collaboration with the clinic to diagnose, validate and understand metabolic diseases.


Research

Mitochondria form a dynamic network in almost every eukaryotic cell, rapidly responding to a variety of cellular demands. Although mitochondria are predominantly known to perform the final steps of aerobic energy metabolism, they are essential for other processes as diverse as steroid and lipid metabolism, iron-sulphur cluster formation, calcium buffering, reactive oxygen species (ROS) formation or apoptosis. Mitochondria are therefore seen as forming a central hub for cellular metabolism and understanding their role within the remaining metabolic network is essential for a variety of complex human diseases. For instance, mitochondrial dysfunction can be observed in several neurodegenerations, heart disease, diabetes mellitus and has been suggested to be a major contributor to the natural ageing process.

For this we use a range of model systems, including genetically modified fruit flies, to broaden our understanding of the molecular interactions that affect mitochondrial metabolism, both in health and disease.
Our research tries to identify the molecular consequences of metabolic derangements, by understanding how mitochondria function within the metabolic system. We also have a special focus on understanding the turnover of mitochondrial transcripts, and how changes in mitochondrial gene expression is regulated on a post-transcriptional level.

Mitochondria contain their own DNA, which is transcribed and translated within the mitochondrial network. Although several factors involved in mitochondrial RNA metabolism have already been identified, the mechanisms of what regulates their involvement in processing, modifying or degrading are still very sparse. With the help of genetically modified fruit fly models we study the molecular mechanisms that determine mitochondrial RNA metabolism and how they interact with mitochondrial translation.

Mitochondrial dysfunction can result in a range of rare inborn errors of metabolism (IEM), but has also been associated with a range of common diseases including cancer, heart failure, neurodegeneration, diabetes mellitus and natural ageing. The complexity and lack of understanding leaves many patients with IEMs undiagnosed. We work in close collaboration with the centre for inherited metabolic diseases at the Karolinska University Hospital to functionally validate novel gene variants identified in patients with IEM.

We combine several approaches, including analysing differentiated induced pluripotent stem (iPS) cells or mutation-specific fly models to fully validate novel genetic variants from patients with IEM. By understanding the molecular, bioenergetic and proteomic alterations in IEM, we believe that we will gain a much better understanding of human metabolism in health and disease.


PI

Anna Wredenberg

MD, PhD

2007 PhD Karolinska Institutet
2009 Swedish Medical Licence
2010 – 2012 PostDoc Max-Planck Institute for Biology of Ageing
2012 – Resident Clinical Genetics | Karolinska University Hospital
2012 – Research Group Leader | Karolinska Institutet
Anna.Wredenberg@ki.se

Anna Wredenberg
Group leader
Christoph Freyer

PhD

2004 PhD University of Newcastle
2004 – 2008 PostDoc Karolinska Institutet
2008 – 2012 PostDoc Max-Planck Institute for Biology of Ageing
2012 – Karolinska University Hospital & Karolinska Institutet

Christoph.Freyer@ki.se

Christoph Freyer
Senior Scientist

PostDocs

Paula Clemente

PhD

2012 PhD Universidad Autónoma de Madrid
2012 – PostDoc Karolinska Institutet

Paula.Clemente@ki.se

Paula Clemente
Senior PostDoc
Aleksandra Pajak

PhD

2013 PhD University of Newcastle
2013 PostDoc Okayama University
2014 – PostDoc Karolinska Institutet

Aleksandra.Pajak@ki.se

Aleksandra Pajak
Senior PostDoc
Version 2

PhD

2011 PhD Universidad Autónoma de Madrid
2012 – PostDoc Karolinska Institutet

Javier.Calvo.Garrido@ki.se

Javier Calvo Garrido
Senior PostDoc
IMG_6524

PhD

2018 PhD IBDM, Marseille
2018 – PostDoc Karolinska Institutet

Najla.ElFissi@ki.se

Najla El Fissi
PostDoc
David Moore

PhD

2017 PhD University of Newcastle
2017 – PostDoc Karolinska Institutet

David.Moore@ki.se

 

David Moore
PostDoc
IMG_6516

PhD

2017 PhD Universidade de Lisboa
2018 – PostDoc Karolinska Institutet

Marco.Moedas@ki.se

Marco Moedas
PostDoc

Students

Camilla Maffezzini

MSc

2014 MSc University of Pavia
2014 – PhD student Karolinska Institutet

Camilla.Maffezzini@ki.se

Camilla Maffezzini
PhD student
Isabelle Laine

MSc

2014 MSc Stockholm University
2014 – PhD student Karolinska Institutet
2015 – Medical student Karolinska Institutet

Isabelle.Laine@ki.se

Isabelle Laine
PhD student
Florian Schober

MSc

2015 MSc Karolinska Institutet
2016 – PhD student Karolinska Institutet

Florian.Schober@ki.se

Florian Schober
PhD student
Helene Bruhn

MSc

2001 MSc Uppsala University
2001 – CMMS Karolinska University Hospital
2015 – PhD student Karolinska Institutet
Helene Bruhn
PhD student

Publications

Richter, U., Evans, M.E., Clark, W.C., Marttinen, P., Shoubridge, E.A., Suomalainen, A., Wredenberg, A., Wedell, A., Pan, T., Battersby, B.J. (2018) RNA modification landscape of the human mitochondrial tRNALys regulates protein synthesis. Nature Communications, 9(1):3966 LINK
 
Paucar, M., Pajak, A., Freyer, C., Bergendal, Å., Döry, M., Laffita-Mesa, J.M., Stranneheim, H., Lagerstedt-Robinson, K., Savitcheva, I., Walker, R.H., Wedell, A., Wredenberg, A., Svenningsson, P. (2018) Chorea, psychosis, acanthocytosis, and prolonged survival associated with ELAC2 mutations. Neurology, pii:10.1212/WNL.0000000000006320 LINK
 
Freyer, C., Clemente, P. & Wredenberg, A. Mitochondrial RNA Turnover in Metazoa. in RNA Metabolism in Mitochondria (eds. Cruz-Reyes, J. & Gray, M. W.) 17–46 (Springer International Publishing, 2018). LINK

Herebian, D.*, Seibt, A.*, Smits, S.H.J., Bünning, G., Freyer, C., Prokisch, H., Karall, D., Wredenberg, A., Wedell,A., López, L.C., Mayatepek, E., Distelmaier, F. (2017) Detection of 6-demethoxyubiquinone in CoQ10 deficiency disorders: Insights into enzyme interactions and identification of potential therapeutics. Molecular Genetics and Metabolism, 121(3):216-223 LINK
 
Siibak, T.*, Clemente, P.*, Bratic, A., Bruhn, H., Kauppila, T.E.S., Macao, B., Schober, F.A., Lesko, N., Wibom, R., Naess, K., Nennesmo, I., Wedell, A., Peter, B., Freyer, C., Falkenberg, M.#, Wredenberg, A.# (2017). A multi-systemic mitochondrial disorder due to a dominant p.Y955H disease variant in DNA polymerase gamma. Human Molecular Genetics, 26 (13): 2515-2525 LINK
 
Tegelberg, S.*, Tomašić, N.*, Kallijärvi, J., Purhonen, J., Elmér, E., Lindberg, E., Gisselsson-Nord, D., Soller, M., Lesko, N., Wedell, A., Bruhn, H., Freyer, C., Stranneheim, H., Wibom, R., Nennesmo, I., Wredenberg, A., Eklund, E.A.#, Fellman, V#. (2017) Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model. Orphanet Journal of Rare Diseases, 12(1): 73 LINK

Kauppila, J.H.K.*, Baines, H.L.*, Bratic, A., Simard, M.-L., Freyer, C., Mourier, A., Stamp, C., Filograna, R., Larsson, N.-G.#, Greaves, L.C.#, & Stewart, J.B.#. (2016). A phenotype-driven approach to generate mouse models with pathogenic mtDNA mutations causing mitochondrial disease. Cell Reports, 16(11): 2980-2990. LINK
 
Haack, T.B.*#, Ignatius, E.*, Calvo-Garrido, J.*, Iuso, A.*, Isohanni, P., Maffezzini, C., Lönnqvist, T., Suomalainen, A., Gorza, M., Kremer,L.S., Graf, E., Hartig, M., Berutti, R., Arce, M.P., Svenningsson, P., Stranneheim, H., Brandberg, G., Wedell, A., Kurian, M.A., Hayflick, S.A., Venco, P., Tiranti, V., Strom, T.M., Dichgans, M., Horvath, R., Holinski-Feder, E., Freyer, C., Meitinger, T., Prokisch, H.#, Senderek, J.#, Wredenberg, A.#, Carroll, C.J.#, & Klopstock, T.#. (2016). Absence of the Autophagy Adaptor SQSTM1/p62 Causes Childhood-Onset Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy. American Journal of Human Genetics, 99(3):735–743  LINK
 
Bratic, A.*, Clemente, P.*, Calvo-Garrido, J., Maffezzini, C., Felser, A., Wibom, R., Wedell, A., Freyer, C.#, Wredenberg, A.# (2016). Mitochondrial polyadenylation is a one-step process required for mRNA integrity and tRNA maturation. PLoS Genetics, 12(5): e1006028. LINK

Gineste, C., Hernandez, A., Ivarsson, N., Cheng, A.J., Naess, K., Wibom, R., Lesko, N., Bruhn, H., Wedell, A., Freyer, C., Zhang, S.-J., Carlström, M., Lanner, J.T., Andersson, D.C., Bruton, J.D., Wredenberg, A.#, & Westerblad, H#. (2015). Cyclophilin D, a target for counteracting skeletal muscle dysfunction in mitochondrial myopathy. Human Molecular Genetics, 24(23): 6580-6587. LINK
 
Jemt, E., Persson, Ö., Shi, Y., Mehmedovic, M., Uhler, J.P., Dávila López, M., Freyer, C., et al. (2015). Regulation of DNA replication at the end of the mitochondrial D-loop involves the helicase TWINKLE and a conserved sequence element. Nucleic Acids Research, 43(19): 9262-9275. LINK
 
Bratic, A., Kauppila, T.E.S., Macao, B., Grönke, S., Siibak, T., Stewart, J.B., Baggio, F., Dols, J., Partridge, L., Falkenberg, M., Wredenberg, A.#, & Larsson, N.-G.# (2015). Complementation between polymerase- and exonuclease-deficient mitochondrial DNA polymerase mutants in genomically engineered flies. Nature Communications, 6: 8808. LINK
 
Clemente, P., Pajak, A., Laine, I., Wibom, R., Wedell, A., Freyer, C.#, & Wredenberg, A#. (2015). SUV3 helicase is requiredfor correct processing of mitochondrial transcripts. Nucleic Acids Research, 43(15): 7398–7413. LINK
 
Freyer, C.*, Stranneheim, H.*, Naess, K.*, Mourier, A., Felser, A., Maffezzini, C., Lesko, N., Bruhn, H., Engvall, M., Wibom, R., Barbaro, M., Hinze, Y., Magnusson, M., Andeer, R., Zetterström, R.H., von Döbeln, U., Wredenberg, A.#, & Wedell, A.# (2015). Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid. Journal of Medical Genetics, 52(11): 779–783. LINK
 
Kishita, Y.*, Pajak, A.*, Bolar, N.A*., Marobbio, C.M.T.*, Maffezzini, C., Miniero, D.V., Monné, M., Kohda, M., Stranneheim, H., Murayama, K., Naess, K., Lesko, N., Bruhn, H., Mourier, A., Wibom, R., Nennesmo, I., Jespers, A., Govaert, P., Ohtake, A., Van Laer, L., Loeys, B.L., Freyer, C., Palmieri, F.#, Wredenberg, A.#, Okazaki, Y.#, & Wedell, A.# (2015). Intra-mitochondrial Methylation Deficiency Due to Mutations in SLC25A26. American Journal of Human Genetics, 97(5): 761–768. LINK

Acuna-Hidalgo, R., Schanze, D., Kariminejad, A., Nordgren, A., Kariminejad, M.H., Conner, P., Grigelioniene , G., Nilsson, D., Nordenskjöld , M., Wedell, A., Freyer, C., Wredenberg, A., et al. (2014). Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway. American Journal of Human Genetics, 95(3): 285–293. LINK

Stranneheim, H., Engvall, M., Naess, K., Lesko, N., Larsson, P., Dahlberg, M., Andeer, R., Wredenberg, A., Freyer, C., et al. (2014). Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism. BMC Genomics, 15(1): 1090. LINK

Wredenberg, A.*, Lagouge, M.*, Bratic, A.*, Metodiev, M.D., Spåhr, H., Mourier, A., et al. (2013). MTERF3 regulates mitochondrial ribosome biogenesis in invertebrates and mammals. PLoS Genetics, 9(1): e1003178. LINK

Hagström, E., Freyer, C., Battersby, B.J., Stewart, J.B., & Larsson, N.-G. (2013). No recombination of mtDNA after heteroplasmy. Nucleic Acids Research, 42(2): 1111-1116. LINK

Milenkovic, D., Matic, S., Kühl, I., Ruzzenente, B., Freyer, C., Jemt, E., et al. (2013). TWINKLE is an essential mitochon- drial helicase required for synthesis of nascent D-loop strands and complete mtDNA replication. Human Molecular Genetics, 22(10): 1983–1993. LINK

Ross, J.M.*, Stewart, J.B.*, Hagström, E., Brené, S., Mourier, A., Coppotelli, G., Freyer, C., et al. (2013). Germline mito- chondrial DNA mutations aggravate ageing and can impair brain development. Nature, 501(7467): 412-415. LINK

Freyer, C., Cree, L.M., Mourier, A., Stewart, J.B., Koolmeister, C., Milenkovic, D., et al. (2012). Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nature Genetics, 44(11): 1282–1285. LINK
 
Ruzzenente, B., Metodiev, M.D., Wredenberg, A., Bratic, A., Park, C.B., Cámara, Y., et al. (2012). LRPPRC is necessary for polyadenylation and coordination of translation of mitochondrial mRNAs. The EMBO Journal, 31(2): 443–456. LINK
 
Ameur, A.*, Stewart, J.B.*, Freyer, C., Hagström, E., Ingman, M., Larsson, N.-G., & Gyllensten, U. (2011). Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genetics, 7(3): e1002028. LINK
 
Bratic, A.*, Wredenberg, A.*, Grönke, S., Stewart, J.B., Mourier, A., Ruzzenente, B., et al. (2011). The bicoid stability factor controls polyadenylation and expression of specific mitochondrial mRNAs in Drosophila melanogaster. PLoS Genetics, 7(10): e1002324. LINK
 
Freyer, C., Park, C.B., Ekstrand, M., Shi, Y., Khvorostova, J., Wibom, R., et al. (2010). Maintenance of respiratory chain function in mouse hearts with severely impaired mtDNA transcription. Nucleic Acids Research, 38(19): 6577–6588. LINK
 
Aydin, J., Andersson, D.C., Hänninen, S. L., Wredenberg, A., Tavi, P., Park, C.B., et al. (2009). Increased mitochondrial Ca2+ and decreased sarcoplasmic reticulum Ca2+ in mitochondrial myopathy. Human Molecular Genetics, 18(2): 278–288. LINK
 
Edgar, D.*, Shabalina, I.G.*, Cámara, Y., Wredenberg, A., Calvaruso, M.A., Nijtmans, L., et al. (2009). Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metabolism, 10(2): 131–138. LINK
 
Naess, K., Freyer, C., Bruhn, H., Wibom, R., Malm, G., Nennesmo, I., et al. (2009). MtDNA mutations are a common cause of severe disease phenotypes in children with Leigh syndrome. Biochimica Et Biophysica Acta, 1787(5): 484–490. LINK
 
Stewart, J.B., Freyer, C., Elson, J.L., & Larsson, N.-G. (2008a). Purifying selection of mtDNA and its implications for understanding evolution and mitochondrial disease. Nature Reviews. Genetics, 9(9), 657–662. LINK
 
Stewart, J.B., Freyer, C., Elson, J.L., Wredenberg, A., Cansu, Z., Trifunovic, A., & Larsson, N.-G. (2008b). Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biology, 6(1): e10. LINK
 
Freyer, C., & Larsson, N.-G. (2007). Is energy deficiency good in moderation? Cell, 131(3): 448–450. LINK
 
Wredenberg, A., Freyer, C., Sandström, M.E., Katz, A., Wibom, R., Westerblad, H., & Larsson, N.-G. (2006). Respiratory chain dysfunction in skeletal muscle does not cause insulin resistance. Biochemical and Biophysical Research Communications, 350(1): 202–207. LINK
 
Trifunovic, A., Hansson, A., Wredenberg, A., Rovio, A.T., Dufour, E., Khvorostov, I., et al. (2005). Somatic mtDNA mutations cause aging phenotypes without affecting reactive oxygen species production., 102(50): 17993–17998. LINK
 
Trifunovic, A., Wredenberg, A., Falkenberg, M., Spelbrink, J.N., Rovio, A.T., Bruder, C.E., et al. (2004). Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature, 429(6990): 417–423. LINK
 
Wredenberg, A., Wibom, R., Wilhelmsson, H., Graff, C., Wiener, H.H., Burden, S.J., et al. (2002). Increased mitochondrial mass in mitochondrial myopathy mice. Proceedings of the National Academy of Sciences of the United States of America, 99(23), 15066–15071. LINK
 
Graff, C., Wredenberg, A., Silva, J.P., Bui, T.H., Borg, K., & Larsson, N.-G. (2000). Complex genetic counselling and prenatal analysis in a woman with external ophthalmoplegia and deleted mtDNA. Prenatal Diagnosis, 20(5): 426–431.
 
Tollbäck, A., Eriksson, S., Wredenberg, A., Jenner, G., Vargas, R., Borg, K., & Ansved, T. (1999). Effects of high resistance training in patients with myotonic dystrophy. Scandinavian Journal of Rehabilitation Medicine, 31(1): 9–16.


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Karolinska Institutet
Division of Molecular Metabolism
Dept. of Medical Biochemistry & Biophysics
Solnavägen 9 | 171 65 Stockholm | Sweden
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