Experimental Studies of Neonatal Mitochondrial Diseases
The rationale of this project is the clinical need to clarify pathophysiological mechanisms of mitochondrial disorders and to develop treatment strategies for the benefit of patients.
Mutations in the mitochondrial assembly factor BCS1L are the most common cause of respiratory chain complex III deficiency, the most severe of them being the neonatal lethal GRACILE syndrome. These patients have hepatopathy, tubulopathy and lactic acidosis at birth, but no signs of encephalopathy possible due to short life span. Knock-in mice generated by prof. Fellman’s group and harboring the human patient mutation display growth failure and progressive liver disorder from the fourth week of age, tubulopathy and short life span. The mice have a disease-free postnatal period until 4 weeks of age, which gives an excellent time window to perform interventions at presymptomatic stage. We utilize this mouse model in studies of disease mechanism and in interventional studies. These include pharmacological treatments and gene therapy (transgenic alternative oxidase, wild-type Bcs1l, hepatocyte transplantation). Promising beneficial effects are emerging from gene therapy.
We have expertise in the following methods: mouse phenotyping, respirometry of mitochondria, blue native PAGE, respiratory chain complex III activity, metabolic assessments (CLAMs, metabolomics, transcriptomics), cardiac investigations on mice (echocardiography, blood pressure measurements). Moreover, we use Drosophila as a model organism in mechanistic studies.
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Postdoctoral Researchers
Janne Purhonen, Ph.D.
Christa Kietz, Ph.D.
Graduate Students
Rishi Banerjee, M.Sci.
Divya Upadhyay, M.Sci.
Staff
Vilma Wanne, M.Sci., Laboratory Coordinator
Purhonen, J, Banerjee Rishi, McDonald A, Fellman V, Kallijärvi J. A sensitive assay for dNTPs based on long synthetic oligonucleotides, EvaGreen dye, and inhibitor-resistant high-fidelity DNA polymerase. Nuclei Acids Research June 2020
Purhonen J, Grigorjev V, Ekiert R, Aho N, Rajendran J, Pietras R, Truvé K, Wikström M, Sharma V, Osyczka A, Fellman V, Kallijärvi J. A spontaneous mitonuclear epistasis converging on Rieske Fe-S protein exacerbates complex III deficiency in mice. Nat Commun. Jan 16th 2020.
Tomašić N, Kotarsky H, de Oliveira Figueiredo R, Hansson E, Mörgelin M, Tomašić I, Kallijärvi J, Elmér E, Jauhiainen M, Eklund EA, Fellman V. Fasting reveals largely intact systemic lipid mobilization mechanisms in respiratory chain complex III deficient mice. BBA Mol Basis Dis 1866(1):165573 (2020)
Rajendran J, Purhonen J, Tegelberg S, Smolander O-P, Mörgelin M, Rozman J, Gailus-Durner V, Fuchs H, Hrabe de Angelis M, Auvinen P, Mervaala E, Jacobs HT, Szibor M, Fellman V, Kallijärvi J. Alternative oxidase-mediated respiration prevents lethal mitochondrial cardiomyopathy. EMBO Mol Med. 11(1). pii: e9456 (2019)
Purhonen J, Rajendran J, Tegelberg S, Smolander O-P, Pirinen E, Kallijärvi J, Fellman V. NAD+ repletion produces no therapeutic effect in mice with respiratory chain complex III deficiency and chronic energy deprivation. FASEB J 32(11):5913-5926 (2018)
Purhonen J, Rajendran J, Uusi-Rauva K, Katayama S, Krjutskov K, Einarsdottir E, Velapugi V, Kere J, Jauhiainen M, Fellman V, Kallijärvi J. Ketogenic diet attenuates hepatopathy in mouse model of respiratory chain complex III deficiency caused by a Bcs1l mutation. Sci Rep 7(1):95 (2017)
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 and Fellman V. Respiratory chain complex III deficiency due to mutated BCS1L: a novel phenotype with encephalomyopathy, partially phenocopied in a Bcs1l mutant mouse model. Orphanet J Rare Dis 12:73 (2017)
Davoudi M, Kotarsky H, Hanson E, Kallijärvi J, Fellman V. Supercomplex formation is modified by SCAF1/COX7A2l assembly factor and pre-complex III in different mouse strains with a homozygous Bcs1l mutation. PLoS One 11(12):e0168774 (2016)
Rajendran J, Tomašić N, Kotarsky H, Hansson E, Velagapudi V, Kallijärvi J, Fellman V. Effect of high-carbohydrate diet on plasma metabolome in mice with mitochondrial respiratory chain complex III deficiency. Int J Mol Sci. 17(11). pii: E1824 (2016)
A mouse model of mitochondrial complex III dysfunction induced by myxothiazol. Davoudi M, Kallijärvi J, Marjavaara S, Kotarsky H, Hansson E, Levéen P, Fellman V. Biochem Biophys Res Commun. 2014 Apr 18;446(4):1079-84. doi: 10.1016/j.bbrc.2014.03.058.
Complex I function and supercomplex formation are preserved in liver mitochondria despite progressive complex III deficiency. Davoudi M, Kotarsky H, Hansson E, Fellman V. PLoS One. 2014 Jan 22;9(1):e86767. doi: 10.1371/journal.pone.0086767.
Mitochondrial respiration in human viable platelets - methodology and influence of gender, age and storage. Sjövall F, Ehinger JK, Marelsson SE, Morota S, Frostner EA, Uchino H, Lundgren J, Arnbjörnsson E, Hansson MJ, Fellman V, Elmér E. Mitochondrion. 2013 Jan;13(1):7-14. doi: 10.1016/j.mito.2012.11.001.
Metabolite profiles reveal energy failure and impaired beta-oxidation in liver of mice with complex III deficiency due to a BCS1L mutation. Kotarsky H, Keller M, Davoudi M, Levéen P, Karikoski R, Enot DP, Fellman V. PLoS One. 2012;7(7):e41156. doi: 10.1371/journal.pone.0041156.
The GRACILE mutation introduced into Bcs1l causes postnatal complex III deficiency: a viable mouse model for mitochondrial hepatopathy. Levéen P, Kotarsky H, Mörgelin M, Karikoski R, Elmér E, Fellman V. Hepatology. 2011 Feb;53(2):437-47. doi: 10.1002/hep.24031.
Mitochondrial hepatopathies in the newborn period. Fellman V, Kotarsky H. Semin Fetal Neonatal Med. 2011 Aug;16(4):222-8. doi: 10.1016/j.siny.2011.05.002.
Characterization of complex III deficiency and liver dysfunction in GRACILE syndrome caused by a BCS1L mutation. Kotarsky H, Karikoski R, Mörgelin M, Marjavaara S, Bergman P, Zhang DL, Smet J, van Coster R, Fellman V. Mitochondrion. 2010 Aug;10(5):497-509. doi: 10.1016/j.mito.2010.05.009.
Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause. Fellman V, Lemmelä S, Sajantila A, Pihko H, Järvelä I. J Hum Genet. 2008;53(6):554-8. doi: 10.1007/s10038-008-0284-0.
GRACILE syndrome, a lethal metabolic disorder with iron overload, is caused by a point mutation in BCS1L. Visapää I, Fellman V, Vesa J, Dasvarma A, Hutton JL, Kumar V, Payne GS, Makarow M, Van Coster R, Taylor RW, Turnbull DM, Suomalainen A, Peltonen L. Am J Hum Genet. 2002 Oct;71(4):863-76.
Iron-overload disease in infants involving fetal growth retardation, lactic acidosis, liver haemosiderosis, and aminoaciduria. Fellman V, Rapola J, Pihko H, Varilo T, Raivio KO. Lancet. 1998 Feb 14;351(9101):490-3.
Samfundet Folkhälsan
Finska Läkaresällskapet
Foundation for Pediatric Research in Finland
Liv-o-Hälsa Foundation
Magnus Ehrnrooth Foundation
Jane and Aatos Erkko Foundation
Stem Cells and Metabolism Research Program, University of Helsinki
Prof. Ildiko Szabo, University of Padova, Italy
Dr. Luis Garcia Lopez, University of Granada, Spain
Dr. Nina Sipari, University of Helsinki, Viikki Metabolomics Unit
Dr. Matthias Mörgelin, Division of Infection Medicine, Clinical Sciences, LU
Dr./MD Pirjo Isohanni, Children’s Hospital, Helsinki, Finland
Dr./MD Risto Lapatto, Children’s Hospital, Helsinki, Finland
Prof. Artur Osyczka, Jagiellonian University, Krakow, Poland
Dr. Leah Biggs, University of Helsinki, Finland
Dr. Satu Kuure, University of Helsinki, Finland
