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
Upadhyay D, Banerjee R, Kallijärvi J, Purhonen J.
Quantification of UDP-GlcNAc using an enzymatic microplate method.
STAR Protoc 5(1):102817 (2024)
Purhonen J, Hofer A, Kallijärvi J.
Quantification of all 12 canonical ribonucleotides by real-time fluorogenic in vitro transcription.
Nucleic Acids Res 52(1):e6 (2024)
Purhonen J, Klefström J, Kallijärvi J.
MYC – an emerging player in mitochondrial diseases.
Front Cell Dev Biol Sep 4;11:1257651 (2023)
Sunden M, Upadhyay D, Banerjee R, Sipari N, Fellman V, Kallijärvi J, Purhonen J.
Enzymatic assay for UDP-GlcNAc and its application in the parallel assessment of substrate availability and protein O-GlcNAcylation.
Cell Rep Methods 3(7):100518 (2023)
Purhonen J, Banerjee R, Wanne V, Sipari N, Mörgelin M, Fellman V, Kallijärvi J.
Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria.
Nat Commun 14(1):2356 (2023)
Uusimaa J, Kettunen J, Varilo T, Järvelä I, Kallijärvi J, Kääriäinen H, Laine M, Lapatto R, Myllynen P, Niinikoski H, Rahikkala E, Suomalainen A, Tikkanen R, Tyynismaa H, Vieira P, Zarybnicky T, Sipilä P, Kuure S, Hinttala R.
The Finnish genetic heritage in 2022: from diagnosis to translational research.
Dis Model Mech 15(10):dmm049490 (2022)
Banerjee R, Purhonen J, Kallijärvi J.
The mitochondrial coenzyme Q junction and complex III: biochemistry and pathophysiology.
FEBS J 289(22):6936-6958 (2022)
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.
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)
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
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
