title: Signal transducer and activator of transcription 2 deficiency is a novel disorder of mitochondrial fission.
abstract: Defects of mitochondrial dynamics are emerging causes of neurological disease. In two children presenting with severe neurological deterioration following viral infection we identified a novel homozygous STAT2 mutation, c.1836 C>A (p.Cys612Ter), using whole exome sequencing. In muscle and fibroblasts from these patients, and a third unrelated STAT2-deficient patient, we observed extremely elongated mitochondria. Western blot analysis revealed absence of the STAT2 protein and that the mitochondrial fission protein DRP1 (encoded by DNM1L) is inactive, as shown by its phosphorylation state. All three patients harboured decreased levels of DRP1 phosphorylated at serine residue 616 (P-DRP1(S616)), a post-translational modification known to activate DRP1, and increased levels of DRP1 phosphorylated at serine 637 (P-DRP1(S637)), associated with the inactive state of the DRP1 GTPase. Knockdown of STAT2 in SHSY5Y cells recapitulated the fission defect, with elongated mitochondria and decreased P-DRP1(S616) levels. Furthermore the mitochondrial fission defect in patient fibroblasts was rescued following lentiviral transduction with wild-type STAT2 in all three patients, with normalization of mitochondrial length and increased P-DRP1(S616) levels. Taken together, these findings implicate STAT2 as a novel regulator of DRP1 phosphorylation at serine 616, and thus of mitochondrial fission, and suggest that there are interactions between immunity and mitochondria. This is the first study to link the innate immune system to mitochondrial dynamics and morphology. We hypothesize that variability in JAK-STAT signalling may contribute to the phenotypic heterogeneity of mitochondrial disease, and may explain why some patients with underlying mitochondrial disease decompensate after seemingly trivial viral infections. Modulating JAK-STAT activity may represent a novel therapeutic avenue for mitochondrial diseases, which remain largely untreatable. This may also be relevant for more common neurodegenerative diseases, including Alzheimer's, Huntington's and Parkinson's diseases, in which abnormalities of mitochondrial morphology have been implicated in disease pathogenesis.
authors.affiliation: 1 Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, Guilford Street, London, UK shamima.rahman@ucl.ac.uk.
authors.forename: Rojeen
authors.initials: R
authors.lastname: Shahni
authors.affiliation: 2 Molecular Immunology Unit, Great Ormond Street Hospital, London, UK.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cale
authors.affiliation: 3 Histopathology Unit, Great Ormond Street Hospital, London, UK.
authors.forename: Glenn
authors.initials: G
authors.lastname: Anderson
authors.affiliation: 4 Department of Biochemistry and Molecular Biology, Monash University, Melbourne 3800, Australia.
authors.forename: Laura D
authors.initials: LD
authors.lastname: Osellame
authors.affiliation: 5 Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Hambleton
authors.affiliation: 3 Histopathology Unit, Great Ormond Street Hospital, London, UK 6 Developmental Neurosciences, UCL Institute of Child Health, London, UK.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Jacques
authors.affiliation: 1 Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, Guilford Street, London, UK.
authors.forename: Yehani
authors.initials: Y
authors.lastname: Wedatilake
authors.affiliation: 7 Department of Clinical Neurosciences, UCL Institute of Neurology, Rowland Hill Street, London, UK.
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: Taanman
authors.affiliation: 2 Molecular Immunology Unit, Great Ormond Street Hospital, London, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Chan
authors.affiliation: 2 Molecular Immunology Unit, Great Ormond Street Hospital, London, UK.
authors.forename: Waseem
authors.initials: W
authors.lastname: Qasim
authors.affiliation: 8 UCL Genetics Institute, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: 9 Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London, UK.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Chalasani
authors.affiliation: 10 Cell and Developmental Biology, University College London, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
authors.affiliation: 2 Molecular Immunology Unit, Great Ormond Street Hospital, London, UK.
authors.forename: Kimberly C
authors.initials: KC
authors.lastname: Gilmour
authors.affiliation: 1 Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, Guilford Street, London, UK 1 Mitochondrial Research Group, Genetics and Genomic Medicine, UCL Institute of Child Health, Guilford Street, London, UK.
authors.forename: Shamima
authors.initials: S
authors.lastname: Rahman
mesh_terms: D017209:Apoptosis / Q000235:genetics; D002675:Child, Preschool; D034281:Dynamins; D004569:Electroencephalography; D005192:Family Health; D005260:Female; D005434:Flow Cytometry; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008297:Male; D008854:Microscopy, Electron; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism*; D063154:Mitochondrial Dynamics / Q000502:physiology*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000473:pathology / Q000648:ultrastructure; D009447:Neuroblastoma / Q000473:pathology; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D012342:RNA, Small Nuclear / Q000494:pharmacology; D050795:STAT2 Transcription Factor / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection
chemical_list: D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D012342:RNA, Small Nuclear; D050795:STAT2 Transcription Factor; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins
keywords: JAK-STAT signalling; STAT2; dynamin-related protein 1 (DRP1); mitochondrial disease; mitochondrial fission; mitochondrial fusion