title: Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism.
abstract: Mitochondrial dysfunction affects cellular energy metabolism, but less is known about the consequences for cytoplasmic biosynthetic reactions. We report that mtDNA replication disorders caused by TWINKLE mutations-mitochondrial myopathy (MM) and infantile onset spinocerebellar ataxia (IOSCA)-remodel cellular dNTP pools in mice. MM muscle shows tissue-specific induction of the mitochondrial folate cycle, purine metabolism, and imbalanced and increased dNTP pools, consistent with progressive mtDNA mutagenesis. IOSCA-TWINKLE is predicted to hydrolyze dNTPs, consistent with low dNTP pools and mtDNA depletion in the disease. MM muscle also modifies the cytoplasmic one-carbon cycle, transsulfuration, and methylation, as well as increases glucose uptake and its utilization for de novo serine and glutathione biosynthesis. Our evidence indicates that the mitochondrial replication machinery communicates with cytoplasmic dNTP pools and that upregulation of glutathione synthesis through glucose-driven de novo serine biosynthesis contributes to the metabolic stress response. These results are important for disorders with primary or secondary mtDNA instability and offer targets for metabolic therapy.
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Joni
authors.initials: J
authors.lastname: Nikkanen
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Forsström
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Liliya
authors.initials: L
authors.lastname: Euro
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Ilse
authors.initials: I
authors.lastname: Paetau
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Kohnz
authors.affiliation: Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, 75007 Uppsala, Sweden.
authors.forename: Liya
authors.initials: L
authors.lastname: Wang
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Chilov
authors.affiliation: Department of Forensic Medicine, University of Helsinki, 00300 Helsinki, Finland.
authors.forename: Jenni
authors.initials: J
authors.lastname: Viinamäki
authors.affiliation: Turku PET Centre, University of Turku, 20520 Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
authors.forename: Anne
authors.initials: A
authors.lastname: Roivainen
authors.affiliation: Turku PET Centre, University of Turku, 20520 Turku, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Marjamäki
authors.affiliation: Turku PET Centre, University of Turku, 20520 Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Liljenbäck
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Ahola
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Jana
authors.initials: J
authors.lastname: Buzkova
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Mügen
authors.initials: M
authors.lastname: Terzioglu
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Nahid A
authors.initials: NA
authors.lastname: Khan
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Sini
authors.initials: S
authors.lastname: Pirnes-Karhu
authors.affiliation: HUSLAB and Department of Pathology, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland.
authors.forename: Anders
authors.initials: A
authors.lastname: Paetau
authors.affiliation: Department of Child Neurology, Children's Hospital, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
authors.affiliation: Department of Forensic Medicine, University of Helsinki, 00300 Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Sajantila
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Child Neurology, Children's Hospital, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.affiliation: Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Nomura
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Battersby
authors.affiliation: Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
authors.forename: Vidya
authors.initials: V
authors.lastname: Velagapudi
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland. Electronic address: christopher.carroll@helsinki.fi.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carroll
authors.affiliation: Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Neurology, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland; Neuroscience Center, University of Helsinki, 00790 Helsinki, Finland. Electronic address: anu.wartiovaara@helsinki.fi.
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000328:Adult; D000818:Animals; D002244:Carbon / Q000378:metabolism; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017240:Mitochondrial Myopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009711:Nucleotides / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013132:Spinocerebellar Degenerations / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D009711:Nucleotides; D012694:Serine; D002244:Carbon; D005492:Folic Acid; C513299:Twnk protein, mouse; D004265:DNA Helicases; C431576:TWNK protein, human; D005978:Glutathione; D005947:Glucose