Format

Send to

Choose Destination
Cell Metab. 2016 Apr 12;23(4):635-48. doi: 10.1016/j.cmet.2016.01.019. Epub 2016 Feb 25.

Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism.

Author information

1
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
2
Departments of Chemistry and Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA.
3
Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, 75007 Uppsala, Sweden.
4
Department of Forensic Medicine, University of Helsinki, 00300 Helsinki, Finland.
5
Turku PET Centre, University of Turku, 20520 Turku, Finland; Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, 20520 Turku, Finland.
6
Turku PET Centre, University of Turku, 20520 Turku, Finland.
7
HUSLAB and Department of Pathology, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland.
8
Department of Child Neurology, Children's Hospital, University of Helsinki, Helsinki University Hospital, 00290 Helsinki, Finland.
9
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.
10
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Medical and Clinical Genetics, University of Helsinki, 00290 Helsinki, Finland.
11
Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland.
12
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland. Electronic address: christopher.carroll@helsinki.fi.
13
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.

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.

PMID:
26924217
DOI:
10.1016/j.cmet.2016.01.019
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center