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Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism. 2016
Joni Nikkanen, and
Saara Forsström, and
Liliya Euro, and
Ilse Paetau, and
Rebecca A Kohnz, and
Liya Wang, and
Dmitri Chilov, and
Jenni Viinamäki, and
Anne Roivainen, and
Päivi Marjamäki, and
Heidi Liljenbäck, and
Sofia Ahola, and
Jana Buzkova, and
Mügen Terzioglu, and
Nahid A Khan, and
Sini Pirnes-Karhu, and
Anders Paetau, and
Tuula Lönnqvist, and
Antti Sajantila, and
Pirjo Isohanni, and
Henna Tyynismaa, and
Daniel K Nomura, and
Brendan J Battersby, and
Vidya Velagapudi, and
Christopher J Carroll, and
Anu Suomalainen
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland.
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.
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