Mitochondrial DNA Replication Defects Disturb Cellular dNTP Pools and Remodel One-Carbon Metabolism
Joni Nikkanen, Saara Forsström, Liliya Euro, Ilse Paetau, Rebecca A Kohnz, Liya Wang, Dmitri Chilov, Jenni Viinamäki, Anne Roivainen, Päivi Marjamäki, Heidi Liljenbäck, Sofia Ahola, Jana Buzkova, Mügen Terzioglu, Nahid A Khan, Sini Pirnes-Karhu, Anders Paetau, Tuula Lönnqvist, Antti Sajantila, Pirjo Isohanni, Henna Tyynismaa, Daniel K Nomura, Brendan J Battersby, Vidya Velagapudi, Christopher J Carroll, Anu Suomalainen, Joni Nikkanen, Saara Forsström, Liliya Euro, Ilse Paetau, Rebecca A Kohnz, Liya Wang, Dmitri Chilov, Jenni Viinamäki, Anne Roivainen, Päivi Marjamäki, Heidi Liljenbäck, Sofia Ahola, Jana Buzkova, Mügen Terzioglu, Nahid A Khan, Sini Pirnes-Karhu, Anders Paetau, Tuula Lönnqvist, Antti Sajantila, Pirjo Isohanni, Henna Tyynismaa, Daniel K Nomura, Brendan J Battersby, Vidya Velagapudi, Christopher J Carroll, Anu Suomalainen
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.
Copyright © 2016 Elsevier Inc. All rights reserved.
Source: PubMed