Journal article

MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria

Ilaria Dalla Rosa, Yolanda Camara, Romina Durigon, Chloe F Moss, Sara Vidoni, Gokhan Akman, Lilian Hunt, Mark A Johnson, Sarah Grocott, Liya Wang, David R Thorburn, Michio Hirano, Joanna Poulton, Robert W Taylor, Greg Elgar, Ramon Marti, Peter Voshol, Ian J Holt, Antonella Spinazzola

PLOS GENETICS | PUBLIC LIBRARY SCIENCE | Published : 2016

Abstract

MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17-/- liver slows the DNA..

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Grants

Awarded by Medical Research Council


Awarded by European Union Marie Curie Fellowship


Awarded by Wellcome Trust


Awarded by Spanish Instituto de Salud Carlos III


Awarded by The Francis Crick Institute


Awarded by EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT


Funding Acknowledgements

This work was supported by awards from the Medical Research Council to AS (MC_PC_13029) and to IJH, and by a European Union Marie Curie Fellowship to AS (PIEF-GA-2009-255578). RWT is supported by a Wellcome Trust Strategic Award (096919/Z/11/Z) and by the UK NHS Highly Specialized Rare Mitochondrial Disorders of Adults and Children Service. DRT is supported by an Australian National Health and Medical Research Council Principal Research Fellowship. RM is supported by the Spanish Instituto de Salud Carlos III (grant PI12/00322) and YC by the Muscular Dystrophy Association-Telethon (AFM Telethon). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.