Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression

Grotehans, N., McGarry, L., Nolte, H., Xavier, V., Kroker, M., Narbona‐Pérez, Á. J., Deshwal, S., Giavalisco, P., Langer, T. and MacVicar, T. (2023) Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression. EMBO Journal, 42(18), e113256. (doi: 10.15252/embj.2022113256) (PMID:37439264) (PMCID:PMC10505918)

Abstract

Replication of the mitochondrial genome and expression of the genes it encodes both depend on a sufficient supply of nucleotides to mitochondria. Accordingly, dysregulated nucleotide metabolism not only destabilises the mitochondrial genome, but also affects its transcription. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with pyrimidine ribonucleotides that are necessary for the transcription of mitochondrial genes. Loss of NME6 function leads to the depletion of mitochondrial transcripts, as well as destabilisation of the electron transport chain and impaired oxidative phosphorylation. These deficiencies are rescued by an exogenous supply of pyrimidine ribonucleosides. Moreover, NME6 is required for the maintenance of mitochondrial DNA when the access to cytosolic pyrimidine deoxyribonucleotides is limited. Our results therefore reveal an important role for ribonucleotide salvage in mitochondrial gene expression.

• Item Type: Articles
• Additional Information: NG and AJNP received support from the Cologne Graduate School of Ageing Research. This work was supported by funds of the Max-Planck-Society and from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – SFB1403 – Projektnummer (414786233) to TL and a Cancer Research UK Career Development Fellowship to TM (RCCFELCDF-May21\100001) and CRUK core funding to the CRUK Beatson Institute (A31287).
• Keywords: Mitochondria, NME6, mitochondrial transcription, mitochondrial DNA, nucleotide metabolism.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: McGarry, Ms Lynn and MacVicar, Dr Thomas
• Authors: Grotehans, N., McGarry, L., Nolte, H., Xavier, V., Kroker, M., Narbona‐Pérez, Á. J., Deshwal, S., Giavalisco, P., Langer, T., and MacVicar, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: EMBO Journal
• Publisher: EMBO Press
• ISSN: 0261-4189
• ISSN (Online): 1460-2075
• Published Online: 13 July 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in EMBO Journal 42(18): e113256
• Publisher Policy: Reproduced under a Creative Commons License