Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression

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...

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Published in:The EMBO journal Vol. 42; no. 18; p. e113256
Main Authors: Grotehans, Nils, McGarry, Lynn, Nolte, Hendrik, Xavier, Vanessa, Kroker, Moritz, Narbona‐Pérez, Álvaro Jesús, Deshwal, Soni, Giavalisco, Patrick, Langer, Thomas, MacVicar, Thomas
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 18.09.2023
Springer Nature B.V
John Wiley and Sons Inc
Subjects:
Deoxyribonucleotides
Electron transport
Electron transport chain
EMBO32
EMBO57
Gene expression
Genes
Genomes
Kinases
Life Sciences
Mitochondria
Mitochondrial DNA
Nucleoside-diphosphate kinase
Nucleosides
Nucleotides
Oxidative phosphorylation
Phosphorylation
Ribonucleotides
Transcription
mitochondrial transcription
NME6
nucleotide metabolism
mitochondria
mitochondrial DNA
ISSN:0261-4189, 1460-2075, 1460-2075
Online Access:Get full text
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Summary: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. Synopsis The source of rNTPs used in mitochondrial transcription, which supports many key processes, is not well understood. This study shows that they are supplied through the phosphorylation of pyrimidine nucleosides via mitochondrial nucleoside diphosphate kinase NME6. NME6 sustains mitochondrial supply of pyrimidine nucleotides. NME6 ensures accumulation of mitochondrial transcripts and respiratory complexes. Pyrimidine nucleoside supplementation restores levels of mitochondrial transcripts and respiratory complexes in cells lacking NME6. NME6‐dependent nucleotide salvage maintains mtDNA when the cytosolic supply of pyrimidine deoxyribonucleotides is limited. Graphical Abstract A mitochondrial nucleoside diphosphate kinase supplies mitochondria with the pyrimidine ribonucleotides they need for transcription.
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See also: PH Wanrooij & A Chabes (September 2023)
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.15252/embj.2022113256