Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression

Replication and expression of the mitochondrial genome depend on the sufficient supply of nucleotide building blocks to mitochondria. Dysregulated nucleotide metabolism is detrimental to mitochondrial genomes and can result in instability of mitochondrial DNA and inflammation. Here, we report that a mitochondrial nucleoside diphosphate kinase, NME6, supplies mitochondria with ribonucleotides to drive the transcription of mitochondrial genes. Moreover, NME6 supports the maintenance of mitochondrial DNA when the access to cytosolic deoxyribonucleotides is limited. Perturbation of NME6 leads to the depletion of mitochondrial transcripts, destabilisation of the electron transport chain and impaired oxidative phosphorylation; deficiencies which are suppressed upon supplementation with pyrimidine ribonucleotides. Our work proposes NME6 and mitochondrial nucleotide metabolism to be untapped therapeutic targets in diseases associated with aberrant mitochondrial gene expression including cancer and autoimmune disorders.