Ribonucleotide synthesis by NME6 fuels mitochondrial gene expression

Area of Science:

• Mitochondrial biology
• Nucleotide metabolism
• Gene expression

Background:

• Mitochondrial genome replication and gene expression require adequate nucleotide supply.
• Disrupted nucleotide metabolism destabilizes mitochondrial DNA and affects transcription.

Purpose of the Study:

• To investigate the role of mitochondrial nucleoside diphosphate kinase 6 (NME6) in supplying pyrimidine ribonucleotides for mitochondrial gene expression.
• To elucidate the consequences of NME6 dysfunction on mitochondrial genome stability and function.

Main Methods:

• Investigated the function of NME6 in yeast models.
• Assessed mitochondrial transcript levels, electron transport chain stability, and oxidative phosphorylation.
• Evaluated the impact of NME6 loss on mitochondrial DNA maintenance under limited nucleotide availability.

Main Results:

• NME6 was identified as a key supplier of pyrimidine ribonucleotides to mitochondria, essential for mitochondrial gene transcription.
• Loss of NME6 function resulted in depleted mitochondrial transcripts, destabilized electron transport chain, and impaired oxidative phosphorylation.
• These defects were rescued by exogenous pyrimidine ribonucleosides, and NME6 was crucial for mitochondrial DNA maintenance when cytosolic pyrimidine deoxyribonucleotides were limited.

Conclusions:

• NME6 plays a critical role in mitochondrial gene expression by ensuring pyrimidine ribonucleotide supply.
• Ribonucleotide salvage is vital for maintaining mitochondrial genome stability and function, particularly under conditions of limited nucleotide availability.
• Dysfunction of NME6 leads to severe mitochondrial defects, underscoring its importance in cellular energy metabolism.