Mitochondrial translation requires folate-dependent tRNA methylation

Area of Science:

• Biochemistry
• Molecular Biology
• Cellular Metabolism

Background:

• Folates are vital for one-carbon metabolism, essential for biosynthesis pathways.
• Mitochondrial folate enzymes are upregulated in proliferating cells and cancers.
• The precise roles of mitochondrial folates in cellular functions are not fully understood.

Purpose of the Study:

• To investigate the specific role of mitochondrial folate metabolism in cellular functions.
• To determine the impact of impaired mitochondrial folate enzyme activity on cellular processes.
• To elucidate the mechanism by which mitochondrial folates influence energy metabolism.

Main Methods:

• Generated human cells lacking serine hydroxymethyltransferase 2 (SHMT2) activity.
• Utilized mitochondrial ribosome profiling to analyze translation.
• Assessed oxidative phosphorylation and respiratory chain enzyme expression.

Main Results:

• Loss of SHMT2 activity impairs mitochondrial translation and oxidative phosphorylation.
• SHMT2 generates 5,10-methylenetetrahydrofolate, providing methyl donors for tRNA modification (taurinomethyluridine).
• Defective tRNA modification leads to ribosome stalling at specific codons, impairing respiratory enzyme expression.

Conclusions:

• Mammalian mitochondria utilize folate-derived one-carbon units for tRNA methylation.
• This tRNA modification is critical for accurate mitochondrial translation and oxidative phosphorylation.
• Disruptions in folate metabolism or SHMT2 function negatively impact cellular energy production.