Cytosolic N6AMT1- dependent translation supports mitochondrial RNA processing

Proc Natl Acad Sci U S A. 2024 Nov 19;121(47):e2414187121. doi: 10.1073/pnas.2414187121. Epub 2024 Nov 6.

Abstract

Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn errors of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic codependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial RNAse P enzyme. In the absence of N6AMT1, or when its catalytic activity is abolished, RNA processing within mitochondria is impaired, leading to the accumulation of unprocessed and double-stranded RNA, thus preventing mitochondrial protein synthesis and oxidative phosphorylation, and leading to an immune response. Our work sheds light on the function of N6AMT1 in protein synthesis and highlights a cytosolic program required for proper mitochondrial biogenesis.

Keywords: OXPHOS; RNA processing; mitochondria; mitochondrial RNA granules; translation.

MeSH terms

  • Animals
  • Cytosol* / metabolism
  • Humans
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Mitochondria* / genetics
  • Mitochondria* / metabolism
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Organelle Biogenesis
  • Oxidative Phosphorylation
  • Protein Biosynthesis*
  • RNA Processing, Post-Transcriptional
  • RNA, Mitochondrial* / genetics
  • RNA, Mitochondrial* / metabolism
  • Ribonuclease P / genetics
  • Ribonuclease P / metabolism

Substances

  • RNA, Mitochondrial
  • Methyltransferases
  • Mitochondrial Proteins
  • Ribonuclease P
  • PRORP protein, human

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