bims-mitran Biomed News
on Mitochondrial translation
Issue of 2025–06–29
four papers selected by
Andreas Kohler, Umeå University



  1. Nat Commun. 2025 Jun 25. 16(1): 5388
      S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
    DOI:  https://doi.org/10.1038/s41467-025-60977-x
  2. Biochimie. 2025 Jun 25. pii: S0300-9084(25)00128-2. [Epub ahead of print]
      Mitochondria contain their own circular genome (mtDNA), which encodes essential components of the oxidative phosphorylation (OXPHOS) system. Mitochondrial DNA transcription is a unique and relatively simple process, requiring a specialized transcription machinery that consists of a RNA polymerase (POLRMT), two transcription factors (TFAM and TFB2M), and an elongation factor (TEFM). During transcription, a non-canonical initiating nucleotide (NCIN) can be incorporated as the first nucleotide, serving as a 5' cap. Mitochondrial transcription produces large polycistronic transcripts, which are subsequently processed by ribonucleases to generate individual messenger RNAs (mt-mRNAs), ribosomal RNAs (mt-rRNAs), and transfer RNAs (mt-tRNAs). This review will specifically focus on the maturation and regulation of mt-mRNAs. Following their release from the primary transcript, mt-mRNAs undergo various post-transcriptional modifications, including methylation, pseudouridylation, and polyadenylation. These modifications play a crucial role in determining mt-mRNAs fate by influencing their stability, translation efficiency, and overall mitochondrial function. Additionally, the spatial organization of these processes within mitochondrial RNA granules (MRGs) suggests a compartmentalized system for mitochondrial gene regulation, ensuring precise coordination between transcription, processing, and translation. A deeper understanding of these post-transcriptional modifications provides valuable insights into mitochondrial gene expression and its broader impact on cellular metabolism.
    Keywords:  LRPPRC/SLIRP; Mitochondrial mRNA; RNA degradation; mitochondrial RNA granule; post-transcriptional modification
    DOI:  https://doi.org/10.1016/j.biochi.2025.06.015
  3. J Biochem. 2025 Jun 20. pii: mvaf037. [Epub ahead of print]
      Mitochondria are intracellular organelles originating from intracellular symbiotic bacteria that play essential roles in life activities such as energy production, metabolism, Ca2+ storage, signal transduction, and cell death. Mitochondria also function as hubs for host defense against harmful stimuli such as infection and inflammation control. However, when cells are exposed to stress, mitochondrial homeostasis is disrupted, and mitochondrial DNA (mtDNA) can leak into the cytoplasm or extracellular space. Leaked mtDNA activates innate immune sensors, causing severe inflammation and contributing to the pathogenesis of human diseases. In this review, we summarize the mechanisms by which mtDNA leaks from the mitochondria and subsequently induces inflammation. We also review the relationship between mtDNA leakage and human diseases.
    Keywords:  human diseases; innate immune response; mitochondria quality control; mitochondrial DNA; mtDNA leakage
    DOI:  https://doi.org/10.1093/jb/mvaf037
  4. Mol Cell. 2025 Jun 20. pii: S1097-2765(25)00472-1. [Epub ahead of print]
      Mitochondrial small open reading frame (ORF)-encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Although ETC complex I assembly is tightly coupled to nutrient availability, including serine, the coordinating mechanism remains unknown. A genome-wide CRISPR screen targeting SEPs revealed that deletion of the LINC00493-encoded microprotein SMIM26 sensitizes cells to one-carbon restriction. SMIM26 interacts with mitochondrial serine transporters SFXN1/2 and the mitoribosome, forming a functional triad that facilitates translation of the complex I subunit mt-ND5. SMIM26 loss impairs serine import, reduces folate intermediates, and disrupts key mitochondrial tRNA modifications (τm5U and τm5s²U), resulting in ND5 translation failure and complex I deficiency. SMIM26 deletion is embryonic lethal in mice and impedes tumor growth in a xenograft model of folate-dependent acute myeloid leukemia. These findings define SMIM26 as a critical integrator of one-carbon flux and complex I biogenesis and establish a paradigm for localized mitochondrial translation through transporter-ribosome interactions.
    Keywords:  complex I; electron transport chain; micropeptides; mitochondria; mitochondrial translation; one-carbon pathway; oxidative phosphorylation; small ORF-encoded peptides
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.033