bims-mitran Biomed News
on Mitochondrial Translation
Issue of 2023‒10‒08
four papers selected by
Andreas Kohler, Umeå University
  1. Mechanisms and regulation of human mitochondrial transcription.
  2. Nuclear genome influences mitochondrial DNA.
  3. Mutation of the PEBP-like domain of the mitoribosomal MrpL35/mL38 protein results in production of nascent chains with impaired capacity to assemble into OXPHOS complexes.
  4. Inter-organellar nucleic acid communication by a mitochondrial tRNA regulates nuclear metabolic transcription.
  1. Nat Rev Mol Cell Biol. 2023 Oct 02.
    Mechanisms and regulation of human mitochondrial transcription.
    Benedict G Tan, Claes M Gustafsson, Maria Falkenberg.
      The expression of mitochondrial genes is regulated in response to the metabolic needs of different cell types, but the basic mechanisms underlying this process are still poorly understood. In this Review, we describe how different layers of regulation cooperate to fine tune initiation of both mitochondrial DNA (mtDNA) transcription and replication in human cells. We discuss our current understanding of the molecular mechanisms that drive and regulate transcription initiation from mtDNA promoters, and how the packaging of mtDNA into nucleoids can control the number of mtDNA molecules available for both transcription and replication. Indeed, a unique aspect of the mitochondrial transcription machinery is that it is coupled to mtDNA replication, such that mitochondrial RNA polymerase is additionally required for primer synthesis at mtDNA origins of replication. We discuss how the choice between replication-primer formation and genome-length RNA synthesis is controlled at the main origin of replication (OriH) and how the recent discovery of an additional mitochondrial promoter (LSP2) in humans may change this long-standing model.
    DOI:  https://doi.org/10.1038/s41580-023-00661-4
  2. Nat Rev Genet. 2023 Oct 06.
    Nuclear genome influences mitochondrial DNA.
    Henry Ertl.
      
    DOI:  https://doi.org/10.1038/s41576-023-00667-w
  3. Mol Biol Cell. 2023 Oct 04. mbcE23040132
    Mutation of the PEBP-like domain of the mitoribosomal MrpL35/mL38 protein results in production of nascent chains with impaired capacity to assemble into OXPHOS complexes.
    Jodie M Box, Jessica M Anderson, Rosemary A Stuart.
      Located in the central protuberance region of the mitoribosome, mitospecific mL38 proteins display homology to PEBP (phosphatidylethanolamine binding protein) proteins, a diverse family of proteins reported to bind anionic substrates/ligands and implicated in cellular signaling and differentiation pathways. In this study, we have performed a mutational analysis of the yeast mitoribosomal protein MrpL35/mL38 and demonstrate that mutation of the PEBP-invariant ligand binding residues Asp(D)232 and Arg(R)288 impacted MrpL35/mL38's ability to support OXPHOS-based growth of the cell. Furthermore, our data indicate these residues exist in a functionally important charged microenvironment, which also includes Asp(D)167 of MrpL35/mL38 and Arg(R)127 of the neighboring Mrp7/bL27m protein. We report that mutation of each of these charged residues resulted in a strong reduction in OXPHOS complex levels that was not attributed to a corresponding inhibition of the mitochondrial translation process. Rather, our findings indicate that a disconnect exists in these mutants between the processes of mitochondrial protein translation and the events required to ensure the competency and/or availability of the newly synthesized proteins to assemble into OXPHOS enzymes. Based on our findings, we postulate that the PEBP-homology domain of MrpL35/mL38, together with its partner Mrp7/bL27m, form a key regulatory region of the mitoribosome.
    DOI:  https://doi.org/10.1091/mbc.E23-04-0132
  4. bioRxiv. 2023 Sep 22. pii: 2023.09.21.558912. [Epub ahead of print]
    Inter-organellar nucleic acid communication by a mitochondrial tRNA regulates nuclear metabolic transcription.
    Christopher Rouya, King Faisal Yambire, Mark L Derbyshire, Hanan Alwaseem, Sohail F Tavazoie.
      Efficient communication between mitochondria and the nucleus underlies homoeostatic metabolic control, though the involved mitochondrial factors and their mechanisms are poorly defined. Here, we report the surprising detection of multiple mitochondrial-derived transfer RNAs (mito-tRNAs) within the nuclei of human cells. Focused studies of nuclear-transported mito-tRNA-asparagine (mtAsn) revealed that its cognate charging enzyme (NARS2) is also present in the nucleus. MtAsn promoted interaction of NARS2 with histone deacetylase 2 (HDAC2), and repressed HDAC2 association with specific chromatin loci. Perturbation of this axis using antisense oligonucleotides promoted nucleotide biogenesis and enhanced breast cancer growth, and RNA and nascent transcript sequencing demonstrated specific alterations in the transcription of nuclear genes. These findings uncover nucleic-acid mediated communication between two organelles and the existence of a machinery for nuclear gene regulation by a mito-tRNA that restricts tumor growth through metabolic control.Highlights: Multiple mitochondrial-derived tRNAs are detected in human cell nucleiMtAsn promotes binding between NARS2 and HDAC2Metabolic alterations driven by mtAsn impact cell proliferationMtAsn inhibition releases HDAC2 to bind and transcriptionally regulate multiple nuclear genes.
    DOI:  https://doi.org/10.1101/2023.09.21.558912
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