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A late-stage assembly checkpoint of the human mitochondrial ribosome large subunit.

<div class='caption-title'>The human mitochondrial transcriptome contains three 2′-O-methylated residues, modified by MRM1, MRM2 and MRM3.</div>
<div class='caption-title'>Ablation of MRM2 leads to a severe impairment of cellular respiration and dysfunction of MRC complexes.</div>
<div class='caption-title'>OxPhos complexes are structurally compromised in the absence of MRM2 due to impaired mitochondrial translation.</div>
Rebelo-Guiomar P, Pellegrino S, Dent KC, Sas-Chen A, Miller-Fleming L, Garone C, Van Haute L, Rogan JF, Dinan A, Firth AE, Andrews B, Whitworth AJ, Schwartz S, Warren AJ, Minczuk M
OpenAccess logo Nat Commun 13 929 (2022)
Cited: 15 times
EuropePMC logo PMID: 35177605

Abstract

Many cellular processes, including ribosome biogenesis, are regulated through post-transcriptional RNA modifications. Here, a genome-wide analysis of the human mitochondrial transcriptome shows that 2'-O-methylation is limited to residues of the mitoribosomal large subunit (mtLSU) 16S mt-rRNA, introduced by MRM1, MRM2 and MRM3, with the modifications installed by the latter two proteins being interdependent. MRM2 controls mitochondrial respiration by regulating mitoribosome biogenesis. In its absence, mtLSU particles (visualized by cryo-EM at the resolution of 2.6 Å) present disordered RNA domains, partial occupancy of bL36m and bound MALSU1:L0R8F8:mtACP anti-association module, allowing five mtLSU biogenesis intermediates with different intersubunit interface configurations to be placed along the assembly pathway. However, mitoribosome biogenesis does not depend on the methyltransferase activity of MRM2. Disruption of the MRM2 Drosophila melanogaster orthologue leads to mitochondria-related developmental arrest. This work identifies a key checkpoint during mtLSU assembly, essential to maintain mitochondrial homeostasis.

Reviews citing this publication (4)

  1. Modopathies Caused by Mutations in Genes Encoding for Mitochondrial RNA Modifying Enzymes: Molecular Mechanisms and Yeast Disease Models. Magistrati M, Gilea AI, Ceccatelli Berti C, Baruffini E, Dallabona C. Int J Mol Sci 24 2178 (2023)
  2. Decoding the ribosome's hidden language: rRNA modifications as key players in cancer dynamics and targeted therapies. Cui L, Zheng J, Lin Y, Lin P, Lu Y, Zheng Y, Guo B, Zhao X. Clin Transl Med 14 e1705 (2024)
  3. Mitochondrial ribosome biogenesis and redox sensing. Brischigliaro M, Sierra-Magro A, Ahn A, Barrientos A. FEBS Open Bio 14 1640-1655 (2024)
  4. Molecular pathways in mitochondrial disorders due to a defective mitochondrial protein synthesis. Antolínez-Fernández Á, Esteban-Ramos P, Fernández-Moreno MÁ, Clemente P. Front Cell Dev Biol 12 1410245 (2024)

Articles citing this publication (11)

  1. Principles of mitoribosomal small subunit assembly in eukaryotes. Harper NJ, Burnside C, Klinge S. Nature 614 175-181 (2023)
  2. Mitoribosome Biogenesis. Conor Moran J, Del'Olio S, Choi A, Zhong H, Barrientos A. Methods Mol Biol 2661 23-51 (2023)
  3. Miniature RNAs are embedded in an exceptionally protein-rich mitoribosome via an elaborate assembly pathway. Valach M, Benz C, Aguilar LC, Gahura O, Faktorová D, Zíková A, Oeffinger M, Burger G, Gray MW, Lukeš J. Nucleic Acids Res 51 6443-6460 (2023)
  4. Structural insights into the role of GTPBP10 in the RNA maturation of the mitoribosome. Nguyen TG, Ritter C, Kummer E. Nat Commun 14 7991 (2023)
  5. A roadmap for ribosome assembly in human mitochondria. Lavdovskaia E, Hanitsch E, Linden A, Pašen M, Challa V, Horokhovskyi Y, Roetschke HP, Nadler F, Welp L, Steube E, Heinrichs M, Mai MM, Urlaub H, Liepe J, Richter-Dennerlein R. Nat Struct Mol Biol (2024)
  6. CLPP-Null Eukaryotes with Excess Heme Biosynthesis Show Reduced L-arginine Levels, Probably via CLPX-Mediated OAT Activation. Key J, Gispert S, Kandi AR, Heinz D, Hamann A, Osiewacz HD, Meierhofer D, Auburger G. Biomolecules 14 241 (2024)
  7. Let's make it clear: systematic exploration of mitochondrial DNA- and RNA-protein complexes by complexome profiling. Potter A, Cabrera-Orefice A, Spelbrink JN. Nucleic Acids Res 51 10619-10641 (2023)
  8. Protocol to study human mitochondrial ribosome using quantitative density gradient analysis by mass spectrometry and complexome profiling analysis. Páleníková P, Minczuk M, Rebelo-Guiomar P. STAR Protoc 4 102605 (2023)
  9. GTPBP8 plays a role in mitoribosome formation in human mitochondria. Cipullo M, Valentín Gesé G, Gopalakrishna S, Krueger A, Lobo V, Pirozhkova MA, Marks J, Páleníková P, Shiriaev D, Liu Y, Misic J, Cai Y, Nguyen MD, Abdelbagi A, Li X, Minczuk M, Hafner M, Benhalevy D, Sarshad AA, Atanassov I, Hällberg BM, Rorbach J. Nat Commun 15 5664 (2024)
  10. Mitochondrial proteins as therapeutic targets in diabetic ketoacidosis: evidence from Mendelian randomization analysis. Xie R, Xie H, Gao H, Xie C, Yuan H, Feng Z. Front Pharmacol 15 1448505 (2024)
  11. The catalytic activity of methyltransferase METTL15 is dispensable for its role in mitochondrial ribosome biogenesis. Mutti CD, Van Haute L, Minczuk M. RNA Biol 21 23-30 (2024)


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