bims-mitran 2022-02-20 papers

Issue of 2022‒02‒20
three papers selected by
Andreas Kohler

Nat Commun. 2022 Feb 17. 13(1): 929

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

Pedro Rebelo-Guiomar, Simone Pellegrino, Kyle C Dent, Aldema Sas-Chen, Leonor Miller-Fleming, Caterina Garone, Lindsey Van Haute, Jack F Rogan, Adam Dinan, Andrew E Firth, Byron Andrews, Alexander J Whitworth, Schraga Schwartz, Alan J Warren, Michal Minczuk.

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.

DOI: https://doi.org/10.1038/s41467-022-28503-5

Nat Struct Mol Biol. 2022 Feb;29(2): 152-161

Structural basis for the context-specific action of the classic peptidyl transferase inhibitor chloramphenicol.

Egor A Syroegin, Laurin Flemmich, Dorota Klepacki, Nora Vazquez-Laslop, Ronald Micura, Yury S Polikanov.

Ribosome-targeting antibiotics serve as powerful antimicrobials and as tools for studying the ribosome, the catalytic peptidyl transferase center (PTC) of which is targeted by many drugs. The classic PTC-acting antibiotic chloramphenicol (CHL) and the newest clinically significant linezolid (LZD) were considered indiscriminate inhibitors of protein synthesis that cause ribosome stalling at every codon of every gene being translated. However, recent discoveries have shown that CHL and LZD preferentially arrest translation when the ribosome needs to polymerize particular amino acid sequences. The molecular mechanisms that underlie the context-specific action of ribosome inhibitors are unknown. Here we present high-resolution structures of ribosomal complexes, with or without CHL, carrying specific nascent peptides that support or negate the drug action. Our data suggest that the penultimate residue of the nascent peptide directly modulates antibiotic affinity to the ribosome by either establishing specific interactions with the drug or by obstructing its proper placement in the binding site.

DOI: https://doi.org/10.1038/s41594-022-00720-y

Nat Cell Biol. 2022 Feb;24(2): 181-193

LONP-1 and ATFS-1 sustain deleterious heteroplasmy by promoting mtDNA replication in dysfunctional mitochondria.

Qiyuan Yang, Pengpeng Liu, Nadine S Anderson, Tomer Shpilka, YunGuang Du, Nandhitha Uma Naresh, Rui Li, Lihua Julie Zhu, Kevin Luk, Josh Lavelle, Rilee D Zeinert, Peter Chien, Scot A Wolfe, Cole M Haynes.

The accumulation of deleterious mitochondrial DNA (∆mtDNA) causes inherited mitochondrial diseases and ageing-associated decline in mitochondrial functions such as oxidative phosphorylation. Following mitochondrial perturbations, the bZIP protein ATFS-1 induces a transcriptional programme to restore mitochondrial function. Paradoxically, ATFS-1 is also required to maintain ∆mtDNAs in heteroplasmic worms. The mechanism by which ATFS-1 promotes ∆mtDNA accumulation relative to wild-type mtDNAs is unclear. Here we show that ATFS-1 accumulates in dysfunctional mitochondria. ATFS-1 is absent in healthy mitochondria owing to degradation by the mtDNA-bound protease LONP-1, which results in the nearly exclusive association between ATFS-1 and ∆mtDNAs in heteroplasmic worms. Moreover, we demonstrate that mitochondrial ATFS-1 promotes the binding of the mtDNA replicative polymerase (POLG) to ∆mtDNAs. Interestingly, inhibition of the mtDNA-bound protease LONP-1 increased ATFS-1 and POLG binding to wild-type mtDNAs. LONP-1 inhibition in Caenorhabditis elegans and human cybrid cells improved the heteroplasmy ratio and restored oxidative phosphorylation. Our findings suggest that ATFS-1 promotes mtDNA replication in dysfunctional mitochondria by promoting POLG-mtDNA binding, which is antagonized by LONP-1.

DOI: https://doi.org/10.1038/s41556-021-00840-5