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.
Highlights
Many cellular processes, including ribosome biogenesis, are regulated through posttranscriptional RNA modifications
Given the severe phenotype caused by ablation of MRM2 in cultured cells, as well as reports of patients harbouring variants in the coding gene presenting with a Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS)-like pathology[13], we investigated the relevance of this protein for whole-organism and tissue-specific homeostasis in a Drosophila melanogaster model
We performed a multidisciplinary analysis of the mitochondrial role of MRM2, a protein that underlies the molecular basis of the MELAS-like syndrome in patients harbouring variants of the coding gene
Summary
I and II, it appears in its mature conformation in state III, in which most of the interfacial RNA components (H80-H93) are in mature-like conformations. In order to investigate the impact of these molecular alterations at the whole organism level, and since muscular tissue is commonly affected in mitochondrial disorders[34], including the MELAS-like presentation of patients harbouring MRM2 mutations[13], DmMRM2 was knocked-down using a pan-muscular driver (Mef2-GAL4) While this did not lead to pupal lethality, adult flies presented considerably impaired locomotor ability in the startle-induced negative geotaxis assay, which monitors neuromuscular function (Fig. 7d). Taken together these data show that MRM2, through its involvement in mtLSU biogenesis, is indispensable for organismal homeostasis
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