bims-mitran 2025-12-07 papers

Issue of 2025–12–07
four papers selected by
Andreas Kohler, Umeå University

Nat Struct Mol Biol. 2025 Dec 03.

Translational activators align mRNAs at the small mitoribosomal subunit for translation initiation.

Joseph B Bridgers, Andreas Carlström, Dawafuti Sherpa, Mary T Couvillion, Urška Rovšnik, Jingjing Gao, Bowen Wan, Sichen Shao, Martin Ott, L Stirling Churchman.

Mitochondrial gene expression is essential for oxidative phosphorylation. Mitochondrial-encoded mRNAs are translated by dedicated mitochondrial ribosomes (mitoribosomes), whose regulation remains elusive. In Saccharomyces cerevisiae, nuclear-encoded mitochondrial translational activators (TAs) facilitate transcript-specific translation by a yet unknown mechanism. Here, we investigated the function of TAs containing RNA-binding pentatricopeptide repeats using selective mitoribosome profiling and cryo-electron microscopy (cryo-EM) structural analysis. These analyses show that TAs exhibit strong selectivity for mitoribosomes initiating on their target transcripts. Moreover, TA-mitoribosome footprints indicate that TAs recruit mitoribosomes proximal to the start codon. Two cryo-EM structures of mRNA-TA complexes bound to mitoribosomes stalled in the post-initiation, pre-elongation state revealed the general mechanism of TA action. Specifically, the TAs bind to structural elements in the 5' untranslated region of the client mRNA and the mRNA channel exit to align the mRNA in the small subunit during initiation. Our findings provide a mechanistic basis for understanding how mitochondria achieve transcript-specific translation initiation without relying on general sequence elements to position mitoribosomes at start codons.

DOI: https://doi.org/10.1038/s41594-025-01726-y

Nat Commun. 2025 Dec 02. 16(1): 10839

Structural insights into cauliflower mitoribosome in translation state and in association with a late assembly factor.

Vasileios Skaltsogiannis, Philippe Wolff, Tan-Trung Nguyen, Nicolas Corre, David Pflieger, Todd Blevins, Yaser Hashem, Philippe Giegé, Florent Waltz.

Ribosomes are key molecular machines that translate mRNA into proteins. Mitoribosomes are specific ribosomes found in mitochondria, which have been shown to be remarkably diverse across eukaryotic lineages. In plants, they possess unique features, including additional rRNA domains stabilized by plant-specific proteins. However, the structural specificities of plant mitoribosomes in translation state remained unknown. We used cryo-electron microscopy to provide a high-resolution structural characterization of the cauliflower mitoribosome, in translating and maturation states. The structure reveals the mitoribosome bound with a tRNA in the peptidyl site, along with a segment of mRNA and a nascent polypeptide. Moreover, using structural data, nanopore sequencing and mass spectrometry, we identify a set of 19 ribosomal RNA modifications. Additionally, we observe a late assembly intermediate of the small ribosomal subunit, in complex with the RsgA assembly factor. This reveals how a plant-specific extension of RsgA blocks the mRNA channel to prevent premature mRNA association before complete small subunit maturation. Our findings elucidate key aspects of translation in angiosperm plant mitochondria, revealing its distinct features compared to other eukaryotic lineages.

DOI: https://doi.org/10.1038/s41467-025-65864-z

J Mol Cell Biol. 2025 Dec 02. pii: mjaf047. [Epub ahead of print]

Slirp2 modulates oogenesis via regulating mitochondrial protein translation.

Jinguo Cao, Jiting Zhang, Zhaoqi Wu, Wei Luan, Yue Zhou, Huihui Huang, Lingling Li, Wen Hu.

Mitochondria are essential organelles responsible for generating ATP through oxidative phosphorylation (OXPHOS). Despite having their own genome, mitochondria rely on a complex interplay with nuclear-encoded proteins to maintain their function, as mutations in these proteins can lead to mitochondrial dysfunction and associated diseases. Mutations in the SLIRP (stem-loop interacting RNA-binding protein) gene are known to cause severe human mitochondrial diseases, and loss of SLIRP function can impair mitochondrial mRNA stability and translation. However, in vivo roles of the SLIRP protein remain inadequately understood. Drosophila melanogaster serves as a powerful model for studying mitochondrial function, particularly in the context of reproductive system development and gametogenesis. In this study, we focus on the role of the fly Slirp2 in oogenesis. Loss of Slirp2 impairs mitochondrial protein synthesis, leading to reduced OXPHOS efficiency, diminished ATP production, and disrupted insulin/mTOR signaling. These defects ultimately promote reactive oxygen species-induced programmed cell death, resulting in infertility. Our findings provide novel insights into the mechanistic role of Slirp2 in mitochondrial function and reproductive biology in vivo. We demonstrate that Slirp2 exhibits species-specific regulation of mitochondrial translation, revealing its complex, context-dependent function. These results have broader implications for understanding mitochondrial diseases, suggesting that the effects of Slirp2 mutations may vary across different organisms and tissue types.

Keywords: SLIRP; Slirp2; mitochondrial diseases; oogenesis

DOI: https://doi.org/10.1093/jmcb/mjaf047

Nat Commun. 2025 Dec 03.

Vacuolar-type H+-ATPase-mediated extra-organellar buffering resolves mitochondrial dysfunction.

Geoffray Monteuuis, Ryan Awadhpersad, Daan van der Kolk, Sachin K Singh, Tuula A Nyman, Alina Malyutina, Nicola Zamboni, Kari Moisio, Juhana Juutila, Ville Hietakangas, Sara Seneca, Christopher J Carroll, Christopher B Jackson.

Mitochondrial dysfunction underlies a wide range of human diseases, including primary mitochondrial disorders, neurodegeneration, cancer, and ageing. To preserve cellular homeostasis, organisms have evolved adaptive mechanisms that coordinate nuclear and mitochondrial gene expression. Here, we use genome-wide CRISPR knockout screening to identify cell fitness pathways that support survival under impaired mitochondrial protein synthesis. The strongest suppressor of aberrant mitochondrial translation defects - besides a compendium of known mitochondrial translation quality control factors - is the loss of the vacuolar-type H+-ATPase (v-ATPase), a key regulator of intracellular acidification, nutrient sensing, and growth signaling. We show that partial v-ATPase loss reciprocally modulates mitochondrial membrane potential (ΔΨm) and cristae structure in both cancer cell lines and mitochondrial disease patient-derived models. Our findings uncover an extra-organellar buffering mechanism whereby partial v-ATPase inhibition mitigates mitochondrial dysfunction by altering pH homeostasis and driving metabolic rewiring as a protective response that promotes cell fitness.

DOI: https://doi.org/10.1038/s41467-025-66656-1