bims-mirnam 2026-03-15 papers

bims-mirnam

Biomed News

on Mitochondrial RNA metabolism

Issue of 2026–03–15
nine papers selected by
Hana Antonicka, McGill University

Translational regulation by oxidative desulfuration of tRNA modifications.
Purification of post-transcriptionally modified tRNAs for enhanced cell-free translation systems.
Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.
Circular RNAs as emerging regulators of mitochondrial function and disease.
Molecular mechanism underlying the specific RNA recognition of mitochondrial helicase DDX28 and its critical role in mitoribosomal biogenesis.
Para-Benzoquinone (pBQ) Modifies Human Mitochondrial Phenylalanyl-tRNA Synthetase and Contributes to Mitochondrial Dysfunction.
Reduced levels of mitochondrial ribosomal protein MRPL54 does not alter Apc related adenoma formation.
EV-Encapsulated Mitochondrial miRNAs: Enhancing Cardiomyocyte Bioenergetics.
ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.

Nat Commun. 2026 Mar 10. pii: 2125. [Epub ahead of print]17(1):

Translational regulation by oxidative desulfuration of tRNA modifications.

Yufeng Mo, Kensuke Ishiguro, Kenjyo Miyauchi, Yuriko Sakaguchi, Yosei Hanzawa, Naho Akiyama, Ayaka Murayama, Kodai Machida, Hiroaki Imataka, Akio Yamashita, Takayuki Ohira, Mikako Shirouzu, Tsutomu Suzuki.

Modifications in the anticodon region of transfer RNA (tRNA) are essential for accurate and efficient protein synthesis. 5-Methyl-2-thiouridine derivatives (xm5s2U) are major modifications at the wobble position of tRNA anticodons decoding purine-ending two-codon sets. Although the thiocarbonyl group of xm5s2U enhances decoding efficiency, it is chemically susceptible to oxidative desulfuration, yielding 4-pyrimidinone derivatives (xm5h2U). Here, we identify xm5h2U derivatives in human cells and mouse tissues and confirm their cellular formation by spike-in experiments. Desulfurized tRNAs carrying 5-methoxycarbonylmethyl-4-pyrimidinone (mcm5h2U) show impaired codon recognition in a human reconstituted in vitro translation system. The mcm5h2U modification reduces aminoacylation of tRNAs for lysine, glutamate, and glutamine, but not arginine. Cryogenic electron microscopy reveals the structural basis of altered AAA/AAG decoding by mcm5h2U at the ribosomal A-site. These findings reveal a mechanism by which oxidative desulfuration of tRNA modifications dynamically regulates codon recognition and protein synthesis under oxidative stress conditions in human and mammalian cells.

DOI: https://doi.org/10.1038/s41467-026-70126-7
Nucleic Acids Res. 2026 Feb 24. pii: gkag208. [Epub ahead of print]54(5):

Purification of post-transcriptionally modified tRNAs for enhanced cell-free translation systems.

Evan M Kalb, Jose L Alejo, Leticia Dias-Fields, Isaac Knudson, Joshua A Davisson, Efren Maldonado, Kanokporn Chattrakun, Shangsi Lin, Jung Yeon Lee, Tianchen He, Alanna Schepartz, Shenglong Zhang, Scott C Blanchard, Aaron E Engelhart, Katarzyna P Adamala.

Transfer RNAs (tRNAs) are utilized by the ribosome to decode the nucleic acid alphabet. tRNA structure, stability, aminoacylation efficiency, and decoding efficacy are governed by their extensive post-transcriptional modifications. In most studies, individual tRNAs are generated using in vitro transcription, which produces tRNAs devoid of these critical site-specific modifications, negatively affecting translation yields and fidelity. To address this challenge, we have developed a purification method that couples tRNA overexpression to DNA hybridization-based purification. Using this approach, we produced native tRNAs from Escherichia coli in high yield and purity while retaining their complement of native post-transcriptional modifications and translational activity. We extend this technique to the purification of Mj-$tRNA_{CUA}^{Opt}$ and Ma-$tRNA_{CUA}^{Pyl}$, tRNAs of critical importance for genetic code expansion. We confirmed that both Mj-$tRNA_{CUA}^{Opt}$ and Ma-$tRNA_{CUA}^{Pyl}$ contain native E. coli post-transcriptional modifications and provide the first complete modification profiles of each. Moreover, we found that in vivo-generated Mj-$tRNA_{CUA}^{Opt}$ and Ma-$tRNA_{CUA}^{Pyl}\ $significantly outperform their in vitro-generated counterparts in amber codon suppression in cell-free translation reactions. Finally, we purified an engineered variant of E. coli$tRNA_{CCA}^{Trp}$, extending our studies to synthetic tRNAs. We present a flexible method that generates modified tRNAs in high yield and purity, addressing a critical and persistent challenge in RNA biochemistry.

DOI: https://doi.org/10.1093/nar/gkag208
Nat Commun. 2026 Mar 13.

Hypusination of the translation factor eIF5A regulates mitochondrial tRNA processing to promote prostate cancer aggressiveness.

Michel Kahi, Abigail Mazzu, Ludovic Batistic, Marc Pujalte-Martin, Victor Tiroille, Anne Vincent, Joseph Murdaca, Loic Trapani, Paraskevi Kousteridou, Oumayma Benaceur, Amine Belaid, Marie Irondelle, Emilie Thomas, Christelle Boscagli, Pierre Bertrand, Heather S Carr, Frédéric Larbret, Emilie Baudelet, Stéphane Audebert, Didier F Pisani, Silvère Baron, Luc Camoin, Mathieu Carlier, Matthieu Durand, Damien Ambrosetti, Yu Chen, Jean-Jacques Diaz, Arnaud Jacquel, Issam Ben-Sahra, Nathalie M Mazure, Pascal Peraldi, Frédéric Bost.

Protein synthesis plays a central role in cancer development and progression. eukaryotic initiation factor 5 A (eIF5A), a translation factor activated by hypusination, is implicated in tumorigenesis, however, its mode of action is still unclear. We find that hypusinated eIF5A (eIF5Ahyp) promotes metastasis and tumor growth in prostate cancer (PCa) by supporting mitochondrial metabolism and translation. eIF5Ahyp controls the subcellular localization of Mitochondrial Ribonuclease P Protein 3 (MRPP3) mRNA encoding a protein essential for mitochondrial tRNA (mt-tRNA) maturation. We show that eIF5Ahyp regulates the nuclear export of MRPP3 mRNA, its expression, thereby promoting mt-tRNA maturation. Our findings establish that MRPP3 enhances mitochondrial metabolism and supports PCa metastasis. Importantly, its expression restores mitochondrial translation and tumor growth inhibited by the downregulation of eIF5Ahyp. Together, we uncover a critical role for eIF5Ahyp in mitochondrial protein synthesis and highlight its broader implications in coordinating the expression of nuclear and mitochondrial genomes, linking hypusination to cancer progression.

DOI: https://doi.org/10.1038/s41467-026-70566-1
Cancer Treat Res Commun. 2026 Mar 04. pii: S2468-2942(26)00076-6. [Epub ahead of print]47 101165

Circular RNAs as emerging regulators of mitochondrial function and disease.

Mehrzad Esmaeili Niasan, Soudeh Ghafouri-Fard.

  Circular RNAs (circRNAs) are a class of covalently closed, non-coding RNAs that have emerged as regulators of gene expression and cellular homeostasis. Accumulating evidence shows that circRNAs are involved in the regulation of mitochondrial function, energy metabolism, and stress responses. Dysregulation of circRNAs has been linked to a wide range of mitochondrial-associated diseases, including neurodegenerative disorders, metabolic syndromes, cardiovascular diseases, and cancers. This review summarizes current knowledge on mitochondrial-related circRNAs, their biogenesis, molecular mechanisms, and pathophysiological roles, with a focus on their potential as diagnostic biomarkers and therapeutic targets.

Keywords:  Cancer; Mitochondria; Neurodegenerative disorder; circRNA

DOI:  https://doi.org/10.1016/j.ctarc.2026.101165
Structure. 2026 Mar 11. pii: S0969-2126(26)00051-1. [Epub ahead of print]

Molecular mechanism underlying the specific RNA recognition of mitochondrial helicase DDX28 and its critical role in mitoribosomal biogenesis.

Jing Cui, Meili Li, Lei Wang, Fudong Li, Ke Ruan, Mengqi Lv, Yunyu Shi.

  Mitochondrial ribosome biogenesis depends on RNA helicases such as DDX28, a DEAD-box helicase that plays an essential role during early mitoribosome large-subunit assembly by interacting with 16S rRNA. Here, we demonstrate that the helicase core domain of DDX28 binds sequence and structure specifically to the H88_L stem-loop in 16S rRNA, with the RecA2 domain residue M431 as a key determinant for substrate selectivity. The N-terminal disordered region of DDX28 enhances nonspecific RNA binding but does not contribute to enzymatic activity. Furthermore, DDX28 deficiency disrupts mitochondrial translation, impairs OXPHOS complex assembly, and leads to metabolic dysfunction, including reduced membrane potential, elevated ROS, and suppressed glycolysis. Transcriptomic and metabolomic analyses reveal a compensatory upregulation of ribosome biogenesis genes alongside a dysregulation of the TCA cycle, oxidative phosphorylation, and lipid metabolism. Our integrated structural and functional study establishes DDX28 as an essential factor for mitoribosome assembly with potential links to mitochondrial disorders.

Keywords:  DDX28; DEAD-box helicase; Mitabolic dysregulation; Mitochondrial dysfunction; RNA recognition

DOI:  https://doi.org/10.1016/j.str.2026.02.009
Chem Res Toxicol. 2026 Mar 11.

Para-Benzoquinone (pBQ) Modifies Human Mitochondrial Phenylalanyl-tRNA Synthetase and Contributes to Mitochondrial Dysfunction.

Debraj Roy, Soham Bose, Anwesha Das, Riya Manna, Dipanwita Roy, Shubhangini Singh Verma, Jagari Bhattacharjee, Surajit Das, Surajit Tudu, Rebecca E Steiner, Madhusudan Das, Nitin Chaudhary, Anirban Bhunia, Alok Ghosh, Michael Ibba, Rajat Banerjee.

Para-benzoquinone (pBQ) is of growing concern as an emerging redox-active environmental pollutant due to its ubiquitous presence in smoke and combustion byproducts. Recent reports have highlighted its potential role as a redox-driven mitotoxicant, although the involvement of specific mitochondrial protein targets remains unexplored. Here, we investigated the effects of pBQ on human mitochondrial phenylalanyl-tRNA synthetase (hmtPheRS), an essential enzyme required for mitochondrial protein synthesis and linked to severe neurodevelopmental disorders. Our biophysical analyses revealed that pBQ enhanced the formation of covalently modified higher-ordered structures of hmtPheRS by 75% and induced conformational instability, thereby significantly reducing its aminoacylation activity. NMR spectroscopy and molecular docking analyses further supported interactions between pBQ and residues within the catalytic domain of hmtPheRS, indicating the formation of a protein adduct. In parallel, exposure of HEK293 cells to sublethal concentrations of pBQ (20-40 μM) resulted in altered cellular redox homeostasis. It also impaired mitochondrial membrane potential and respiration, disrupted mitochondrial dynamics, and activated mitophagy. Consistent with the broad reactivity of pBQ and its ability to induce oxidative stress, these findings suggest that hmtPheRS is a vulnerable mitochondrial target whose modification may contribute to mitochondrial dysfunction, together with other redox-dependent pathways. Together, this work highlights mitochondrial aminoacyl-tRNA synthetases as an underexplored class of proteins susceptible to redox-active environmental pollutants.

DOI: https://doi.org/10.1021/acs.chemrestox.5c00493
PLoS One. 2026 ;21(3): e0344161

Reduced levels of mitochondrial ribosomal protein MRPL54 does not alter Apc related adenoma formation.

Claudia N Spaan, Eileen Daniels, Wouter L Smit, Ruben J de Boer, Joana Silva, Jacqueline L M Vermeulen, S Meisner, Vanesa Muncan, Riekelt H Houtkooper, Jarom Heijmans.

Reprogramming of energy metabolism is one of the hallmarks of cancer cells and mutations that modify wild type intestinal cells to colon carcinomas increases cellular energy expenditure. Mitochondria are the main site for ATP production in (cancer) cells and disrupting their function results in impaired tumor forming efficacy. The mitochondrial ribosomal proteins (MRPs) constitute the ribosome specifically in mitochondria, and as such are crucial for the translation process of the electron transport chain complex subunits. We hence aimed to explore the consequence of reduced MRP expression on adenomagensis and investigate this in a genetic mouse model with bodywide heterozygosity for Mrpl54. We show that Mrpl54 heterozygosity does not alter adenoma formation, intestinal proliferation or apoptosis in a heterozygous Apc model. Furthermore, diminished Mrpl54 expression did not decrease stemness or global parameters of metabolism in colorectal cancer cell lines.

DOI: https://doi.org/10.1371/journal.pone.0344161
Int J Mol Sci. 2026 Feb 26. pii: 2224. [Epub ahead of print]27(5):

EV-Encapsulated Mitochondrial miRNAs: Enhancing Cardiomyocyte Bioenergetics.

Dhienda C Shahannaz, Tadahisa Sugiura.

  Mitochondrial dysfunction lies at the core of numerous cardiac pathologies, yet restoring mitochondrial health remains a therapeutic frontier. In recent years, extracellular vesicles (EVs) have emerged as nature's delivery nanocarriers, capable of transporting a wide array of biomolecules, including mitochondrial-associated microRNAs (mito-miRs). These miRNAs regulate bioenergetics, redox homeostasis, and apoptotic signaling-making them prime candidates for non-cellular mitochondrial therapy. This review explores the evolving landscape of mitochondrial miRNA encapsulation within EVs, focusing on their potential to restore mitochondrial transcriptional and metabolic programs governing ATP synthesis and redox balance, enhance cellular energy output, and mitigate oxidative stress. We integrate insights from stem cell biology, RNA epigenetics, systems cardiology, and bioengineering, offering a unifying framework for therapeutic applications across ischemic heart disease, heart failure, and chemotherapy-induced cardiomyopathy. An integrative narrative synthesis of recent peer-reviewed literature was performed across major biomedical databases, prioritizing mechanistic studies linking EV-mediated mito-miR delivery to cardiomyocyte mitochondrial function. By harmonizing multi-omic signaling, vesicle engineering, and mitochondrial medicine, this review seeks to guide future research toward targeted, customizable, and scalable bioenergetic interventions-unlocking a next-generation path for cardiovascular regeneration.

Keywords:  RNA therapeutics; cardiomyocyte bioenergetics; extracellular vesicles (EVs); heart failure; miRNA engineering; mitochondrial microRNAs; non-cellular mitochondrial therapy; regenerative cardiology; systems biology; translational nanomedicine

DOI:  https://doi.org/10.3390/ijms27052224
Cell Rep. 2026 Mar 06. pii: S2211-1247(26)00104-X. [Epub ahead of print]45(3): 117026

ADAR1 regulates dsRNA formation in nuclear and mitochondrial transcripts through editing-dependent and -independent mechanisms.

Heegwon Shin, Tyler J Dorrity, Justin Aruda, Kenenni A Wiegand, Jung Seung Nam, Jiping Yang, Aidan S Jones, Jake A Gertie, Meera K Singh, Yuanjun Yin, Keer He, Rafan Sarker, Rajesh K Soni, Yousin Suh, Iok In Christine Chio, Silvi Rouskin, Hachung Chung.

  Endogenous (self) double-stranded RNAs (dsRNAs) in human cells can activate innate immune responses. ADAR1, an A-to-I editing enzyme of dsRNAs, suppresses aberrant immune activation by self-dsRNAs. However, how ADAR1 influences the cellular dsRNA landscape remains unclear. We show that human ADAR1 downregulates self-dsRNA abundance through editing-dependent and editing-independent mechanisms. We further conducted quantitative dsRNA sequencing on wild-type and ADAR1-deficient cells. dsRNAs are enriched in protein-coding mRNAs-especially those with repetitive elements and elongated 3' UTRs-and mitochondrial RNAs. ADAR1-regulated dsRNA transcripts consist of nuclear-encoded mRNAs and, unexpectedly, mitochondria-encoded RNAs rarely edited by ADAR1. Accordingly, dsRNAs accumulate to high levels within the mitochondria of ADAR1-deficient cells. Mass spectrometry and biochemical assays can detect ADAR1p150 in mitochondrial fractions. Notably, ADAR1 loss sensitizes cells to inflammation under mitochondrial stress (e.g., herniation and X-ray irradiation). Hence, we show that dsRNAs regulated by ADAR1 go beyond A-to-I edited transcripts and that ADAR1 can control mitochondrial dsRNAs.

Keywords:  A-to-I editing; ADAR1; AGS; Aicardi-Goutieres syndrome; CP: immunology; CP: molecular biology; IFN; PKR; double-stranded RNA; dsRNA; dsRNA-seq; innate immunity; mitochondria; mitochondrial stress; protein kinase R; type 1 interferon

DOI:  https://doi.org/10.1016/j.celrep.2026.117026