bims-mirnam 2026-02-01 papers

bims-mirnam

Biomed News

on Mitochondrial RNA metabolism

Issue of 2026–02–01
sixteen papers selected by
Hana Antonicka, McGill University

RNA modifications in cancer and their detection: a review.
Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease.
Mapping RNA-Binding Proteins on the Ribosome by Tethered Micrococcal Nuclease.
Mitochondria as sources and targets of cellular signaling.
Pleiotropic regulation of mitochondrial translational factors in governing proliferation, apoptosis and metastasis during cancer progression.
Molecular Insights into Widespread Pseudouridine RNA Modifications: Implications for Women's Health and Disease.
Ab initio detection of multiple epitranscriptomic modifications from Oxford nanopore technology direct RNA sequencing data.
Decoding RNA-Protein interactions using high-throughput methods.
EPR spectroscopy in the study of ribosomal complexes.
Structures of naked mole-rat, tuco-tuco, and guinea pig ribosomes-is rRNA fragmentation linked to translational fidelity?
Overcoming chemoresistance in nasopharyngeal carcinoma: minocycline as a mitochondrial translation inhibitor.
Ribosomal RNA methylation in HSCs: it's so "good for you".
Dual-TERM enables simultaneous profiling of 5' and 3' terminal modifications in small RNAs by integrating enzymatic treatment with PBA-PAGE.
ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.
Deficient mitochondrial tRNA modifications arising from TRMU mutation led to the liver-specific failure.
Assessment of phylogenetic informativeness in mitochondrial and nuclear genes for mammalian systematics using sparse learning.

Jpn J Clin Oncol. 2026 Jan 30. pii: hyag018. [Epub ahead of print]

RNA modifications in cancer and their detection: a review.

Bo-Yi Yu, Hiroki Ueda.

  Ribonucleic acid (RNA) modifications, once viewed as static structural features, are now recognized as dynamic regulators of the 'epitranscriptome' that shape RNA fate. In cancer, dysregulation of RNA-modification writers, erasers, and readers reprograms RNA metabolism and translation, promoting tumorigenesis, metastasis, therapy resistance, and immune evasion. Across messenger RNAs, ribosomal RNA (rRNAs), transfer (tRNAs), and diverse non-coding RNAs, aberrant modification patterns drive alternative splicing, generate onco-ribosomes, enforce codon-biased translation, and remodel gene-expression networks in a context-dependent manner. This review summarizes how major RNA modifications-including m6A, m5C, pseudouridine, inosine, and ac4C-and their regulators contribute to cancer biology, together with disease-associated changes in rRNA, tRNA, and regulatory non-coding RNAs. We then discuss emerging diagnostic and prognostic biomarkers, druggable nodes within the epitranscriptomic machinery, and combination strategies that integrate RNA-modification targeting with existing therapies and immunotherapy. Finally, we outline key technologies for mapping RNA modifications, comparing mass spectrometry and NGS-based chemical or antibody-enrichment approaches with the expanding capabilities of nanopore direct RNA sequencing. Recent advances in nanopore direct RNA sequencing technologies, leveraging new chemistry (e.g. RNA004) and deep-learning basecallers (e.g. Dorado), increasingly enable single-molecule, multi-modification profiling, accelerating discovery despite inherent technical challenges. Collectively, biological, clinical, and technological progress is transforming the epitranscriptome into a tractable dimension of cancer biology and a promising source of future biomarkers and RNA-targeted precision therapies.

Keywords:  RNA modifications; nanopore direct RNA sequencing; non-coding RNA

DOI:  https://doi.org/10.1093/jjco/hyag018
Cells. 2026 Jan 10. pii: 127. [Epub ahead of print]15(2):

Targeting of Human Mitochondrial DNA with Programmable pAgo Nuclease.

Beatrisa Rimskaya, Ekaterina Kropocheva, Elza Shchukina, Egor Ulashchik, Daria Gelfenbein, Lidiya Lisitskaya, Vadim Shmanai, Svetlana Smirnikhina, Andrey Kulbachinskiy, Ilya Mazunin.

  Manipulating the mitochondrial genome remains a significant challenge in genetic engineering, primarily due to the mitochondrial double-membrane structure. While recent advances have expanded the genetic toolkit for nuclear and cytoplasmic targets, precise editing of mitochondrial DNA (mtDNA) has remained elusive. Here we report the first successful mitochondrial import of a catalytically active RNA-guided prokaryotic Argonaute protein from the mesophilic bacterium Alteromonas macleodii (AmAgo). By guiding AmAgo to the single-stranded D- or R-loop region of mtDNA using synthetic RNA guides, we observed a nearly threefold reduction in mtDNA copy number in human cell lines. This proof of concept study demonstrates that a bacterial Argonaute can remain active within the mitochondrial environment and influence mtDNA levels. These findings establish a foundational framework for further development of programmable systems for mitochondrial genome manipulation.

Keywords:  DNA editing; mitochondria; mtDNA copy number; prokaryotic Argonaute proteins

DOI:  https://doi.org/10.3390/cells15020127
Biochemistry. 2026 Jan 26.

Mapping RNA-Binding Proteins on the Ribosome by Tethered Micrococcal Nuclease.

Chia Yi Yao, Simpson Joseph.

RNA-binding proteins (RBPs) are essential regulators of posttranscriptional gene expression, influencing mRNA processing, translation, and stability. Defining their binding sites on RNA is key to understanding how they assemble into functional ribonucleoprotein (RNP) complexes, but existing footprinting and cross-linking approaches often yield low signal-to-noise, variable efficiency, or require highly purified complexes. To address these limitations, we developed Tethered Micrococcal Nuclease Mapping (TM-map), a sequencing-based strategy that determines the three-dimensional binding sites of RBPs on RNA in vitro. In TM-map, the RBP is fused to micrococcal nuclease (MNase), which upon Ca2+ activation cleaves proximal RNA regions, producing fragments whose 3' termini report the spatial proximity of the fusion. We first validated TM-map using the bacteriophage MS2 coat protein bound to its cognate RNA stem-loop engineered into the Escherichia coli ribosome. Cleavage sites mapped proximal to the engineered stem-loop, confirming that tethered MNase reliably reports local protein-RNA proximity on the ribosome surface. We then applied TM-map to the Drosophila Fragile X Mental Retardation Protein (FMRP), a translational regulator with an unresolved ribosome-binding site. Both N- and C-terminal MNase-FMRP fusions produced reproducible cleavage clusters on the 18S rRNA localized to the body and head of the 40S subunit. The similar profiles suggest that FMRP's termini are conformationally flexible and sample multiple orientations relative to the ribosome, consistent with a dynamic interaction rather than a fixed binding mode. TM-map thus provides a simple, proximity-based, and generalizable in vitro approach for visualizing RBP-RNA interactions within native RNP assemblies.

DOI: https://doi.org/10.1021/acs.biochem.5c00660
Mol Cell. 2026 Jan 28. pii: S1097-2765(26)00028-6. [Epub ahead of print]

Mitochondria as sources and targets of cellular signaling.

Anna Meichsner, Verian Bader, Konstanze F Winklhofer.

  Mitochondria are multifunctional organelles that, in addition to providing energy, coordinate various signaling pathways essential for maintaining cellular homeostasis. Their suitability as signaling organelles arises from a unique combination of structural and functional plasticity, allowing them to sense, integrate, and respond to a wide variety of cellular cues. Mitochondria are highly dynamic-they can fuse and divide, pinch off vesicles, and move around, facilitating interorganellar communication. Moreover, their ultrastructural peculiarities enable tight regulation of fluxes across the inner and outer mitochondrial membranes. As organelles of proteobacterial origin, mitochondria harbor danger signals and require protection from the consequences of membrane damage by efficient quality control mechanisms. However, mitochondria have also been co-opted by eukaryotic cells to react to cellular damage and promote effective immune responses. In this review, we provide an overview of our current knowledge of mitochondria as both sources and targets of cellular signaling.

Keywords:  ISR; MAVS; NEMO; NF-κB; UPRmt; cGAS/STING; cardiolipin; inflammation; innate immune signaling; membrane contact sites; mitochondria; mtDNA; mtRNA; signaling

DOI:  https://doi.org/10.1016/j.molcel.2026.01.008
World J Clin Oncol. 2026 Jan 24. 17(1): 113600

Pleiotropic regulation of mitochondrial translational factors in governing proliferation, apoptosis and metastasis during cancer progression.

Nikita Agarwal, Uttam Sharma, Akshi Shree, Rajiv Ranjan Kumar, Jaya Kanta Gorain, Vaishnavi Vishwas, Farhana Jahan, Archna Singh, Jayanth Kumar Palanichamy, Deepam Pushpam, Radhika Bakhshi, Anita Chopra, Ranjit Kumar Sahoo, Atul Batra, Surender K Sharawat, Sameer Bakhshi.

  Mitochondrial translation relies on the coordinated activity of mitoribosomes, mitochondrial ribosome proteins, mitochondria-specific transfer RNAs, and dedicated translation factors, including mitochondrial initiation factor 2/3, mitochondrial elongation factor Tu, mitochondrial elongation factor Ts, mitochondrial elongation factor G1/G2, mitochondrial elongation factor 4, mitochondrial ribosome recycling factor, and mitochondrial release factor 1A. These components collectively drive the synthesis of 13 essential polypeptides encoded by mitochondrial DNA, all constituting subunits of the oxidative phosphorylation complexes. Although mitochondrial metabolism is increasingly recognized as a key player in cancer, the specific contribution of mitochondrial translation to cancer progression remains poorly explored. This gap in knowledge limits our understanding of how mitochondrial dysfunction contributes to tumor initiation, progression, and therapy resistance. Herein, in this review, we highlight how dysregulation of mitochondrial translation factors can influence major cancer hallmarks such as sustained proliferative signaling, resistance to apoptosis, and increased invasion and metastasis. In addition, we discuss the known molecular mechanisms that link defects in mitochondrial translation to oncogenic features. We also consolidate current insights into the mitochondrial translation machinery and discuss recent evidence of its role in cancer, aiming to emphasize mitochondrial translation as a contributor to malignancy and a potential therapeutic target.

Keywords:  Cancer; Hallmark; Mitochondrial ribosomal proteins; Mitochondrial translation; Mitochondrial translation factors

DOI:  https://doi.org/10.5306/wjco.v17.i1.113600
Biology (Basel). 2026 Jan 14. pii: 142. [Epub ahead of print]15(2):

Molecular Insights into Widespread Pseudouridine RNA Modifications: Implications for Women's Health and Disease.

Qiwei Yang, Ayman Al-Hendy, Thomas G Boyer.

  Pseudouridine (Ψ), the most abundant RNA modification, plays essential roles in shaping RNA structure, stability, and translational output. Beyond cancer, Ψ is dynamically regulated across numerous physiological and pathological contexts-including immune activation, metabolic disorders, stress responses, and pregnancy-related conditions such as preeclampsia-where elevated Ψ levels reflect intensified RNA turnover and modification activity. These broad functional roles highlight pseudouridylation as a central regulator of cellular homeostasis. Emerging evidence demonstrates that Ψ dysregulation contributes directly to the development and progression of several women's cancers, including breast, ovarian, endometrial, and cervical malignancies. Elevated Ψ levels in tissues, blood, and urine correlate with tumor burden, metastatic potential, and therapeutic responsiveness. Aberrant activity of Ψ synthases such as PUS1, PUS7, and the H/ACA ribonucleoprotein component dyskerin alters pseudouridylation patterns across multiple RNA substrates, including rRNA, tRNA, mRNA, lncRNAs, snoRNAs, and ncRNAs. These widespread modifications reshape ribosome function, modify transcript stability and translational efficiency, reprogram RNA-protein interactions, and activate oncogenic signaling programs. Advances in high-resolution, site-specific Ψ mapping technologies have further revealed mechanistic links between pseudouridylation and malignant transformation, highlighting how modification of distinct RNA classes contributes to altered cellular identity and tumor progression. Collectively, Ψ and its modifying enzymes represent promising biomarkers and therapeutic targets across women's cancers, while also serving as sensitive indicators of diverse non-cancer physiological and disease states.

Keywords:  RNA modification; epitranscriptomics; female cancers; gynecological diseases; pseudouridine; pseudouridine synthases; reproductive biology; sex-specific regulation; women health

DOI:  https://doi.org/10.3390/biology15020142
Brief Bioinform. 2026 Jan 07. pii: bbaf709. [Epub ahead of print]27(1):

Ab initio detection of multiple epitranscriptomic modifications from Oxford nanopore technology direct RNA sequencing data.

Adriano Fonzino, Bruno Fosso, Grazia Visci, Carmela Gissi, Graziano Pesole, Ernesto Picardi.

  Charting the eukaryotic epitranscriptome by direct RNA sequencing is promising but still very challenging, as current bioinformatics tools are based on modification-unaware software and require multiple modification-specific learning steps. Here, we introduce NanoSpeech, a modification-aware basecaller for the ab initio simultaneous detection of multiple modified bases using a transformer model, and NanoListener, which implements a simulated randomers strategy for robust training datasets and a new generation of ONT basecallers. NanoListener and NanoSpeech are independent of the specific ONT chemistry. Once a training dataset has been created, a single model with an expanded vocabulary can accurately basecall both unmodified and modified bases.

Keywords:  ONT RNA basecalling; RNA editing; RNA modifications; direct RNA sequencing; epitranscriptomics

DOI:  https://doi.org/10.1093/bib/bbaf709
RNA Biol. 2026 Jan 28.

Decoding RNA-Protein interactions using high-throughput methods.

Marianne Régis, Paola Pulcina, Dmitry Kretov.

  RNA-binding proteins (RBPs) constitute a diverse class of proteins essential for every stage of gene expression process. Many RBPs are also linked to human diseases and pathologies. Understanding the molecular grammar of RNA-protein interactions is critical for deciphering the regulatory RNA code. This review provides a comprehensive overview of Massively Parallel Binding Assays (MPBAs), high-throughput techniques that use large libraries of RNA or protein variants to systematically investigate RNA - protein interactions. We describe the underlying principles of both in vitro and in vivo approaches, their applications, as well as their strengths and weaknesses. We conclude by outlining future directions and challenges in the field that will help drive the development of novel methods to better understand the RBP recognition code.

Keywords:  RNA-binding proteins; RNA-protein interactions; high-throughput approaches; massively parallel binding assays; microRNAs; sequence space

DOI:  https://doi.org/10.1080/15476286.2026.2623240
Biophys Rev. 2025 Oct;17(5): 1215-1231

EPR spectroscopy in the study of ribosomal complexes.

Olesya Krumkacheva, Alexey Malygin, Dmitri Graifer, Mikhail Kolokolov, Elena Bagryanskaya.

  Protein synthesis is a fundamental biological process universally mediated by ribosomes-complex ribonucleoprotein assemblies responsible for translating genetic information into functional proteins. Despite significant structural information provided by X-ray crystallography and cryo-electron microscopy (cryo-EM), certain dynamic features of ribosomal function, particularly those involving RNA conformational flexibility and transient interactions, remain challenging to characterize. Electron Paramagnetic Resonance (EPR) spectroscopy, combined with site-directed spin labeling (SDSL), has emerged as a robust complementary approach for probing structural dynamics and conformational heterogeneity in ribosomal complexes. This review summarizes recent advances in applying EPR spectroscopy, particularly pulse dipolar EPR (DEER/PELDOR), to investigate human ribosomal complexes. We discuss methodological aspects of spin-labeling strategies for mRNA, comparing various nitroxide-based labels and highlighting their specific advantages for probing ribosomal interactions. Through representative examples, we illustrate how different EPR techniques yield complementary structural information in studying ribosome-RNA interactions. Key findings include the identification of alternative mRNA conformations within ribosomal complexes, characterization of labile RNA binding sites near the mRNA entry channel, and elucidation of stabilization effects mediated by tRNA interactions. Furthermore, we demonstrate how the integration of EPR data with molecular modeling facilitates accurate interpretation of distance distributions, enabling the correlation of experimental findings with atomic-level structural models. Finally, we address current methodological limitations of EPR spectroscopy, outlining promising perspectives and anticipated advancements in this evolving field.

Keywords:  Conformational heterogeneity; DEER/PELDOR; EPR spectroscopy; Pulse dipolar EPR; RNA; Ribosome; Translation; mRNA dynamics

DOI:  https://doi.org/10.1007/s12551-025-01348-0
Nucleic Acids Res. 2026 Jan 22. pii: gkag006. [Epub ahead of print]54(3):

Structures of naked mole-rat, tuco-tuco, and guinea pig ribosomes-is rRNA fragmentation linked to translational fidelity?

Cristina Gutierrez-Vargas, Swastik De, Suvrajit Maji, Zheng Liu, Zhonghe Ke, Martina Nieß, Andrei Seluanov, Vera Gorbunova, Joachim Frank.

Ribosomes are central to protein synthesis in all organisms. In mammals, the ribosome functional core is highly conserved. Remarkably, two rodent species, the naked mole-rat (NMR) and tuco-tuco, display fragmented 28S ribosomal RNA (rRNA), coupled with high translational fidelity and long lifespan. The unusual ribosomal architecture in the NMR and tuco-tuco has been speculated to be linked to high translational fidelity. Here, we show, by single-particle cryo-electron microscopy, that despite the fragmentation of their rRNA, NMR and tuco-tuco ribosomes retain their core functional architecture. Compared to ribosomes of the guinea pig, a phylogenetically related rodent without 28S rRNA fragmentation, ribosomes of NMR and tuco-tuco exhibit poorly resolved density for certain expansion segments. In contrast, the structure of the guinea pig ribosome shows high similarity to the human ribosome. Enhanced translational fidelity in the NMR and tuco-tuco may stem from subtle, allosteric effects in dynamics, linked to rRNA fragmentation.

DOI: https://doi.org/10.1093/nar/gkag006
Discov Oncol. 2026 Jan 27.

Overcoming chemoresistance in nasopharyngeal carcinoma: minocycline as a mitochondrial translation inhibitor.

Fang Xiang, Qiong Dai, Wei Chen.

  Chemo-resistance poses a major challenge in nasopharyngeal carcinoma (NPC) treatment, necessitating novel therapeutic approaches. Through a chemical screen, we identified minocycline as a selective inhibitor of chemo-resistant NPC cells, demonstrating potent cytotoxicity while sparing non-cancerous cells. Mechanistically, minocycline inhibited mitochondrial translation, leading to reduced activities of mitochondrial complexes I and IV, impaired oxygen consumption, and disrupted mitochondrial respiration. Its cytotoxic effects were dependent on oxygen availability and an intact mitochondrial respiratory chain, as evidenced by its diminished efficacy under anoxic conditions. Genetic knockdown of mitochondrial elongation factor Tu (EF-Tu), a critical regulator of mitochondrial translation, mimicked the effects of minocycline, further validating mitochondrial translation as a therapeutic target. In a chemo-resistant NPC xenograft model, minocycline significantly suppressed tumor growth, reduced Ki-67 expression, and impaired mitochondrial function in tumor-derived cells. These findings highlight mitochondrial translation inhibition as a promising strategy to overcome chemo-resistance in NPC and identify minocycline as a potential therapeutic agent.

Keywords:  Chemoresistance; EF-Tu; Minocycline; Mitochondrial translation; Nasopharyngeal carcinoma

DOI:  https://doi.org/10.1007/s12672-025-03598-6
Blood. 2026 Jan 29. 147(5): 476-478

Ribosomal RNA methylation in HSCs: it's so "good for you".

Judith López, Konstantinos Tzelepis.

DOI: https://doi.org/10.1182/blood.2025032073
Int J Biol Macromol. 2026 Jan 23. pii: S0141-8130(26)00393-4. [Epub ahead of print]344(Pt 1): 150467

Dual-TERM enables simultaneous profiling of 5' and 3' terminal modifications in small RNAs by integrating enzymatic treatment with PBA-PAGE.

Huiru Yang, Bin Zhang, Sijing Zhu, Shuaibiao Zhang, Xiaofei Yu, Lei Zhang, Guodong Ren, Susu Chen.

  Small RNAs carry diverse terminal modifications that reflect their biogenesis and affect their stability and function. However, simultaneously discriminating these modifications remains challenging with existing methods. Here, we present Dual TERminal Modification analysis (Dual-TERM), a gel-based strategy that integrates enzymatic pretreatment with phenylboronic acid polyacrylamide gel electrophoresis (PBA-PAGE) to resolve 5' and 3' terminal modifications in small RNAs. Using synthetic RNAs, we demonstrated that Dual-TERM reliably distinguished four major 3' terminal ribose modifications (3'-OH, 3'-Nm, 3'-P, and 3'-cP) based on large band shifts and detected 5' phosphorylation status based on slight mobility changes. We validated the method with endogenous small RNAs-including miRNAs, piRNAs, and 5' tRNA halves-from mammals and plants, confirming species-specific modification patterns. With its simplicity and sensitivity, Dual-TERM provides a versatile tool for characterizing terminal modifications in small RNAs and has the potential to be adapted for high-throughput profiling when coupled with next-generation sequencing.

Keywords:  Polyacrylamide gel electrophoresis; Small RNAs; Terminal modification

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150467
Nat Commun. 2026 Jan 29.

ALKB-1-dependent tRNA methylation is required for efficient paternal mitochondrial elimination.

Zhenhuan Luo, Yimin Li, Chenyang He, Dan Wu, Wenyu Dai, Liubing Hu, Jing Yang, Brian L Harry, Zhenyu Ju, Nektarios Tavernarakis, Hao Wang, Qin-Li Wan, Qinghua Zhou.

Maternal mitochondrial inheritance is secured by mechanisms that exclude paternal mitochondrial DNA (mtDNA). While, epigenetic modifications are vital for spermatogenesis and embryo development, their roles in the paternal mitochondrial elimination (PME) remain poorly understood. Here, we identify ALKB-1, a DNA/RNA demethylase, as a pivotal factor for efficient PME in Caenorhabditis elegans (C. elegans), acting through ALKB-1-dependent modulation of tRNA m1A methylation. Mechanistically, ALKB-1 inactivation leads to m1A hypermethylation of tRNA, which subsequently disrupts protein translation, impairs mitochondrial proteostasis, and increases ROS levels. This cascade activates the oxidative stress response factor SKN-1/Nrf2 and initiates the mitochondrial unfolded protein response (UPRmt) through ATFS-1, causing accumulation of mitochondria and mtDNA in sperm, which ultimately impedes efficient paternal mitochondrial removal and negatively impacts male fertility and embryonic development. Our findings describe a mechanism whereby ALKB-1-mediated tRNA m1A epitranscriptomic modifications are necessary for maintaining mitochondrial quality control, thereby influencing PME efficiency, underscoring the importance of this epitranscriptomic stress checkpoint in upholding proper mitochondrial inheritance during reproduction.

DOI: https://doi.org/10.1038/s41467-026-68813-6
J Biol Chem. 2026 Jan 22. pii: S0021-9258(26)00038-4. [Epub ahead of print] 111168

Deficient mitochondrial tRNA modifications arising from TRMU mutation led to the liver-specific failure.

Xiao He, Qinghai Zhang, Chao Chen, Yutao Wu, Kai Wang, Shihao Yao, Haiyan Sun, Min-Xin Guan.

Posttranscriptional nucleotide modifications of tRNAs play the critical roles in their structure and function. Deficient τm5s2U modifications of mitochondrial tRNAGlu, tRNAGln and tRNALys arising from TRMU mutations primarily manifest the liver failure. However, mechanisms of tissue specificity in TRMU-induced deficiencies remain largely elusive. In this report, we demonstrated that the loss of τm5s2U in mitochondrial tRNAs due to TRMU-deficiency caused the tissue-specific manifestation that contributed to pathogenesis of liver failures in the zebrafish. A wide range levels of τm5s2U in tRNALys, tRNAGlu, and tRNAGln occurred across the zebrafish brain, muscle, eye, liver and ovum tissues. Striking differences in tissue-specific effects of conformation, stability and aminoacylation of tRNAGlu, tRNALys and tRNAGln were observed among five tissues of trmu knockout (KO) zebrafish. Notably, livers are vulnerable to the loss of τm5s2U of tRNAs, evidenced by more severe failures in these tRNA metabolisms including conformation, instability and aminoacylation in liver than those in other four tissues of trmuKO zebrafish. These aberrant tRNA metabolisms altered the assembly, stability, and activities of complexes I, III and IV, especially pronounced in the liver of trmuKO zebrafish. Notably, livers displayed the highest ratios in the levels and activities of complex I to complex II in across five tissues, indicating the liver-specific electron flow preferences through complex I to coenzyme Q to complex III. These tissue-specific complex I deficiencies manifested the liver failures including hepatic steatosis and enlargement. Our findings provide new insights into the mechanism of liver-specific defects arising from the aberrant nucleotide modification of mitochondrial tRNAs.

DOI: https://doi.org/10.1016/j.jbc.2026.111168
Front Bioinform. 2025 ;5 1704212

Assessment of phylogenetic informativeness in mitochondrial and nuclear genes for mammalian systematics using sparse learning.

Carlos G Schrago, Beatriz Mello.

  Despite the growing availability of nuclear genomic data, mitochondrial genes remain the most widely used molecular markers in mammalian systematics. However, a quantitative assessment of the phylogenetic information content of mitochondrial loci compared to nuclear loci has never been carried out. Here, we apply a sparse learning approach based on Lasso regression to evaluate the contribution of alignment sites to phylogenetic likelihoods, providing the first estimates of phylogenetically effective lengths for markers commonly used in mammalian systematics. Analyzing more than 30,000 complete mammalian mitochondrial genomes and nuclear panels composed of either 100 randomly selected complete coding sequences or of partial gene segments from conventional markers, we examined phylogenetic informativeness at two taxonomic levels: within-species and among-species. On average, ∼32% of mitochondrial sites and ∼38% of nuclear sites were classified as phylogenetically informative. We found that the number of phylogenetically informative sites were positively correlated with total gene length. Therefore, longer mitochondrial genes, particularly ND5, COX1, and CYTB, harbored the largest numbers of informative sites. Although nuclear coding sequences contained, on average, more informative sites, mitochondrial genes also yielded consistent resolution of among-species relationships. Overall, our results provide the first large-scale, quantitative comparison of phylogenetic information content across mammalian mitochondrial and nuclear genes, offering a principled framework for marker selection in future systematics studies that can be broadly applied to any lineage.

Keywords:  Lasso regression; mitochondrial genome; molecular taxonomy; phylogenetic informativeness; phylogenetic signal; sparse learning; species delimitation

DOI:  https://doi.org/10.3389/fbinf.2025.1704212