bims-mirnam 2026-06-07 papers

Issue of 2026–06–07
six papers selected by
Hana Antonicka, McGill University

Hum Mol Genet. 2026 Jun 01. pii: ddag042. [Epub ahead of print]35(10):

MRPS22 variants alter mitochondrial ribosome assembly in patients with leukodystrophy, movement disorder and intellectual impairment.

Ruth I C Glasgow, Finn Lennartsson, Snjolaug Arnardottir, Dmitrii Igorevich Shiriaev, Sandrina P Correia, Marco Moedas, Lucía Peña-Pérez, Martin Paucar, Karin Naess, Helene Bruhn, Nicole Lesko, Rolf Wibom, Joanna Rorbach, Christoph Freyer, Anna Wedell, Sofia Ygberg, Erik A Eklund, Anna Wredenberg.

Mitochondrial diseases are clinically and genetically heterogeneous, often complicating diagnosis. Here, we describe four unrelated individuals with suspected mitochondrial disease who shared similar neuroimaging features, including bilateral symmetrical supra- and infratentorial white-matter abnormalities, together with variable movement disorders and intellectual impairment. Whole-genome sequencing identified the same homozygous MRPS22 variant (c.798_799delinsTA) in all four patients. MRPS22 encodes a component of the mitochondrial small ribosomal subunit (mtSSU). Functional studies in patient-derived fibroblasts showed impaired mitoribosome assembly and reduced de novo mitochondrial translation. Despite largely preserved steady-state levels of OXPHOS proteins, respiratory chain analysis identified a mild, isolated complex I deficiency. Proteomic profiling revealed reduced levels of mitochondrial ribosomal proteins and dysregulation of mitochondrial translation pathways. In line with the proteomic findings, RNA sequencing of fibroblasts from three patients revealed a distinct transcriptional signature compared with controls, with mitochondrial translation emerging as the most affected pathway. Mitochondrial-encoded transcripts were decreased, whereas nuclear-encoded mitochondrial genes were generally increased. Structural modelling suggested that the variant disrupts key interactions important for mitoribosome stability. While previously reported MRPS22 variants have been associated with severe, often prenatal-onset disease, the individuals described here exhibited a milder phenotype, thereby expanding the clinical spectrum of MRPS22-related disorders. Together, these findings support the pathogenicity of this variant and highlight the value of integrated genomic and functional analyses in diagnosing mitochondrial disease.

Keywords: MRPS22; adult-onset; mS22; mitochondrial ribosome; translation

DOI: https://doi.org/10.1093/hmg/ddag042

bioRxiv. 2026 May 19. pii: 2026.05.18.725941. [Epub ahead of print]

Mapping the interactome of human tRNA methyltransferase TRMT1 using dual proximity labeling.

Angel D'Oliviera, Sophie Olson, Harrison Bernhard, Yanbao Yu, Jeffrey S Mugridge.

Transfer RNA methyltransferase 1 (TRMT1) installs N2-methylguanosine and N2,N2-dimethylguanosine modifications at position 26 of mammalian tRNAs, supporting tRNA structure, translation, and cellular response to redox stress. However, the local environment and interactome of TRMT1 in the cell is poorly defined. Here, we use APEX2-based proximity labeling of the N- and C-terminus of TRMT1, coupled with label-free quantitative proteomics to map candidate TRMT1-proximal proteins in HEK293T cells. Mass spectrometry data was acquired using both data-independent acquisition (DIA) and data-dependent acquisition (DDA) methods, and it was found that DIA substantially increased proximity proteome coverage, reproducibility, and the number of significantly enriched candidate hits compared to the DDA method. N- and C-terminal APEX2-TRMT1 constructs captured largely overlapping proteomes, suggesting the dual-labeling strategy provides a robust map of proximal proteins. Analysis of the significant TRMT1-proximal proteins reveals enrichment in RNA processing and ribonucleoprotein-associated factors, in addition to hits connected to tRNA modification, tRNA biogenesis, and redox-associated biology. These data provide a proteome-scale view of TRMT1-associated cellular proteins and environments, and lay the groundwork for future validation of functional TRMT1 interaction networks.
Significance: Fusing APEX2 enzyme to both N-terminal and C-terminal of the bait enhanced the sensitivity for identification of protein interactions.Combining APEX2-based endogenous labeling with DIA mass spectrometry increases reproducibility and depth of proximity proteome.The study provides a rich source of potential interacting or proximally close proteins to TRMT1, which warrants further validation studies.

DOI: https://doi.org/10.64898/2026.05.18.725941

Nat Commun. 2026 May 30.

Mitochondrial RNA degradation regulates differentiation, stemness, and immune sensitivity in acute myeloid leukemia.

Geethu Emily Thomas, Veronique Voisin, Kazem Nouri, Rose Hurren, Karen Kai-Lin Fang, Ali Chegini, Marcela Gronda, Yongran Yan, Neil MacLean, Yulia Jitkova, Dakai Ling, Mary Ma, Xiao Ming Wang, Andrea Arruda, Vito Spadavecchio, Mark D Minden, Li Zhang, Jong Bok Lee, Aaron D Schimmer.

Eukaryotic cells have separate genomes in the nucleus and mitochondria. Mitochondrial DNA is transcribed bi-directionally to generate mitochondrial RNA (mtRNA) and dsRNA as a by-product of this transcription. We demonstrate that mtRNA transcription and degradation are increased in AML (Acute Myeloid Leukemia) cells and stem cells resulting in higher rates of mtRNA turnover. We discover that the mitochondrial degradosome, SUV3 and PNPase, is upregulated in AML cells and stem cells and functionally important for degradation of mtRNA and mitochondrial dsRNA (double stranded RNA) in AML. Depleting SUV3 or PNPase impairs mtRNA degradation and promotes the accumulation of dsRNA. dsRNA that accumulates after depleting SUV3 or PNPase, stimulates IFN-I signaling that induces AML differentiation, decreases stemness and increases sensitivity to immune-mediating cytotoxicity. Thus, this work highlights mitochondrial RNA regulation in AML and identifies a mechanism by which mtRNA turnover influences AML differentiation, stem cell function, and immune sensitization.

DOI: https://doi.org/10.1038/s41467-026-73558-3

Acta Pharmacol Sin. 2026 Jun 03.

Echoes in the powerhouse: mito-lncRNAs contribution to cardiac function and disease.

Abdallah Iddy Chaurembo, Na Xing, Zi-Feng Huang, Baraka Simon Mayamba, Francis Chanda, Yun-Tao Liang, Yong-Fang Lin, Wen-Hui Deng, Jian-Yuan Huang, Zeng-Yu He, Zheng Tan, Chi Shu, Han-Bin Lin.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, and its progression is closely linked to mitochondrial dysfunction in cardiomyocytes. Given the high energy demands of the heart, precise regulation of mitochondrial homeostasis, including oxidative phosphorylation, reactive oxygen species balance, calcium handling, and mitophagy, is essential for maintaining cardiac function. Emerging evidence has identified mitochondrial-associated long non-coding RNAs (mito-lncRNAs) as important regulators of these processes. Mito-lncRNAs comprise both nuclear-encoded transcripts that translocate to mitochondria and mitochondrial genome-encoded lncRNAs that function within the organelle. These molecules modulate mitochondrial gene expression, respiratory chain stability, metabolic flux, and stress responses, thereby influencing the pathogenesis of acute myocardial infarction, heart failure, diabetic cardiomyopathy, pulmonary hypertension, and cardiac remodeling. In this review, we categorize mito-lncRNAs based on their genomic origin and mitochondrial localization and summarize their mechanistic roles in cardiovascular physiology and disease. Moreover, the review highlights context-dependent effects of key transcripts such as LIPCAR, MALAT1, RMRP, H19, and lncND5. We further discuss the emerging value of mito-lncRNAs as circulating biomarkers and examine the major challenges that currently limit therapeutic translation, including cardiac- and mitochondrial-specific delivery, mechanistic ambiguity, species conservation, and technical limitations in detection. A deeper understanding of mito-lncRNA biology may provide new insights into mitochondrial regulation in the heart and inform the development of novel diagnostic and therapeutic strategies for CVDs.

Keywords: Mito-lncRNA; cardiovascular diseases; mitochondrial dysfunction; non-coding RNA

DOI: https://doi.org/10.1038/s41401-026-01830-9

Genome Biol. 2026 May 30.

FIRST-seq: a nanopore-based cDNA sequencing platform for RNA modification and structure profiling.

Oguzhan Begik, Gregor Diensthuber, Ivana Borovska, John S Mattick, Danny Incarnato, Eva Maria Novoa.

RNA modifications induce reverse transcription (RT) errors in an enzyme- and context-dependent manner, enabling transcriptome-wide mapping and RNA structure probing. We present FIRST-seq, a flexible, cost-effective nanopore cDNA method that avoids second-strand synthesis and PCR, making it compatible with any RT enzyme and enabling single-nucleotide resolution RT signature analysis. Benchmarking multiple RT enzymes and buffers identified conditions that reduce premature termination and enhance error detection. Coupled with DMS probing, FIRST-seq accurately detects m1A and m3C at unpaired sites, recapitulating known RNA structures in vitro and in vivo. FIRST-seq offers a versatile platform for profiling chemical-induced and natural RNA modifications using long-read sequencing.

DOI: https://doi.org/10.1186/s13059-026-04115-w

Dis Model Mech. 2026 Jun 01. pii: dmm.052690. [Epub ahead of print]

Multiple mechanisms lead to loss-of-function effects of SARS2 variants: implications for genotype-phenotype analyses.

Christina Del Greco, Stephanie M Laureano Figueroa, Anthony Antonellis.

Seryl-tRNA synthetase 2 (SARS2) encodes the enzyme responsible for charging tRNA with serine in the mitochondria. SARS2 has been associated with a spectrum of recessive diseases including HUPRA syndrome and progressive spastic paresis (PSP). Previous studies showed that pathogenic SARS2 variants cause decreased tRNA charging; however, the mechanism by which specific variants lead to distinct recessive phenotypes has not been defined. To address this lack of knowledge, we studied an allelic series of 11 pathogenic SARS2 variants for differential effects on mitochondrial function. These efforts revealed compelling variant-dependent effects on oxygen consumption that will be useful for phenotype-genotype correlations. Interestingly, certain variants (including the most commonly detected pathogenic SARS2 variant, R402H) did not affect mitochondrial function in our model system. Computational and functional studies revealed that two missense variants in exon 13 (D390G and R402H) reduce exon inclusion, suggesting loss-of-function effects via impaired transcript processing. Overall, this study expands our understanding of SARS2 biology, reveals differential effects that pathogenic variants have on SARS2 function, and provides the foundation for defining the clinical heterogeneity of patient phenotypes.

Keywords: HUPRA syndrome; Mitochondrial tRNA synthetase; Progressive spastic paresis

DOI: https://doi.org/10.1242/dmm.052690