bims-ripira 2026-03-08 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–03–08
eleven papers selected by
Martín Lopo

Integrative multi-omics and machine learning identify mitochondrial biomarkers for pathogen-specific sepsis stratification and translational prioritization.
A Novel Truncating Pathogenic Variant in RRM2B in a Kurdish Family With Autosomal-Dominant Chronic Progressive External Ophthalmoplegia Plus (PEOA5).
Late-onset TK2 deficiency in adults: Long-term clinical outcomes of deoxynucleoside therapy.
Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.
[Decreased plasma citrulline is a biochemical marker in newborn screening for MT-ATP6-associated mitochondrial disease: two case reports and a literature review].
Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.
Growth Differentiation Factor-15 as a Clinical Biomarker of Frailty, Sarcopenia and Functional Decline: A Systematic Literature Review.
3-Methyl Glutaconic Aciduria and Elevated Plasma Growth Differentiation Factor 15 Level in an Adult with Monoallelic SPG7 Pathogenic Variant.
Melatonin as a radioprotectant against mitochondrial damage.
Interleukin-6-Associated Pyroptosis, Apoptosis, and Necroptosis via JAKs/STAT3-RIPK1 Axis: A Potential Mechanism for CD4+ T-Cell Depletion in Bacterial Sepsis.
Mitochondrial dysfunction: a new target for traditional Chinese medicine in the treatment of chronic heart failure.

Eur J Med Res. 2026 Mar 06.

Integrative multi-omics and machine learning identify mitochondrial biomarkers for pathogen-specific sepsis stratification and translational prioritization.

Chaoyuan Jin, Ruijinlin Hao, Bate Gonggaoang, Qingxia Dai, Xingxing Ren, Jie Shen.

   BACKGROUND: Sepsis is a leading cause of critical illness and mortality, yet substantial heterogeneity limits risk stratification and biomarker translation. Mitochondrial dysfunction is widely implicated in sepsis, but genetically supported, multi-layer regulatory features and their clinical relevance remain incompletely characterized.
METHODS: We integrated publicly available sepsis GWAS summary statistics (general sepsis: 1634 cases/454,714 controls; gram-positive sepsis: 168/456,180; gram-negative sepsis: 383/455,965) with blood-based molecular QTL resources (including GTEx v8 whole blood, n = 670) to prioritize mitochondrial genes and infer regulatory cascades. Independent whole-blood transcriptomic cohorts (the GAinS cohort, GSE65682, n = 802; GSE54514, n = 163) were used for clinical and pathogen-specific expression characterization. We developed machine learning models using mitochondrial gene features and evaluated performance by internal tenfold cross-validation.
RESULTS: We identified mitochondrial genes with convergent genetic, epigenetic, and transcriptional regulatory evidence, showing stronger effects in inner membrane and matrix compartments. Transcriptomic analyses supported clinically relevant dysregulation and pathogen-associated patterns. In predictive modeling, aggregating mitochondrial gene features improved discrimination, with the best-performing random forest model achieving an AUC of 0.91 under internal cross-validation. These results require validation in independent external cohorts.
CONCLUSIONS: This study provides a genetically supported, multi-omics framework linking compartment-specific mitochondrial dysregulation to sepsis heterogeneity and nominates candidate biomarkers for prioritization. The reported model performance reflects internal resampling and requires validation in independent clinical cohorts and future multi-omics profiling (including metabolomics) before translational implementation.

Keywords:  Epigenetics; Mendelian randomization; Mitochondrial dysfunction; Multi-omics; Sepsis

DOI:  https://doi.org/10.1186/s40001-026-04065-w
J Clin Neuromuscul Dis. 2026 Mar 01. 27(3): 108-111

A Novel Truncating Pathogenic Variant in RRM2B in a Kurdish Family With Autosomal-Dominant Chronic Progressive External Ophthalmoplegia Plus (PEOA5).

Demian Mayer, Emmanouela Kartsonaki, Einar Wilder-Smith, André Schaller, Stefan Frank, Stephan Bohlhalter, Violeta Mihaylova.

   OBJECTIVES: To report a family with autosomal-dominant chronic progressive external ophthalmoplegia due to a novel truncating pathogenic variant in RRM2B and to show the challenges facing clinicians in diagnosing rare neuromuscular diseases.
METHODS: Four family members were examined. Muscle biopsy, mitochondrial DNA analysis, next generation sequencing, and targeted mitochondrial gene panel followed by Sanger sequencing and complementary deoxyribonucleic acid analysis were performed.
RESULTS: A novel heterozygous RRM2B truncating variant c.968_972del p.(Phe323*) was identified. complementary deoxyribonucleic acid analysis showed expression of both RRM2B alleles.
CONCLUSIONS: The proband was initially misdiagnosed as myasthenia gravis. Based on the phenotype and family history, chronic progressive external ophthalmoplegia was suspected and confirmed by finding of a novel RRM2B variant. The detection of another truncating pathogenic variant in exon 9 of RRM2B further supports this exon as mutation hot spot and underlines the role of the C-terminal highly conserved amino acids for the interaction of the p53R2 dimer with the R1 dimer.

Keywords:  ; CPEO; mitochondrial disease; mtDNA deletions

DOI:  https://doi.org/10.1097/CND.0000000000000514
Mitochondrion. 2026 Feb 28. pii: S1567-7249(26)00028-0. [Epub ahead of print]89 102138

Late-onset TK2 deficiency in adults: Long-term clinical outcomes of deoxynucleoside therapy.

Hacer Durmus, Asuman Gedikbaşı, Serdar Ceylaner, Arman Çakar, Sezan Mergen, Esen Kıyan, Yesim Gülşen Parman.

   OBJECTIVE: To evaluate the long-term efficacy and safety of deoxynucleoside therapy in adult patients with late-onset thymidine kinase 2 deficiency (TK2d).
BACKGROUND: TK2d is a mitochondrial myopathy causing progressive weakness, respiratory insufficiency, and early mortality. While nucleoside supplementation benefits pediatric cases, evidence in adults remains limited.
METHODS: Six genetically confirmed adults with TK2d were treated under compassionate-use protocols in Turkey, receiving escalating doses of oral or PEG-administered Doxecitine and Doxribtimine up to 800 mg/kg/day. Functional and clinical outcomes included the 6-minute walk test (6MWT), Hammersmith Functional Motor Scale Expanded (HFMSE), forced vital capacity (FVC), Fatigue Severity Scale (FSS), and body mass index (BMI).
RESULTS: Over a median follow-up of 24 (range 6-36) months, therapy was associated with sustained functional and respiratory improvements. Mean 6MWT increased from 152 m at baseline to 468 m at 24 months and exceeded 600 m in patients with 36-month data. The mean HFMSE increased from 20.5 at baseline to 24.5 at 3 months, 29 at 6 months. Patients with the longest follow-up reached a mean HFMSE of 58 at 36 months. FVC, which had declined before treatment, stabilized or improved in all patients (mean increase from 36% to 55.6% at 36 months). The youngest patient achieved near-normal respiratory function. Fatigue severity decreased by ∼ 30%, and BMI improved notably in underweight individuals. Treatment was generally well tolerated; transient liver enzyme elevations and mild gastrointestinal side effects resolved spontaneously.
CONCLUSIONS: Deoxynucleoside therapy appears effective and well tolerated in adults with TK2d, producing sustained functional and respiratory gains. Early treatment initiation is crucial to maximize benefit; though partial improvements may occur even in advanced disease.

Keywords:  Deoxynucleoside Therapy; Late-onset; TK2 deficiency

DOI:  https://doi.org/10.1016/j.mito.2026.102138
Mitochondrion. 2026 Feb 28. pii: S1567-7249(26)00027-9. [Epub ahead of print]88 102137

Patient-derived TWNK variants recapitulate multisystem Perrault syndrome pathology in a mouse model.

Wei Wang, Xiang Dong, Chun-Yu Cao, Hong-Bo Li, Ya-Feng Lv.

  Perrault syndrome (PS) is a rare autosomal-recessive disorder characterized by bilateral sensorineural hearing loss, ovarian dysgenesis in females, and variable neurological impairment. Pathogenic variants in TWNK, encoding the mitochondrial helicase Twinkle, disrupt mtDNA maintenance and underlie a subset of PS cases. Here, we generated the first mouse models carrying patient-specific TWNK missense mutations c.814G > A (p.Ala272Thr) and c.1166C > T (p.Ala389Val), both in homozygosity and compound heterozygosity, using CRISPR/Cas9 editing. Mutant mice exhibit profound hearing loss, locomotor hypoactivity, and axonal peripheral neuropathy, while overall growth remains normal. Molecular assays reveal a significant reduction in mtDNA copy number and ATP content in muscle and brain, accompanied by impaired respiratory-chain function. These phenotypes faithfully recapitulate core features of human PS, establishing a genetically precise in vivo platform to dissect disease mechanisms and to evaluate targeted therapies for mitochondrial dysfunction and sensorineural hearing loss.

Keywords:  Mitochondrial dysfunction; Mouse model; Perrault syndrome; Sensorineural hearing loss; TWNK; mtDNA

DOI:  https://doi.org/10.1016/j.mito.2026.102137
Zhongguo Dang Dai Er Ke Za Zhi. 2026 Feb 15. pii: 1008-8830(2026)02-0250-07. [Epub ahead of print]28(2): 250-256

[Decreased plasma citrulline is a biochemical marker in newborn screening for MT-ATP6-associated mitochondrial disease: two case reports and a literature review].

Hui-Ming Yan, Ying Quan, Ying Zhou, Luo Jiang, Liang-Yu Zhang, Zheng-Qing Wan, Hui Xi.

  This report describes the potential diagnostic value of decreased plasma citrulline (pCit) levels for the early recognition of MT-ATP6-related mitochondrial disease. Two cases were reported, and relevant literature was reviewed. Case 1: Onset occurred at 3 months of age with an acute presentation that rapidly progressed to metabolic crisis, multiorgan failure, and central respiratory failure, resulting in death in early infancy. Case 2: Onset occurred at 6 months of age with progressive developmental delay. Brain magnetic resonance imaging revealed bilateral symmetric basal ganglia lesions, and Leigh syndrome was diagnosed. Following citrulline supplementation and comprehensive intervention, improvements were observed in intellectual development and metabolic indices. Both patients carried the MT-ATP6 variant m.8993T>G (p.L156R), confirming MT-ATP6-associated mitochondrial disease. This case series indicates that decreased pCit on newborn screening is an early biochemical marker of MT-ATP6-associated mitochondrial disease. Early diagnosis and metabolic intervention are beneficial for prognosis.

Keywords:  Hypocitrullinemia; MT- ATP6; Mitochondrial disease; Newborn screening; m.8993T>G

DOI:  https://doi.org/10.7499/j.issn.1008-8830.2505143
Genet Med. 2026 Jan;pii: S1098-3600(25)00267-9. [Epub ahead of print]28(1): 101620

Charting the phenotypic landscape of mitochondrial diseases through a systematic evaluation of pathogenic mitochondrial DNA and nuclear gene variants.

Thiloka Ratnaike, Siddharth Ramanan, Nour Elkhateeb, Ramya Narayanan, Jenny Yang, Eszter Sara Arany, Manya Mirchandani, Rachael Piper, Katherine Schon, M Eren Kule, Christopher Gilmartin, Angela Lochmüller, Emogene Shaw, Rita Horváth, Patrick F Chinnery.

   PURPOSE: Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically.
METHODS: Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes.
RESULTS: MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without.
CONCLUSION: MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Keywords:  HPO; Mitochondrial disease; Phenotype similarity; Rare disease; UMAP

DOI:  https://doi.org/10.1016/j.gim.2025.101620
Ageing Res Rev. 2026 Mar 03. pii: S1568-1637(26)00077-2. [Epub ahead of print] 103085

Growth Differentiation Factor-15 as a Clinical Biomarker of Frailty, Sarcopenia and Functional Decline: A Systematic Literature Review.

Ainsley Ryan Yan Bin Lee, Vidhya S Nachammai, Anjin Hong, Amanda Weiling Tan, Chun En Yau, Chen Ee Low, Reshma Aziz Merchant.

   BACKGROUND: With an aging population globally, prevention of frailty and sarcopenia will become a public health priority. Growth Differentiation Factor-15 (GDF-15), a stress-responsive cytokine of the TGF-β superfamily, has emerged as a promising biomarker linking mitochondrial dysfunction, cellular senescence, and systemic inflammation to biological and phenotypic aging.
OBJECTIVES: This systematic literature review systematically synthesizes the clinical evidence on GDF-15 as a biomarker of frailty, sarcopenia, and physical function, highlighting patterns, gaps, and the biological plausibility of its role as a predictive marker and therapeutic target.
METHODS: Following PRISMA guidelines, we searched CENTRAL, Embase, MEDLINE, and PubMed up to February 2026. Studies involving adult human participants with measured serum GDF-15 levels and assessments of frailty or sarcopenia were included. Data were extracted and grouped thematically by population type, study design, and outcome domains. Narrative synthesis was used to compare findings and explore heterogeneity.
RESULTS: From 1027 records, 35 studies were included, spanning community-dwelling adults, hospitalized patients, and individuals with cardiovascular, metabolic, gastrointestinal, and respiratory diseases. Elevated GDF-15 levels were consistently associated with poorer physical performance and greater frailty severity. Longitudinal studies suggested predictive value for future functional decline, although associations with sarcopenia were less consistent. Sex-specific variations and methodological heterogeneity, including assay techniques and diagnostic criteria, were key sources of variability. Interventional studies demonstrated limited modulation of GDF-15 levels through physical activity alone.
CONCLUSIONS: These findings support the integration of GDF-15 into precision geriatric care, though further longitudinal and interventional studies, including those evaluating the incremental value of adding GDF-15 to existing screening tools for frailty, sarcopenia, and functional status, are required to establish its clinical utility.

Keywords:  Growth Differentiation Factor 15; Physical, function; frailty; sarcopenia, handgrip strength

DOI:  https://doi.org/10.1016/j.arr.2026.103085
Acta Myol. 2025 Dec;44(4): 138-142

3-Methyl Glutaconic Aciduria and Elevated Plasma Growth Differentiation Factor 15 Level in an Adult with Monoallelic SPG7 Pathogenic Variant.

Bukola A Olarewaju, Ehab Y Harahsheh, Khaled I Dweik, Judy B Tejon, Shaymaa Shurrab, Stephen A Johnson, Dimitar K Gavrilov, Mayowa A Osundiji.

  Pathogenic variants in SPG7 cause autosomal dominant progressive muscular atrophy. SPG7 encodes an inner mitochondrial membrane protein, paraplegin. Burgeoning lines of evidence have continued to suggest important roles for paraplegin in mitochondria function. Here we report elevated levels of biochemical markers of mitochondria dysfunction [3-methylglutaconic acid and 3-methylglutaric acid (in urine and blood) as well as plasma Growth Differentiation Factor 15 (GDF 15)] in a 65-year-old woman with a heterozygous pathogenic SPG7 variant [c.1529C > T (p.Ala510Val)], and evidence of muscle disease as well as chronic cerebral vasculopathy.

Keywords:  aciduria; atrophy; methyl-glutaconic; mitochondria; muscle; paraplegin

DOI:  https://doi.org/10.36185/2532-1900-1593
Int J Radiat Biol. 2026 Mar 03. 1-11

Melatonin as a radioprotectant against mitochondrial damage.

Tsutomu Shimura, Jiayu Wu, Maho Aizawa, Yui Takahashi, Megumi Sasatani, Asako J Nakamura, Akira Ushiyama.

   PURPOSE: Conventional radioprotectants are designed to be administered before radiation exposure, while few have been identified that are effective when administered post-exposure. Irradiation generates intracellular reactive oxygen species (ROS) that induce mitochondrial damage, causing the release of mitochondrial contents into the cell cytoplasm and ensuing cell death. This mitochondrial damage occurs a few hours after radiation exposure, so mitochondria-targeted radioprotection can be effective when administered post-exposure. Here, we examined the efficacies of the glutathione (GSH) peroxidase activators melatonin and mitoEbselen-2 against radiation-induced mitochondrial damage.
MATERIALS AND METHODS: Human TIG-3 fibroblasts were exposed to ionizing radiation (IR), and cGAS-positive cytosolic DNA was detected by immunostaining with double-strand DNA and cGAS antibodies as an indicator of mitochondrial (mt)DNA leakage. Mitochondrial membrane potential (Δψm) was also measured using JC-1, while radiation-induced senescence was detected by β-gal staining. Mice were exposed to whole-body irradiation with or without melatonin treatment to assess radioprotective efficacy in vivo.
RESULTS: Radiation exposure induced mitochondrial damage in TIG-3 cells as evidenced by cytosolic mtDNA leakage, Δψm depolarization, and accelerated cellular senescence. Melatonin and mitoEbselen-2 protected against both irradiation-induced and H2O2-induced mitochondrial damage, suggesting that these agents act as ROS scavengers. Melatonin also maintained Δψm after irradiation and inhibited cellular senescence. However, prolonged mitoEbselen-2 treatment indicated potential cytotoxicity as shown by Δψm loss. Melatonin mitigated the release of exosome mtDNA into the plasma of mice, as well as radiation-induced damage to blood cells and testicular tissue.
CONCLUSIONS: Melatonin can protect against irradiation-induced mitochondrial damage, suggesting utility for mitigating the health effects of accidental radiation exposure.

Keywords:  Melatonin; Nrf2; cytosolic DNA; mitochondria; radiation protection

DOI:  https://doi.org/10.1080/09553002.2026.2636299
Crit Care Med. 2026 Mar 05.

Interleukin-6-Associated Pyroptosis, Apoptosis, and Necroptosis via JAKs/STAT3-RIPK1 Axis: A Potential Mechanism for CD4+ T-Cell Depletion in Bacterial Sepsis.

Zhaofeng Kang, Chaoyao Hou, Siyuan Qi, Zhanfei Li, Xiangjun Bai, Xijie Dong.

   OBJECTIVES: Sepsis triggers both excessive inflammation and immunosuppression, the latter partly characterized by CD4+ T-cell depletion. The mechanisms underlying this depletion, especially its interplay with cytokine storms driven by inflammatory factors such as interleukin (IL)-6, remain unclear. This study aimed to elucidate the molecular mechanisms contributing to CD4+ T-cell depletion in sepsis, focusing specifically on the IL-6/Janus kinases (JAKs)/signal transducer and activator of transcription 3 (STAT3) signaling axis and programmed cell death.
DESIGN: Prospective cohort study.
SETTING: Adult ICUs at a university hospital.
PATIENTS: Adult sepsis and septic shock patients without any documented immune comorbidity.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: A prospective analysis enrolled 151 patients (93 sepsis, 58 septic shock) and 20 controls. Flow cytometry and enzyme-linked immunosorbent assay were used to assess immune cell populations and cytokine profiles, with multivariate analyses exploring their interrelationships. An additional 30 sepsis patients and ten controls were recruited to investigate mechanisms. Peripheral blood mononuclear cells (PBMCs) underwent RNA sequencing (RNA-seq). Isolated CD4+ T cells were stimulated with IL-6 in vitro, followed by treatment with specific inhibitors targeting pyroptosis, apoptosis, necroptosis, the JAKs/STAT3 pathway, or receptor-interacting protein kinase 1 (RIPK1). Western blotting, flow cytometry, immunofluorescence, Cell Counting Kit-8 assays, and interferon-gamma staining evaluated cell death pathways, PANoptosome (a complex mediating apoptosis, pyroptosis and necroptosis)-assembly, and function. Significant CD4+ T-cell loss occurred in both sepsis and septic shock groups, strongly correlating with elevated IL-6 levels. Sepsis PBMC RNA-seq revealed activated IL-6/JAKs/STAT3 signaling and upregulated apoptosis/pyroptosis/necroptosis genes. In vitro, IL-6 induced pyroptosis, apoptosis, and necroptosis (PANoptosis) in CD4+ T cells via IL-6/JAKs/STAT3-dependent RIPK1-PANoptosome assembly. Inhibiting JAKs/STAT3 or RIPK1 significantly reduced PANoptosis, partially restored CD4+ T-cell viability and functional capacity.
CONCLUSIONS: PANoptosis has been observed to be a form of CD4+ T-cell death in sepsis patients. Evidence suggests that IL-6 may be associated with the exhaustion process, mechanistically involving the activation of the JAKs/STAT3 pathway. It is also hypothesized that this process might be linked to RIPK1-PANoptosome-mediated PANoptosis.

Keywords:  ; Janus kinases/signal transducer and activator of transcription 3 signaling pathway; interleukin-6; pyroptosis, apoptosis, and necroptosis; sepsis

DOI:  https://doi.org/10.1097/CCM.0000000000007088
Chin J Nat Med. 2026 Mar;pii: S1875-5364(26)61104-1. [Epub ahead of print]24(3): 289-299

Mitochondrial dysfunction: a new target for traditional Chinese medicine in the treatment of chronic heart failure.

Fuyun Jia, Yadong Wang, Shengwei Gao, Rui Zhang, Shichuan Chen, Hui Zhang, Yinan Ma, Zhengwei Zhang, Junchi Guo, Xi Zhang, Qiang Xu.

  Chronic heart failure (CHF) remains a global health challenge with limited therapeutic options. Mitochondrial dysfunction is a key pathological feature, and traditional Chinese medicine (TCM) shows unique potential in targeting this mechanism. Evidence from human and animal models of heart failure indicates that TCM can restore mitochondrial function by regulating mitochondrial Ca²⁺ homeostasis, oxidative stress, energy metabolism, mitochondrial dynamics, and mitophagy. TCM-based treatment of CHF offers notable clinical advantages, including improved therapeutic efficacy, enhanced cardiac function, and reduced incidence of major cardiovascular events. Experimental studies demonstrate that TCM decoctions and monomers modulate signaling pathways such as PPAR-RXRα, NF-κB, and PI3K/AKT to alleviate oxidative stress. TCM also increases AMPK activity via phosphorylation of PGC-1α, indirectly promoting mitochondrial biogenesis; attenuates calcium influx and enhances Ca²⁺ reuptake, thereby ameliorating myocardial mitochondrial dysfunction in CHF; and improves CHF by rebalancing mitochondrial dynamics and autophagy.

Keywords:  Chronic heart failure; Mitochondrial dysfunction; Traditional Chinese medicine

DOI:  https://doi.org/10.1016/S1875-5364(26)61104-1