bims-ripira 2026-01-25 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–01–25
eleven papers selected by
Martín Lopo

Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.
Elevated circulating cell-free mitochondrial DNA in fabry disease: insights into inflammatory activation.
Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.
NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.
Blood Cell Mitochondrial Respiration Increases With Age and Varies by Sex in Healthy Adults.
Metabolomic profiling of patients with sepsis-associated encephalopathy.
Mitochondrial DNA Fragment Dynamics in Acute and Chronic Human Immunodeficiency Virus: Insights From Human and Nonhuman Primate Models.
NMR-based urinary biomarkers in pediatric primary mitochondrial disorders and chronic kidney disease: shared mitochondrial dysfunction, diverging biosignatures.
Gut Microbiota and Mitochondrial Dysfunction in Autism: Clinical Correlations and Future Directions.
NLRP10 engages oxidized DNA through a Schiff-base mechanism and dissociates from NLRP3 upon inflammasome activation.
Solute Carrier Family 19 Member 1 Mediates Acquired Bortezomib Resistance in Multiple Myeloma Through Chronic Stimulator of Interferon Genes Activation and Mitochondrial DNA Release.

Adv Sci (Weinh). 2026 Jan 22. e23368

Mitochondrial Transplantation as a Therapeutic Strategy for Inherited Mitochondrial Diseases.

Parmeshar Singh, Amir Tahavvori, Cyrus E Kuschner, Blanca B Espin, Jacob Kazmi, Sofhia V Ramos, Tai Yin, Kei Hayashida, Kanako Ito-Hagiwara, Yusuke Endo, Keitaro Yoshioka, Jun Hagiwara, Avijot Sohi, Alisha Oropallo, Ghania Haddad, Timmy Li, Lance B Becker, Junhwan Kim.

  Mitochondria are essential organelles responsible for cellular energy production and diverse metabolic processes. Mitochondrial dysfunction is implicated in a wide range of diseases. Specifically, genetic mitochondrial diseases, arising from mutations in mitochondrial or nuclear DNA, lead to significant mitochondrial deficits, which result in debilitating and often life-threatening symptoms. Conventional treatments frequently fail to address these underlying mitochondrial defects, leaving few therapeutic options. Mitochondrial transplantation (MTx), an emerging therapeutic approach involving the delivery of healthy exogenous mitochondria to target cells, has demonstrated beneficial effects in various mitochondria-mediated diseases in both preclinical and early clinical studies. However, its application to inherited mitochondrial disorders remains largely unexplored and raises important questions about the need for repeated or continuous administration to sustain therapeutic effects. This review systematically examines the potential of MTx for inherited mitochondrial disorders by classifying these diseases by mitochondrial and nuclear DNA origin, critically assessing MTx evidence and mechanisms, and identifying unique translational requirements for chronic inherited disorders. While significant challenges remain, MTx represents a promising approach to directly address mitochondrial dysfunction in these life-threatening conditions with limited therapeutic alternatives.

Keywords:  chronic diseases; genetic diseases; mitochondrial transplantation; therapeutics

DOI:  https://doi.org/10.1002/advs.202523368
Front Immunol. 2025 ;16 1706045

Elevated circulating cell-free mitochondrial DNA in fabry disease: insights into inflammatory activation.

Yujing Yuan, Xinyu Zhang, Yawen Zhao, Yikang Wang, Jingyi Huang, Qingqing Wang, Xueqin Song, Jianwen Deng, Zhaoxia Wang, Yun Yuan, Wei Zhang.

   Objective: This study aimed to investigate mitochondrial dysfunction and its role in the pathogenesis of Fabry disease (FD) by analyzing circulating cell-free DNA (ccf-DNA) in patients with FD.
Methods: Sixty-six FD patients and 21 healthy controls (ctrls) were enrolled. Levels of plasma mitochondrial- (ccf-mtDNA) and nuclear-derived ccf-DNA (ccf-nDNA) were quantified by quantitative reverse-transcription PCR (RT-qPCR), and 14 inflammatory cytokines were measured in treatment-naïve patients. Associations among ccf-DNA levels, cytokine profiles, disease biomarkers, and clinical markers were analyzed, with subgroup analyses stratified by sex, genotype, clinical subtype, and disease severity.
Results: Treatment-naïve patients exhibited significantly higher ccf-mtDNA (z=-4.530, P-adj<0.001) and mtDNA/nDNA ratio (z=-2.613, P-adj=0.014) compared with ctrls. In the long-term enzyme replacement therapy (ERT) group (> 12 months), ccf-mtDNA copy number remained elevated (z=-3.141, P-adj=0.006), whereas the mtDNA/nDNA ratio did not differ significantly (z=-1.013, P-adj=0.311). No differences in ccf-nDNA were observed between treatment-naïve patients or the long-term ERT group compared with ctrls. Receiver operating characteristic analysis demonstrated the strong diagnostic performance of ccf-mtDNA (area under the curve=0.860), with 70% sensitivity and 91% specificity at an optimal cut-off value of 1,793,188.04 copies. Both ccf-mtDNA and mtDNA/nDNA ratio correlated positively with inflammatory cytokines including interleukin-17F and tumor necrosis factor-β, with stronger associations observed in male patients with classic FD. No correlations were observed with disease duration, α-galactosidase A activity, plasma globotriaosylsphingosine or clinical markers after adjustment for age and sex. Similarly, ccf-DNA measures did not differ significantly by sex, GLA mutation type (truncated vs. non-truncated), FD subtype (classic vs. non-classic), or across subgroups defined by disease severity or organ involvement (high vs. low MSSI, with or without hypertrophic cardiomyopathy, with or without chronic kidney disease, mild vs. severe white matter lesions, with or without neuralgia, or mild vs. severe pain).
Conclusions: Mitochondrial dysfunction, reflected by elevated ccf-mtDNA, is implicated in FD pathogenesis and may be linked to inflammatory activation. ccf-mtDNA represents a promising diagnostic biomarker for FD, potentially offering an additional therapeutic target when combined with ERT.

Keywords:  Fabry disease; ccf-mtDNA; enzyme replacement therapy; inflammatory cytokines; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fimmu.2025.1706045
J Inherit Metab Dis. 2026 Jan;49(1): e70147

Exploring Outcome Measures for Mitochondrial Myopathies; Insights From a Longitudinal Study on TK2 Deficiency.

Paloma Martín-Jimenez, Laura Bermejo-Guerrero, Luz Edith Ochoa, María Navarro-Riquelme, Rocío Garrido-Moraga, Aurelio Hernández-Laín, Ana Hernández-Voth, Adrián González Quintana, Ana Bermejo-Moriñigo, Violeta González-Méndez, Cristina Martín-Arriscado Arroba, Dimitrii Smirnov, Nikita Konstantinovskiy, Joaquín Arenas, Miguel Ángel Martin, Alberto Blázquez, Cristina Domínguez-González.

  Thymidine kinase 2 deficiency (TK2d) is an ultra-rare autosomal recessive mitochondrial myopathy with variable presentations, including late-onset forms beginning after age 12. Unlike early-onset disease, the natural history of late-onset TK2d remains poorly defined. We conducted a prospective, single-centre natural history study of 11 untreated patients with late-onset TK2d over 24 months. The median age at symptom onset was 27.2 years. Clinical phenotypes included progressive myopathy (n = 7), chronic progressive external ophthalmoplegia plus (n = 2), and exercise intolerance (n = 2). Most patients (72%) required non-invasive ventilation, and 70% showed axonal polyneuropathy. All patients carried biallelic pathogenic TK2 variants, with p.Lys202del being the most common (13/22 alleles). Muscle biopsies demonstrated mitochondrial DNA depletion and multiple deletions, and muscle MRI consistently showed selective involvement of the sartorius, gracilis and gluteus maximus, whose fat fraction correlated with motor impairment. Functional assessments revealed a mean forced vital capacity of 70.4%, an NSAA score of 25.9, a six-minute walk distance of 479.5 m, and a 100-m run time of 60.5 s. Serum GDF15 levels were elevated (median 2747.5 pg/mL) and significantly correlated with motor and respiratory function. Over 2 years, patients showed measurable clinical deterioration, with declines in NSAA (-2.65 points), FVC (-9.11%), and worsening 100-meter run times (+6 s). This study provides the first prospective longitudinal characterization of late-onset TK2d and identifies clinically relevant, quantifiable outcomes that may inform future therapeutic trials targeting this underrepresented patient population. Moreover, these results are also relevant for the design of clinical trials in other mitochondrial myopathies.

Keywords:  GDF15; TK2 deficiency; biomarkers; late‐onset; mitochondrial myopathy; natural history

DOI:  https://doi.org/10.1002/jimd.70147
JCI Insight. 2026 Jan 23. pii: e181812. [Epub ahead of print]11(2):

NAD+ and Sirt5 restore mitochondrial bioenergetics failure and improve locomotor defects caused by sucla2 mutations.

Joy Richard, Giulia Lizzo, Noélie Rochat, Adrien Jouary, Pedro Tm Silva, Alice Parisi, Stefan Christen, Sofia Moco, Michael B Orger, Philipp Gut.

  Mitochondria-derived acyl-coenzyme A (acyl-CoA) species chemically modify proteins, causing damage when acylation reactions are not adequately detoxified by enzymatic removal or protein turnover. Defects in genes encoding the mitochondrial respiratory complex and TCA cycle enzymes have been shown to increase acyl-CoA levels due to reduced enzymatic flux and result in proteome-wide hyperacylation. How pathologically elevated acyl-CoA levels contribute to bioenergetics failure in mitochondrial diseases is not well understood. Here, we demonstrate that bulk succinylation from succinyl-CoA excess consumes the enzymatic cofactor NAD+ and propagates mitochondrial respiratory defects in a zebrafish model of succinyl-CoA ligase deficiency, a childhood-onset encephalomyopathy. To explore this mechanism as a therapeutic target, we developed a workflow to monitor behavioral defects in sucla2-/- zebrafish and show that hypersuccinylation is associated with reduced locomotor behavior and impaired ability to execute food hunting patterns. Postembryonic NAD+ precursor supplementation restores NAD+ levels and improves locomotion and survival of sucla2-/- zebrafish. Mechanistically, nicotinamide and nicotinamide riboside require the NAD+-dependent desuccinylase Sirt5 to enhance oxidative metabolism and nitrogen elimination through the urea cycle. Collectively, NAD+ supplementation activates Sirt5 to protect against damage to mitochondria and locomotor circuits caused by protein succinylation.

Keywords:  Cell biology; Genetic diseases; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/jci.insight.181812
Aging Cell. 2026 Feb;25(2): e70387

Blood Cell Mitochondrial Respiration Increases With Age and Varies by Sex in Healthy Adults.

Howard J Phang, Jaclyn Bergstrom, Benjamin Keri, Stephanie R Heimler, Stephen Dozier, Lina M Scandalis, David Wing, Daniel Moreno, Nina N Sun, Anthony J A Molina.

Mitochondrial dysfunction is recognized as a biological hallmark of aging; however, bioenergetic capacity across the healthy human life course remains insufficiently characterized. While aging is generally associated with a systemic decline in mitochondrial function ("age-related bioenergetic decline"), recent research suggests that age-related bioenergetic differences are context dependent. Blood cells are extensively utilized as accessible samples for human bioenergetic profiling; therefore, our goal was to characterize bioenergetic capacity in platelets, peripheral blood mononuclear cells (PBMCs), monocytes, and lymphocytes of healthy adults from the San Diego Nathan Shock Center Clinical Cohort representative of the adult life course (20-80+ years of age). In our sample of 72 adults, we found that chronological age was positively associated with PBMC (maximal respiration [Max] β = 0.147, p = 0.028) and lymphocyte respiratory capacity (Max β = 0.135, p = 0.041). Notably, the pattern of age-related differences varied by sex; age showed a weak positive association with platelet respiration (Max β = 0.219, p = 0.037) in men but not in women. Similarly, age showed a strong positive association with PBMC respiration (Max β = 0.206, p = 0.018) in women but not in men. We also explored the relationship between glycolysis and respiration and found strong positive associations in platelets, PBMCs, and monocytes, but not lymphocytes. It is possible that, despite our cohort consisting of healthy, disease-free individuals, the elevated respiratory capacity in older adults may be reflective of compensatory mechanisms that require further investigation. Nonetheless, these findings underscore the importance of considering biological context, such as donor health, sex, and tissue type, in understanding age-related bioenergetic differences.

DOI: https://doi.org/10.1111/acel.70387
Biomed Khim. 2025 Dec;71(6): 441-453

Metabolomic profiling of patients with sepsis-associated encephalopathy.

E D Kessenikh, K M Bykova, E A Murashko, Ya A Dubrovskii, V V Dorofeykov, I A Savvina.

  Sepsis-associated encephalopathy (SAE) is a condition characterized by acute brain dysfunction developed in the absence of a primary infection in the central nervous system. The aim of this study was to perform a pilot, untargeted metabolomic profiling of the blood plasma of SAE patients to identify metabolic changes potentially associated with the pathological condition and to generate hypotheses for further studies of its pathogenesis, as well as to the search for promising biomarkers, and the assessment of the severity of the patient's condition. Metabolomic profiling was performed using HPLC-HR-MS, followed by statistical analysis of the obtained data. This blinded, randomized, controlled clinical trial revealed significant differences in the metabolic profiles of the study and control groups. Functional analysis showed the metabolic pathways most affected by pathological processes in SAE patients. These included metabolism of acylcarnitines, lysophosphatidylcholines, and taurine, folate biosynthesis, and the drug metabolism involving the cytochrome P450 pathway. In SAE patients with impaired consciousness, including delirium and coma, decreased levels of long-chain acylcarnitines and lysophosphatidylcholines were observed. The metabolomic profiles of SAE patients differed significantly between the groups of deceased and surviving patients: concentrations of sulfur-containing amino acids were significantly lower in the group of deceased than in the group of survivors. Our study identified 64 candidate biomarkers that could potentially be used to predict sepsis outcomes. However, further study is needed using an expanded and independent cohort of patients.

Keywords:  metabolites; metabolomics; sepsis; sepsis-associated encephalopathy

DOI:  https://doi.org/10.18097/PBMCR1599
J Infect Dis. 2026 Jan 20. pii: jiag014. [Epub ahead of print]

Mitochondrial DNA Fragment Dynamics in Acute and Chronic Human Immunodeficiency Virus: Insights From Human and Nonhuman Primate Models.

Jing Sun, Lolita S Nidadavolu, Hsing-Yu Hsu, Rohan G Rajagopal, Jacquie Astemborski, Yuqiong Wu, Yutong Jiang, Jonah B Sacha, Paul Kievit, Beth D Jamieson, Charles T Roberts, Gregory D Kirk, Todd T Brown, Peter M Abadir.

   BACKGROUND: Circulating cell-free mitochondrial DNA (ccf-mtDNA) fragments are released into the bloodstream following cell death and are associated with comorbidities seen in people with HIV-1 (PWH). However, ccf-mtDNA dynamics in acute and chronic HIV infection remain unclear.
METHODS: We quantified short and long ccf-mtDNA fragments in serum from 2 cohorts of PWH and people without HIV (PWoH), collected at 1, 3, and 5 years in the first cohort (N = 890) and 1 and 5 years in the second (N = 427). Mixed-effect linear regression models were used to analyze longitudinal associations of ccf-mtDNA levels with HIV status and markers (CD4-cell count, viral load). In parallel, we examined ccf-mtDNA levels in nonhuman primates (NHPs) before and after simian immunodeficiency virus (SIV) infection and following 3 and 6 months of ART.
RESULTS: In both human cohorts, PWH had significantly lower levels of short and long ccf-mtDNA fragments compared with PWoH. Individuals with lower CD4 T-cell counts exhibited further reductions in ccf-mtDNA levels. In NHPs, short ccf-mtDNA levels increased after infection, peaking before ART initiation (P = .001), and subsequently declined, reaching levels below baseline after 6 months on ART. Long ccf-mtDNA fragments remained stable during the early post-ART phase but declined significantly by 6 months (P = .02).
CONCLUSIONS: Chronic HIV infection and treated SIV infection are associated with reduced ccf-mtDNA levels, particularly in advanced disease stages. Further research is needed to clarify their role in immune activation, chronic inflammation, and aging-related comorbidities in PWH and their applicability as clinically relevant biomarkers of these processes.

Keywords:  HIV-1; aging; cell-free DNA fragment; longitudinal cohort; nonhuman primate

DOI:  https://doi.org/10.1093/infdis/jiag014
Metabolomics. 2026 Jan 19. 22(1): 17

NMR-based urinary biomarkers in pediatric primary mitochondrial disorders and chronic kidney disease: shared mitochondrial dysfunction, diverging biosignatures.

Margarida Paiva Coelho, João E Rodrigues, Teresa Costa, Aureliano Dias, Inês C R Graça, Hugo Rocha, Laura Vilarinho, Esmeralda Martins, Ana M Gil.

   BACKGROUND: Renal involvement is a recognized feature of primary mitochondrial disorders (PMD), either at presentation or during the disease course. Simultaneously, the metabolomic fingerprint of chronic kidney disease (CKD) is often associated with underlying mitochondrial dysfunction. This study aimed to characterize urinary metabolic signatures in genetically confirmed paediatric PMD without chronic kidney disease, comparing them to healthy controls, suspected (unconfirmed) mitochondrial disease (SMD), and non-mitochondrial CKD.
METHODS: We performed untargeted 1H NMR metabolomic profiling of 76 urine samples from 51 paediatric patients and 10 healthy controls. PMD patients in acute decompensation or known CKD and statistical outlier samples were excluded. Final comparisons included genetically confirmed PMD without CKD (n = 13), SMD (n = 10), non-mitochondrial CKD (n = 28; 17 at stages 1-2 and 9 at stages 3-5), and healthy controls (n = 10). Spectral data were analyzed using multivariate statistical approaches-including principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA)-as well as univariate methods with Mann-Whitney U for pairwise group metabolite comparison.
RESULTS: Urinary metabolic profiles of PMD patients differed from healthy controls and CKD patients. Multivariate analysis revealed a strong discriminative ability between PMD and controls (Q² = 0.53) and advanced CKD (Q2 = 0.78). Compared to controls, PMD patients had increased levels of Krebs cycle intermediates (cis-aconitate, fumarate and succinate), creatine, tryptophan, homovanillate (HVA) and hypoxanthine, as well as decreased histidine. All, except fumarate and histidine, remained discriminative when comparing PMD to CKD. CKD patients showed a diverging metabolomic fingerprint with 1-methylnicotinamide (MNA) and 2-hydroxyisobutyrate emerging as potential CKD-specific biomarkers, effectively discriminating between CKD stage 3-5 from earlier stages and controls. A five-metabolite panel comprising cis-aconitate, fumarate, HVA, tryptophan and histidine achieved high diagnostic performance for identifying PMD, with an area under the curve (AUC) of 0.836 (PMD vs. controls) and AUC = 0.783 across all groups. This biosignature integrates metabolites involved in distinct functional domains including energy metabolism, neurotransmitter turnover and amino acid metabolism and renal handling.
CONCLUSION: Urinary metabolomic profiling by NMR revealed a distinct biosignature in pediatric PMD patients without renal involvement, characterized by elevated levels of tryptophan, HVA, and Krebs cycle intermediates, and diminished histidine. The divergent changes in tryptophan, histidine and HVA, suggest a mitochondria-specific metabolic phenotype in PMD. These findings support the use of urinary NMR metabolomics as a non-invasive tool for biomarker discovery in PMD and highlight the potential of integrated, multiparametric metabolic fingerprints for diagnostic refinement and patient stratification.

Keywords:  Biomarkers; Metabolomics; NMR; Pediatric CKD; Primary mitochondrial disorders; Urine

DOI:  https://doi.org/10.1007/s11306-025-02363-8
Mol Neurobiol. 2026 Jan 23. 63(1): 392

Gut Microbiota and Mitochondrial Dysfunction in Autism: Clinical Correlations and Future Directions.

Sonalika Bhalla, Rajnish Srivastava.

  Autism spectrum disorder (ASD) is a multifactorial, neuro-psychiatric, and neurodevelopmental illness possessing impaired social, behavioral, and communicative presentations. Research suggested the important role of the gut-brain axis in ASD, especially related to gut dysbiosis and mitochondrial dysfunction. This review comprehensively summarizes the existing evidence of the association between gut microbiota, microbial metabolites, and mitochondrial dysfunction in ASD, comprising of clinical, experimental, and epidemiological data over the last decade. The focus was on the research that clarifies the gut-mitochondria crosstalk and role in ASD pathophysiology. ASD patients demonstrate a substantial shift in the variety of gut microbiota, such as a decrease in the number of beneficial microbes and the growth of pathogenic taxa. These changes affect the biosynthesis of major neuroactive metabolites executing immune modulation and neurotransmission. The review detects the microbial metabolites that regulate mitochondrial activity through mechanisms like vagus nerve, intestinal hormones, and immune signaling. The different mitochondrial signaling pathways were inhibited including AMPK, mTOR, and NF-κB. Preventive interventions that concentrate on modulation of the microbiome and mitochondria may present a prospective line of therapy. Nevertheless, uncovered gaps should be mentioned in future research, multi-omics studies, longitudinal studies, and the protocol to understand the components of gut-brain axis in ASD to develop personalized therapy.

Keywords:  Autism spectrum disorder; Gut microbiome; Gut-brain axis; Mitochondrial pathways

DOI:  https://doi.org/10.1007/s12035-026-05702-5
Commun Biol. 2026 Jan 22. 9(1): 72

NLRP10 engages oxidized DNA through a Schiff-base mechanism and dissociates from NLRP3 upon inflammasome activation.

Julia Elise Cabral, Angela Lackner, Wenjin Jiang, Sophia Lin, Haitian Zhou, Anna Wu, Courtney Demos, Minh Anh Pham, Reginald McNulty.

Mitochondrial DNA release into the cytosol is a critical event in innate immune activation, often acting as a damage-associated molecular pattern (DAMP) that triggers inflammasome assembly. Here, we demonstrate that NLRP3 is involved in the release of D-loop mtDNA into the cytosol. We further show that NLRP3 interacts with NLRP10. NLRP10-mediated oxidized DNA cleavage involves a Schiff base intermediate and is inhibited by small molecules known to inhibit glycosylases. These findings support a model where NLRP10 interaction with oxidized DNA may contribute to long-term senescence secretory phenotype and modulate inflammasome activation. Our study highlights a novel mechanism by which NLRP10 can respond to mitochondrial stress signals to influence innate immunity and suggests therapeutic potential for targeting these interactions in inflammatory diseases.

DOI: https://doi.org/10.1038/s42003-025-09501-x
Cell Biol Int. 2026 Feb;50(2): e70130

Solute Carrier Family 19 Member 1 Mediates Acquired Bortezomib Resistance in Multiple Myeloma Through Chronic Stimulator of Interferon Genes Activation and Mitochondrial DNA Release.

Yixuan Chen, Xianyi Wu, Mingxuan Tang, Xin Li, Xiaotao Wang.

  Acquired drug resistance is a major cause of poor prognosis in multiple myeloma (MM). Bortezomib (BTZ), a first-line therapeutic agent, is highly effective in MM; however, resistance remains a significant clinical challenge. Our previous work implicated Solute Carrier Family 19 Member 1 (SLC19A1) in hypoxia and immune modulation, suggesting its potential role in malignant progression. Here, we found that SLC19A1 expression was elevated in MM patients, particularly in those with acquired resistance. Overexpression of SLC19A1 enhanced the proliferation and invasiveness of human myeloma cell lines but did not confer primary BTZ resistance. Using a continuous-BTZ-exposure model, we demonstrated that SLC19A1 overexpression mediated acquired resistance via chronic activation of the stimulator of interferon genes (STING) pathway. This sustained activation triggered the unfolded protein response, dysregulated the endoplasmic reticulum-mitochondrial axis, and induced mitochondrial DNA (mtDNA) release. Treatment with the SLC19A1 inhibitor sulfasalazine or the STING inhibitor H-151 reduced mtDNA release and restored BTZ sensitivity. These findings highlight SLC19A1 and STING signaling as potential therapeutic targets for overcoming acquired drug resistance in MM.

Keywords:  SLC19A1; STING; drug resistance; mitochondrial DNA; multiple myeloma

DOI:  https://doi.org/10.1002/cbin.70130