bims-ripira 2026-05-24 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–05–24
sixteen papers selected by
Martín Lopo

Presepsin as a Prognostic Biomarker for Short-Term Mortality in Adult Patients With Sepsis: A Systematic Review.
Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.
Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.
Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review.
The role of the nucleus in the control of mitochondrial precursor proteins in yeast.
Aberrant methylation of mitochondrial genes as a link between oxidative phosphorylation dysregulation and the pathogenesis of hypospadias: a multiomics and clinical sample study.
Mitochondrial aminoacyl-tRNA synthetase (ARS)-defects: a review of phenotypes and therapeutic strategies in 899 patients.
A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype.
Quantitative assessment of efficacy and evaluation of feasibility of exercise training protocols in adult and pediatric primary mitochondrial disease.
Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.
Mitochondria transfer in neurological disorders: the key role of neuroglia.
Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.
Diurnal dynamics and psychobiological regulation of cell-free mitochondrial and nuclear DNA in human saliva.
Mitoredox Shifts in Mitochondrial Dysfunction.
Krill Oil for Pain in Elders (KOPE): Protocol for a Pilot, Double-Blind, Randomized Controlled Trial Assessing Feasibility and Acceptability of 4 g/d Krill Oil Supplementation in Older Adults with Chronic Musculoskeletal Pain and Mobility Limitations.
The progress of mitochondrial function and transfer in stem cell regulation and therapy.

Cureus. 2026 Apr;18(4): e107323

Presepsin as a Prognostic Biomarker for Short-Term Mortality in Adult Patients With Sepsis: A Systematic Review.

Akshay Rajeev, Sabah Shakeel Shaikh, Harnoor Kaur, Archit Sharma, Palangutde Katherine Dimowo, Bhavna Murugesh.

  Sepsis is a life-threatening medical condition that continues to be a significant global health concern. It is well recognised as a leading cause of morbidity and mortality among hospitalised and critically ill patients of all age groups. Several clinical severity scores, such as the Sequential Organ Failure Assessment (SOFA) and the Acute Physiology and Chronic Health Evaluation II (APACHE), are commonly used to identify and categorise sepsis. However, such clinical tools often require multiple physiological parameters and may not always provide rapid prognostic information. Similarly, inflammatory biomarkers such as C-reactive protein and procalcitonin exhibit variable prognostic value when used alone. Presepsin, a soluble CD14 subtype released when macrophages and monocytes are activated as part of the human innate immune response to infection, has emerged as a promising biomarker to predict infection severity and adverse outcomes in sepsis. This systematic review was conducted to evaluate whether presepsin could serve as a reliable marker to predict short-term (28-day or 30-day) mortality among adult patients with sepsis. A detailed literature search and screening were conducted using PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020) guidelines across multiple electronic databases, including PubMed, ScienceDirect, Cochrane Library, and Embase. Following the screening process, a total of 19 observational studies and one systematic review were ultimately selected for the final analysis. Presepsin levels were generally higher in patients with greater disease severity and frequently higher in non-survivors. Although presepsin demonstrated moderate prognostic performance, established clinical severity scores often outperformed presepsin. Overall, existing evidence suggests that presepsin may provide additional prognostic value when integrated with established clinical scoring tools.

Keywords:  presepsin (cd14-st); scd14; sepsis and septic shock; sepsis markers; sepsis prognosis

DOI:  https://doi.org/10.7759/cureus.107323
J Neuromuscul Dis. 2026 May 20. 22143602261432401

Nucleoside therapy for thymidine kinase 2 deficiency: Long-term outcomes from a Brazilian cohort.

Cristiane Araujo Martins Moreno, Tatiana Ribeiro Fernandes, Clara Gontijo Camelo, Gabriel Keller, Filipe Di Pace, Gabriella Corrêa Dousseau, Alulin Tácio Quadros Santos Monteiro Fonseca, Eliene Dutra Campos, Ana Paula Dos Anjos Lança, Mariana Cunha Artilheiro, André Macedo Serafim da Silva, Michelle Abdo Paiva, Andres Nascimento, Edmar Zanoteli.

  BackgroundThymidine Kinase 2 deficiency (TK2d) is a rare, mitochondrial DNA (mtDNA) depletion/deletions syndrome leading to a severe and progressive myopathic disorder. Nucleoside supplementation (deoxythymidine and deoxycytidine) has been shown to favorably alter the disease's course, particularly in severe infantile-onset cases. Long-term data on efficacy and safety, especially in the adult patient population, remain limited.MethodsThis is a retrospective, long-term follow-up study of 14 TK2d patients (five children and nine adults with childhood-onset disease) treated with nucleosides. Patients were systematically evaluated over a period ranging from 9 to 36 months, with assessments conducted every 3 months during the first year of treatment, and every 6 months thereafter. Comprehensive functional assessments of motor, respiratory, and bulbar function were performed. Periodic measurements of liver and pancreatic function monitored safety and tolerability.ResultsAll 14 TK2d patients showed beneficial effects across motor, respiratory, and bulbar function domains. Among pediatric patients, a rapid treatment response was observed early on, with functional gains sustained and continuing beyond 12 months of therapy. Adults experienced substantial improvements in motor and respiratory capacity but most of them reported severe gastrointestinal symptoms. Liver and pancreatic enzymes abnormalities were noticed mainly in adults.ConclusionsDeoxythymidine and deoxycytidine were found to be safe and beneficial in this long-term cohort of TK2d patients, but elevation in liver and pancreatic enzymes were present and required regular monitorization. This study provided valuable evidence supporting this therapy as an effective and safe, long-term disease-modifying treatment option for both pediatric and adult patients.

Keywords:  Mitochondrial Myopahty; TK2 deficiency; deoxythymidine and deoxycytidine; mtDNA depletion syndrome; nucleosides therapy

DOI:  https://doi.org/10.1177/22143602261432401
Sci Rep. 2026 May 18.

Mavodelpar in patients with primary mitochondrial myopathy: a phase 1 trial.

Renae J Stefanetti, Chiara Pizzamiglio, Alasdair P Blain, Oliver M Russell, Lisa Alcock, Gavin Hudson, Jane Newman, Naomi Thomas, Charlotte Warren, Huizhong Su, Helen A L Tuppen, Philip Brown, David Houghton, Heather Hunter, Albert Z Lim, Yi Shiau Ng, Catherine Feeney, Iwona Skorupinska, Louise Germain, Enrico Bugiardini, Michael G Hanna, Robert McFarland, Robert D S Pitceathly, Gráinne S Gorman.

  Primary mitochondrial myopathies (PMM) are rare, genetically-defined disorders characterised by defects of oxidative phosphorylation, predominantly affecting skeletal muscle. This Phase 1b open-label trial evaluated mavodelpar, a selective peroxisome proliferator-activated receptor delta (PPARδ) agonist, over 12 weeks (Part A), with an optional 36 week extension (Part B) in adults with PMM. The primary objective was to assess safety and tolerability, with secondary assessments of pharmacokinetics, pharmacodynamics, and exploratory performance, patient-reported, and muscle biopsy outcomes. Of the 23 participants who received mavodelpar, 17 completed Part A; none completed Part B due to premature study termination during the COVID-19 pandemic. Adverse events were mild-moderate severity, with headache and constipation most common (4/23 participants; 17.4% each). Exploratory measures showed a mean increase of 104 m in the twelve minute walk test (95% CI: 53 to 156) and a mean reduction of -10.5 points in patient-reported fatigue (95% CI: -16.3 to -4.6). No consistent changes in mitochondrial function were detected in muscle biopsies (n = 10), while transcriptomic profiling (n = 6) revealed modest upregulation of fatty acid-metabolism pathways. Although findings from this Phase 1b trial supported progression to later-phase evaluation, the subsequent Phase 2b trial did not demonstrate clinical efficacy for mavodelpar. The results reported here should be interpreted as exploratory and not indicative of therapeutic benefit. Nevertheless, this Phase 1b trial provides important methodological insights to inform future PMM clinical trial design and outcome measure development.

Keywords:  Mitochondrial disease; Mitochondrial myopathy; Outcome measures; Peroxisome proliferator-activated receptor delta (PPARδ) agonist; Phase 1 trial; Rare disease

DOI:  https://doi.org/10.1038/s41598-026-43287-0
Transl Pediatr. 2026 Apr 30. 15(4): 161

Living donor liver transplantation in a pediatric patient with mitochondrial DNA depletion syndrome caused by two novel POLG1 mutations: a case report and literature review.

Yanhao Li, Fuxiao Xie, Lin Wei, Zhijun Zhu.

   Background: Mitochondrial DNA depletion syndrome (mtDDS) is a rare genetic disorder caused by mutations in nuclear genes responsible for mitochondrial DNA maintenance, most notably POLG1. The disease is characterized by diverse clinical manifestations, including myopathy, hepatopathy, and neurological deficits. Due to its phenotypic heterogeneity, diagnosing mtDDS in pediatric populations remains a significant clinical challenge, often leading to delays in life-saving interventions.
Case Description: We report the case of an 11-month-old male infant presenting with acute liver failure and recurrent hypoglycemia. Laboratory findings revealed elevated liver enzymes, jaundice, and persistent metabolic distress. Notably, the patient lacked the neurological symptoms typically associated with POLG1 mutations, complicating the initial clinical picture. Genetic analysis via whole exome sequencing (WES) identified two novel compound heterozygous mutations in the POLG1 gene (695G>A and 1735C>T), confirming the diagnosis of mtDDS. Following the diagnosis, the patient underwent a successful liver transplantation, which resulted in significant clinical stabilization and improved quality of life.
Conclusions: This case expands the known mutational spectrum of the POLG1 gene and highlights an atypical presentation of mtDDS isolated to hepatic dysfunction. Our findings underscore the critical importance of early genetic testing, such as WES, in infants with unexplained liver failure or metabolic crises. Timely diagnosis is essential to guide surgical interventions like liver transplantation, which can effectively improve outcomes. Clinicians should maintain a high index of suspicion for underlying mitochondrial genetic defects in pediatric hepatopathy to facilitate early intervention and long-term management.

Keywords:  Mitochondrial DNA depletion syndrome (mtDDS); POLG1 gene mutation; case report; liver dysfunction; living donor liver transplantation (LDLT)

DOI:  https://doi.org/10.21037/tp-2025-1-883
Protein Sci. 2026 Jun;35(6): e70622

The role of the nucleus in the control of mitochondrial precursor proteins in yeast.

Kira Ritzenhofen, Stefano Rossi, Axel Mogk, Fabian den Brave.

  Mitochondria are essential organelles of eukaryotic cells, with vital roles in energy production, biosynthesis of macromolecules, and intracellular signaling. Their function depends on a complex proteome with proteins targeted to different mitochondrial sub-compartments. Synthesis of precursors of mitochondrial proteins (mitoPREs) mostly occurs in the cytosol followed by post-translational import. Delay or block of mitochondrial import leads to mitoPRE accumulation in the cytosol, where they interact with cytosolic protein quality control (PQC) factors and might get re-routed to other cellular organelles, including the nucleus. Recent research implies the nucleus as a central hub in cellular PQC. Here, not only nuclear but also proteins from other organelles, including mitochondria or the cytosol, are handled by intra-nuclear PQC factors. In addition, the nucleus controls the expression of mitochondrial proteins and PQC components involved in handling mitoPREs and surveilling the integrity of mitochondrial import channels. In this review, we discuss recent insights from yeast on the dual function of the nucleus in controlling the biogenesis of mitoPREs and as a compartment for quality control of non-imported mitoPREs. We additionally describe how mitochondrial dysfunction and defects in mitochondrial import trigger compensatory stress responses inside the nucleus. Here, nuclear targeting of non-imported mitoPREs may serve as a direct signal to adjust stress response pathways to the status of mitochondrial import.

Keywords:  chaperones; mitochondria; nucleus; protein quality control; protein sorting; stress response; ubiquitin‐proteasome system

DOI:  https://doi.org/10.1002/pro.70622
Transl Androl Urol. 2026 Apr 27. 15(4): 134

Aberrant methylation of mitochondrial genes as a link between oxidative phosphorylation dysregulation and the pathogenesis of hypospadias: a multiomics and clinical sample study.

Hongchao Yang, Jian Wang, Youtian Zhang, Wei Wang, Liqiong Guo, Shuhao Shi, Zhenhua Zhang, Yong Guan, Hualei Cui.

   Background: Hypospadias is among the most prevalent congenital malformations in male newborns. Despite its clinical significance, the molecular etiology of hypospadias has not extensively characterized. Although environmental exposures, epigenetic dysregulation, and mitochondrial dysfunction have been identified as potential contributing factors, the role of mitochondrial DNA (mtDNA) methylation in the pathogenesis of hypospadias has not been systematically examined. Therefore, this study aimed to investigate the potential involvement of mtDNA methylation in hypospadias and to explore its association with mitochondrial gene expression and oxidative phosphorylation-related pathways.
Methods: To investigate mtDNA-related epigenetic alterations in hypospadias, an integrated analysis of transcriptomic and methylomic data was conducted. Alongside control specimens, preputial tissue samples were obtained from patients diagnosed with distal, midshaft, and proximal hypospadias. RNA sequencing (RNA-seq) was performed to profile gene expression. Subsequent functional enrichment analyses were conducted to identify the key disturbed biological pathways. Additionally, mtDNA methylation patterns were examined via publicly available methylation datasets, and this was followed by targeted validation with bisulfite pyrosequencing in order to facilitate the quantification of site-specific methylation levels of the selected mitochondrial genes.
Results: RNA-seq identified 96 differentially expressed genes (DEGs), of which 87 were upregulated and 9 downregulated. Subsequent functional enrichment analysis indicated that oxidative phosphorylation (OXPHOS)- and reactive oxygen species (ROS)-related pathways were the most significantly affected biological processes. Further analysis of mitochondrial gene transcriptomes revealed broadly similar upregulation patterns across different hypospadias subtypes, with MT-CO1, MT-CO3, MT-RNR2, and MT-ND6 being identified as the commonly dysregulated genes. Methylation analysis of target genes revealed unique epigenetic features in hypospadias tissue: MT-CO1 and MT-RNR2 exhibited significant hypomethylation, MT-ND6 showed hypermethylation, and MT-CO3 demonstrated no significant methylation changes. Notably, this methylation pattern was not significantly different across clinical subtypes, suggesting that it may represent a potentially shared epigenetic feature independent of anatomical classification.
Conclusions: Our findings indicate that aberrant mtDNA methylation is associated with altered mitochondrial gene expression and disrupted OXPHOS in hypospadias. This type of epigenetic dysregulation may impair mitochondrial energy metabolism and redox balance, thereby contributing to abnormal urethral development. These results constitute novel evidence linking mitochondrial epigenetic modifications to the pathogenesis of hypospadias and highlights potential of molecular targets in future risk assessment, early diagnosis, and preventive interventions.

Keywords:  Hypospadias; mitochondrial DNA methylation (mtDNA methylation); mitochondrial dysfunction; multiple transcriptomic profiling; oxidative phosphorylation (OXPHOS)

DOI:  https://doi.org/10.21037/tau-2026-0251
Genet Med. 2026 May 20. pii: S1098-3600(26)00926-3. [Epub ahead of print] 102608

Mitochondrial aminoacyl-tRNA synthetase (ARS)-defects: a review of phenotypes and therapeutic strategies in 899 patients.

Eva M M Hoytema van Konijnenburg, Jingjing Ying, Gajja S Salomons, Saskia B Wortmann, Irena J J Muffels, Sabine A Fuchs.

   PURPOSE: Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are crucial for protein translation. The number of identified patients with mitochondrial (mt)ARS-deficiencies is rapidly increasing, but treatment is limited to supportive care. Recently, cognate amino acid supplementation has been explored. Early diagnosis and insights into the natural history are necessary to evaluate potential treatment effects.
METHODS: We performed a scoping literature search for patients with mtARS-deficiencies focusing on phenotype (using Human Phenotype Ontology (HPO) terms), disease progression, death rate and targeted treatments.
RESULTS: We identified 899 patients with 19 different mtARS-deficiencies with a wide variation in age of disease presentation (0-63 years), clinical symptoms and death rate (0-57%). Although neurological problems were common across many mtARS-deficiencies, symptoms were surprisingly different and highly specific for one or a few ARS-deficiencies. Supplementation with cognate amino acids, has been explored in 11 patients, but studies were largely observational and the observed effects were variable.
CONCLUSION: MtARS-deficiencies are an important subgroup within primary mitochondrial disorders with already 899 patients reported. The genotype-phenotype correlation between specific symptoms and mtARS-deficiencies is not yet understood. Treatment with cognate amino acids is a theoretically appealing potential disease-modifying treatment modality that needs to be explored further with well-designed controlled studies.

Keywords:  Aminoacyl-transfer RNA (tRNA) synthetase; mitochondrial disorder; mtARS-deficiency

DOI:  https://doi.org/10.1016/j.gim.2026.102608
Acta Med Port. 2026 May 18.

A Novel Combination of Biallelic Variants in the VARS2 Gene: A Severe Phenotype.

Joana Capela, Mariana Reis, Inês Almeida, Marta Novo, Ana Ramalho, Patrícia Lipari, Márcia Rodrigues.

  To our knowledge, only 29 individuals have been described in the literature with biallelic pathogenic variants in the valyl-tRNA synthetase 2 (VARS2) gene, responsible for changes in the mitochondrial respiratory chain complex. We report two siblings with a novel combination of biallelic variants in the VARS2 gene (c.1079C>T p.Ala360Val, likely pathogenic, and c.1258G>A p.Ala420Thr, likely pathogenic). Both presented early hypertrophic cardiomyopathy and lactic acidosis, with fatal outcomes within the first year of life. The first also presented severe fetal growth restriction and a ventricular septal defect; the second developed epilepsy, respiratory failure, and psychomotor delay. This genotype may be linked to a particularly severe cardiac phenotype. Our report broadens the clinical and genetic spectrum of VARS2-related mitochondrial disease, highlights the variability of phenotypic expression, and reinforces the importance of early molecular diagnosis in neonatal-onset cardiomyopathy. Genetic confirmation enables accurate genetic counselling and consideration of prenatal or preimplantation diagnosis in future pregnancies.

Keywords:  Cardiomyopathy; Epilepsy; Hypertrophic; Mitochondrial Diseases; Valine-tRNA Ligase/genetics

DOI:  https://doi.org/10.20344/amp.23831
BMC Med. 2026 May 22.

Quantitative assessment of efficacy and evaluation of feasibility of exercise training protocols in adult and pediatric primary mitochondrial disease.

Isaac Martin, Jean Flickinger, Imon Rahaman, Tejas Sarna, Elizabeth B Ballance, Nicholas Ginelli, James T Peterson, Arkady Uryash, Jose A Adams, Rui Xiao, Zarazuela Zolkipli-Cunningham.

   BACKGROUND: Exercise has been demonstrated to be effective in the general population and in a small number of Primary Mitochondrial Disease (PMD) human studies, raising the potential of exercise as standard of care in PMD. However, standardized exercise prescriptions have not been established in this heterogeneous patient population. This study aimed to identify effective and feasible exercise training protocols, to inform the design of rigorous exercise studies in adults and/or children with PMD. This was achieved through integration of a structured feasibility evaluation preceded by a quantitative review of published PMD studies, with specific focus on subgroup analyses by exercise type (aerobic, resistance, interval, and combination exercise).
METHODS: A systematic literature review was conducted to identify published exercise studies in PMD cohorts. Due to the limited number of PMD exercise studies, the search was expanded to include disorders with secondary mitochondrial dysfunction (SMD), with similar symptoms of muscle weakness, muscle fatigue and exercise intolerance, as occurs in PMD. In total, 77 studies comprising 109 exercise training protocols were identified. Of those, a quantitative analysis was performed on 37 PMD and SMD studies reporting key outcome measures to assess the effects of aerobic, resistance, combination or interval exercise training. All 109 exercise training protocols were then systematically evaluated for feasibility, as defined by the likelihood of successful implementation in future exercise studies of PMD, using a standardized scoring system.
RESULTS: Results of our quantitative analysis demonstrate the significant effect of distinct exercise types including aerobic exercise training on relative peak oxygen consumption (VO2), peak work, and Short-Form 36 (SF-36) physical summary score; and combination (interval/resistance/inspiratory muscle training) exercise training on relative peak VO2 and SF-36 across PMD studies. Feasibility evaluation across PMD and SMD studies involving expert group consensus review identified high-intensity circuit training (HICT), low-intensity steady-state (LISS) aerobic exercise, low-intensity resistance training, and blood flow restriction resistance training (BFR-RT) as being potentially feasible and effective in PMD.
CONCLUSIONS: Results of this study highlight specific exercise training protocols that merit assessment in future rigorously designed exercise studies to determine their feasibility and therapeutic efficacy in adults and/or children with PMD.

Keywords:  Aerobic training; Exercise intervention; Mitochondrial Myopathy; Outcome measures.; Primary Mitochondrial Disease; Resistance training

DOI:  https://doi.org/10.1186/s12916-026-04944-3
Pharmacol Res. 2026 May 18. pii: S1043-6618(26)00142-8. [Epub ahead of print] 108227

Review article: Improving Mitochondrial Function: Current Therapeutic Perspectives in Neurodegenerative Diseases.

Julia Brechtel, Christine Lietz, Selin Akpinar Adscheid, Kristina Friedland.

  Mitochondrial dysfunction is considered one of the key drivers of neurodegeneration and pathological aging, characterized by impaired energy production, oxidative stress, disrupted mitophagy, and biogenesis. Because mitochondria regulate bioenergetics, redox balance, and neuronal survival, therapeutic strategies that restore mitochondrial integrity are of growing interest. This review outlines mechanisms of mitochondrial function and failure, links them to Alzheimer's and Parkinson's disease, and summarizes evidence on phytochemicals and mitochondria-targeted small molecules, which enhance biogenesis, mitophagy, respiratory efficiency, and antioxidant defence in preclinical models together with life-style interventions. Although many compounds demonstrate preventive rather than restorative benefit and clinical evidence remains limited, next-generation approaches, including nanoparticles for mitochondrial delivery, mtDNA editing, and mitochondrial transfer, suggest increasing therapeutic potential. We underline that future success will rely on improved delivery, synergistic combinations, and rigorous clinical trials. Mitochondria-directed therapies may ultimately provide disease-modifying or preventive strategies for neurodegenerative disorders.

Keywords:  Alzheimer’s Disease; Mitochondria-Targeted Therapies; Mitochondrial Dynamics; Mitochondrial Dysfunction; Parkinson’s Disease; Phytochemicals; Small Molecule

DOI:  https://doi.org/10.1016/j.phrs.2026.108227
Mol Neurodegener. 2026 May 21.

Mitochondria transfer in neurological disorders: the key role of neuroglia.

Jie Jiao, Hui Chen, Alexei Verkhratsky, Yixun Su, Chenju Yi.

  Mitochondria transfer has emerged as a distinctive mechanism for intercellular communication and neuronal homeostasis. Neurones, owing to their unique bioenergetic demands, are particularly vulnerable to mitochondrial dysfunction, a shared pathogenetic feature across many neurological conditions, including neurodegenerative disorders, cerebrovascular diseases, and brain injuries. Intercellular transfer of mitochondria represents a potential adaptive mechanism rectifying compromised mitochondrial function. Neuroglial cells, especially astrocytes and microglia, frequently act as mitochondrial donors, supplying functional mitochondria to stressed neurones to restore bioenergetic capacity and influence disease trajectories. However, mitochondria transfer is intrinsically context dependent and can exert opposing effects. In addition to providing metabolic support, damaged mitochondria may also be transferred, propagating pathological signals, and exacerbating tissue injury. Moreover, in advanced disease states, mitochondrial malfunction often affects all cell types in the nervous system, including neuroglia, limiting the availability of healthy endogenous mitochondrial donors. This review critically examines mitochondria transfer in neurological diseases, with a focus on glial contribution and underlying mechanisms, and outlines key challenges and opportunities for advancing both mechanistic understanding and therapeutic translation.

Keywords:  Ageing; Extracellular vesicles; Mitochondrial transplantation; Neurodegeneration; Neuroglia; Traumatic brain injury; Tunnelling nanotubes

DOI:  https://doi.org/10.1186/s13024-026-00953-1
Mitochondrion. 2026 May 16. pii: S1567-7249(26)00059-0. [Epub ahead of print] 102169

Electron microscopy visualization of cell-free mitochondrial DNA-associated vesicular structures in human plasma, serum, and saliva.

Alexandra Volos, Soah Grace Franklin, Jeremy Michelson, Shannon Rausser, Jonathan R Brestoff, Martin Picard.

  Human biofluids contain cell-free mitochondrial DNA (cf-mtDNA) and extracellular mitochondria (ex-Mito), creating the challenge of defining their origins, destinations, mechanisms of regulation, and purposes. To expand our understanding of vesicular structures across human biofluids, we present a descriptive electron microscopy analysis of circulating particles from cf-mtDNA-enriched plasma (citrate, heparin, and EDTA), serum (red and gold top), and saliva collected from ten healthy participants (5 females, 5 males, mean age 44.9 years). Ex-mito and extracellular vesicles (EVs) were isolated by centrifugation followed by size-exclusion chromatography, imaged by transmission electron microscopy, and morphometrically analyzed. In parallel, cf-mtDNA was quantified in each biofluid to confirm enrichment. The resulting catalog of the most common circulating particles in plasma, serum, and saliva show that circulating double-membrane extracellular particles are present across human biofluids, along with EVs and other particle types. Combining imaging with cf-mtDNA quantification, we show that individuals with higher plasma cf-mtDNA concentrations tend to contain more double-membrane, ex-Mito-like particles. These preliminary and largely qualitative results do not directly demonstrate but are consistent with the concept of mitochondria transfer and/or signaling between cells and tissues. The image inventory provided here expands our knowledge of cell-free mitochondrial biology and provides a resource to inform biofluid selection and technical considerations in future studies quantifying ex-Mito and cf-mtDNA.

Keywords:  cell-free material; circulating; human; image repository; imaging; microscopy; mitochondria; study design; vesicles

DOI:  https://doi.org/10.1016/j.mito.2026.102169
Brain Behav Immun. 2026 May 20. pii: S0889-1591(26)00573-8. [Epub ahead of print] 106825

Diurnal dynamics and psychobiological regulation of cell-free mitochondrial and nuclear DNA in human saliva.

Alexander Behnke, David Shire, Samantha Leonard, Aidan Park, Lauren Petri, Anjali Goyal, Clemens Kirschbaum, Martin Picard, Caroline Trumpff.

Cell-free mitochondrial DNA (cf-mtDNA) has emerged as a dynamic molecular signal responsive to psychological stress and a potential biomarker of stress-related physiological adaptations. While previous work has established the acute stress reactivity of cf-mtDNA in saliva, little is known about its diurnal regulation. In this intensive-sampling study, we characterized the diurnal dynamics of saliva cf-mtDNA across one weekday and one weekend day in healthy adults (N = 25, 52% female, 826 samples). Saliva was collected at awakening, during the first hour post-awakening, and at hourly intervals throughout the day. Using a quantitative PCR-based assay, we observed a robust cf-mtDNA awakening response, with concentrations peaking approximately 45 min after waking (2.5-fold change, Cohen's d = 0.90), followed by a second peak at 180 min post-awakening (5.7-fold change, d = 1.70) and relatively stable levels thereafter. Saliva cf-mtDNA closely tracked cell-free nuclear DNA (cf-nDNA) across time points (rS = 0.85), suggesting shared release mechanisms. Diurnal cf-mtDNA showed limited correspondence with cortisol and other hormones in saliva. Psychosocial stress indicators-including daily hassles, lack of social support, negative emotional affect, trait anxiety, fatigue, and depressive symptoms-were associated with higher awakening cf-mtDNA levels, a diminished awakening response, and lower diurnal variability. These findings suggest that saliva cf-mtDNA exhibits a diurnal rhythm and is sensitive to psychosocial stress exposure. By establishing its diurnal patterns and individual-level variability, this study advances saliva cf-mtDNA as a promising non-invasive biomarker to dynamically capture stress-related mitochondrial signaling.

DOI: https://doi.org/10.1016/j.bbi.2026.106825
Free Radic Biol Med. 2026 May 21. pii: S0891-5849(26)00787-2. [Epub ahead of print]

Mitoredox Shifts in Mitochondrial Dysfunction.

Walter H Moos, Douglas V Faller, Ioannis P Glavas, Iphigenia Kanara, Krishna Kodukula, Julie Pernokas, Mark Pernokas, Carl A Pinkert, Whitney R Powers, Konstantina Sampani, Kosta Steliou, Demetrios G Vavvas.

  Mitochondrial dysfunction underlies a broad spectrum of primary and secondary disorders, yet current frameworks do not fully capture how diverse genetic, metabolic, and environmental stressors converge on shared pathological outcomes. Here, we propose that mitoredox shifts - bidirectional disruptions in mitochondrial redox homeostasis that alter mitochondrial quality control and genome-stability pathways - serve as a unifying axis linking oxidative stress, mitochondrial quality control failure, heteroplasmy dynamics, and regulated cell death. Both hyperactive and hypoactive mitochondrial states destabilize redox balance, altering PINK1/Parkin-dependent and receptor-mediated mitophagy, disrupting proteostasis, and reshaping mitochondrial network dynamics. These redox-driven perturbations influence the propagation of pathogenic mtDNA variants, modulate tissue-specific threshold effects, and bias cells toward apoptosis, ferroptosis, cuproptosis, and other regulated cell death pathways. We synthesize emerging evidence across mitochondrial genetics, bioenergetics, and redox signaling to outline how mitoredox shifts accelerate disease progression in both primary mitochondrial syndromes and secondary mitochondrial dysfunction. We further evaluate the expanding landscape of diagnostic biomarkers, including FGF21, GDF15, imaging-based oculomics, and high-throughput proteomic and genomic assays. In parallel, we highlight therapeutic strategies aimed at restoring redox balance, enhancing mitophagy, or shifting mitochondrial network composition by diluting dysfunctional organelles through mitochondrial transplantation. By emphasizing mitoredox imbalance as a recurrent feature of disease, this work synthesizes emerging diagnostic and therapeutic approaches across rare and common mitochondrial disorders.

Keywords:  Biomarkers; cuproptosis; ferroptosis; heteroplasmy; mitochondria; mitophagy; mitoredox medicine; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.307
Br J Nutr. 2026 May 18. 1-31

Krill Oil for Pain in Elders (KOPE): Protocol for a Pilot, Double-Blind, Randomized Controlled Trial Assessing Feasibility and Acceptability of 4 g/d Krill Oil Supplementation in Older Adults with Chronic Musculoskeletal Pain and Mobility Limitations.

Javier A Tamargo, Katarina Simic, Samira Capote, Rene Przkora, Kimberly T Sibille, Yenisel Cruz-Almeida, Stephen D Anton.

  Mobility limitations due to chronic musculoskeletal pain are a major contributor to disability in older adults, yet current pharmacological treatments often have limited efficacy and increase the risk of polypharmacy. Omega (ω)-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have demonstrated anti-inflammatory and analgesic properties, but are under-consumed among older U.S. adults. Krill oil, a marine-derived source of EPA and DHA with enhanced bioavailability compared to typical fish oils and additional bioactive compounds such as astaxanthin and choline, may offer a promising nutritional intervention. This pilot study will assess the feasibility and acceptability of a 3-month randomized, double-blind, placebo-controlled trial of krill oil supplementation (4 g/day: 1,288 mg EPA+DHA, 0.45 mg astaxanthin, 320 mg choline) versus placebo (mixed vegetable oils) in 40 community-dwelling adults aged ≥60 years with chronic musculoskeletal pain. Primary outcomes include feasibility (recruitment, retention, adherence) and acceptability (participant satisfaction). Secondary outcomes include changes in the omega-3 index, ω-6/ω-3 ratio, and inflammation (hs-CRP), as well as exploratory changes in pain intensity and functional interference, and physical function (Short Physical Performance Battery, 6-Minute Walk Test). Findings will inform the design of future fully powered trials that may ultimately contribute to the evidence for omega-3 supplementation as a non-pharmacological strategy to support healthy aging and functional independence in older adults.

Keywords:  Aging; Chronic Pain; Nutritional Supplementation; Omega-3 Fatty Acids; Physical Function

DOI:  https://doi.org/10.1017/S0007114526107557
J Physiol Biochem. 2026 May 21. pii: 53. [Epub ahead of print]82(1):

The progress of mitochondrial function and transfer in stem cell regulation and therapy.

Yubing Zhang, Zhuojian Qu, Zhiliang Guo, Lijuan Zhang, Hong Li, Xiaoyun Zhang, Xiumei Guan, Xiaodong Cui, Wenxu Wang, Min Cheng.

  Mitochondria, serving as central organelles for energy metabolism, play a critical regulatory role in stem cell self-renewal and differentiation-a function increasingly supported by accumulating evidence and closely linked to various aging-related diseases. Central to their function in stem cell pluripotency are several key mechanisms, such as the control of reactive oxygen species, mitophagy, and mitochondrial-endoplasmic reticulum communication. Mitochondrial transfer, as an emerging intercellular communication mechanism, can enhance stem cell pluripotency and function by replacing damaged mitochondria or activating mitophagy in recipient cells. However, different transfer mechanisms can induce distinct effects on recipient cells. The development of artificial mitochondrial transfer technology, compared to traditional cell transplantation, reduces immune rejection and offers new strategies for stem cell therapy. This review examines the interplay between mitochondrial function and stem cell fate determination, discusses the therapeutic potential of mitochondrial transfer in stem cell-based regenerative strategies, and establishes a theoretical framework for understanding and treating mitochondrial dysfunctions and aging-associated pathologies.

Keywords:  Mitochondrial function; Mitochondrial transfer; Mitophagy; Reactive oxygen species; Stem cell regulation

DOI:  https://doi.org/10.1007/s13105-026-01192-0