bims-ripira Biomed News
on RRM2B MDMD in Adults
Issue of 2026–01–18
thirteen papers selected by
Martín Lopo
  1. Assessment of circulating cell-free mitochondrial DNA as a damage associated molecular pattern in predicting severity and mortality of sepsis and septic shock patients.
  2. Research Progress on Idebenone in Neurodegenerative Diseases.
  3. Evaluation of MASSARRAY technique in detecting mitochondrial disease mutations.
  4. Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
  5. FALCON-qPCR: a new method for the quantification of oxidative lesions in mitochondrial DNA.
  6. A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
  7. Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.
  8. The dual regulation of mitophagy in myocardial injury: From molecular mechanisms to targeted therapies.
  9. MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
  10. Exercise and Brain Health: Expert Review.
  11. What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
  12. The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?
  13. Cardiac Sympathetic Innervation and Ventricular Arrhythmias in Structural Heart Disease: Current Peripheral Neuromodulation Therapies and Emerging Therapeutic Targets.
  1. Eur J Trauma Emerg Surg. 2026 Jan 13. 52(1): 18
    Assessment of circulating cell-free mitochondrial DNA as a damage associated molecular pattern in predicting severity and mortality of sepsis and septic shock patients.
    Bushra, Safia Begum, Shaik Iqbal Ahmed, Akbar Pasha, Ramesh Kande, Mohammed Affan Osman Khan, Aleem Ahmed Khan.
       BACKGROUND: Sepsis and septic shock are life-threatening conditions with high mortality, presenting challenges in predicting disease severity and outcomes. Cell-free mitochondrial DNA (mtDNA) has emerged as a potential mediator in sepsis pathogenesis, acting as a damage-associated molecular pattern (DAMP) that exacerbates inflammation. The present study aimed to assess cell-free mtDNA levels as predictors of mortality and disease severity, and to determine their correlation with established clinical markers.
    METHODS: A prospective study enrolled 150 participants, including healthy controls (n = 50) and patients (n = 100, of which 50 had sepsis and 50 had septic shock). Plasma cell-free mtDNA levels were quantified using RT-qPCR, and Receiver operating characteristic (ROC) curves were used to evaluate the predictive ability of cell-free mtDNA for 28-day mortality. The cell-free mtDNA correlated with clinical markers, including C-reactive protein (CRP), Sequential Organ Failure Assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE II), Procalcitonin (PCT), neutrophil-to-lymphocyte ratio (NLR), and lactate.
    RESULTS: Cell-free mtDNA levels were significantly elevated in sepsis and septic shock patients compared to controls, and higher in septic shock compared to sepsis patients. Non-survivors exhibited significantly higher cell-free mtDNA levels than survivors across both sepsis and septic shock subgroups. Cell-free mtDNA demonstrated a superior predictive value for 28-day mortality, area under the curve (AUC = 0.865) compared to clinical markers (CRP, SOFA, PCT, NLR, and Lactate). Furthermore, cell-free mtDNA levels showed a positive correlation with CRP, followed by SOFA, NLR, and PCT.
    CONCLUSION: Elevated circulating cell-free mtDNA levels were associated with severity and mortality in sepsis and septic shock, and may act as a valuable molecular tool for predicting disease outcomes. The study's findings warrant further investigation into the potential of cell-free mtDNA as a future component of clinical management strategies in sepsis.
    Keywords:  Circulating cell-free mitochondrial DNA; DAMPs; Inflammation; Sepsis; Septic shock
    DOI:  https://doi.org/10.1007/s00068-025-03058-4
  2. Aging Med (Milton). 2025 Dec;8(6): 624-633
    Research Progress on Idebenone in Neurodegenerative Diseases.
    Yanqing Zhang, Yanhong Ren, Xiaoran Zhu, Tianhao Liu, Rundong Han, Yuqing Fang, Zhangning Zhao, Fei Mao, Yalin Wang, Xian Li, Xiuhua Li.
      In recent years, significant progress has been made in understanding the therapeutic potential of idebenone (IDE), a synthetic analogue of Coenzyme Q10, in neurodegenerative diseases (NDs). This review comprehensively examines the pharmacological properties of IDE and its emerging applications in various NDs, with particular emphasis on Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, and Huntington's disease. We elucidate IDE's multifaceted neuroprotective mechanisms, including its potent antioxidant activity that reduces reactive oxygen species production, its ability to enhance mitochondrial bioenergetics, and its regulatory effects on cellular metabolism. Additionally, we critically evaluate current clinical research findings and discuss the translational potential of IDE in ND therapeutics. The accumulated evidence strongly supports IDE as a promising mitochondrial-targeted agent capable of mitigating disease symptoms and modifying disease progression in multiple neurodegenerative disorders. This review highlights both the current achievements and future directions for IDE-based interventions in ND treatment.
    Keywords:  antioxidants; idebenone; mitochondria; neurodegenerative diseases; neuroprotection
    DOI:  https://doi.org/10.1002/agm2.70047
  3. Clin Chim Acta. 2026 Jan 10. pii: S0009-8981(26)00002-1. [Epub ahead of print]583 120820
    Evaluation of MASSARRAY technique in detecting mitochondrial disease mutations.
    Nahuda Chetu, Preyaporn Onsod, Budsaba Rerkamnuaychoke, Teerapong Siriboonpiputtana, Takol Chareonsirisuthigul.
      Mitochondrial diseases are caused by mutations in mitochondrial DNA (mtDNA), leading to impaired energy production, cellular dysfunction, and tissue damage. Accurate and efficient detection of mitochondrial DNA (mtDNA) mutations is crucial for diagnosis and patient management. This study aimed to evaluate the performance of MassARRAY in detecting mtDNA mutations compared to the routinely used MLPA technique. 34 EDTA blood samples from patients with suspected mitochondrial disorders were analyzed using MassARRAY and MLPA methods. MassARRAY was customized to detect 14 mtDNA loci, while MLPA targeted six fixed genetic loci. Both techniques detected five positive cases: three with the m.11778G > A mutation (8.82%) and two with the m.14484 T > C mutation (5.88%). Additionally, MassARRAY uniquely identified the m.12026 A > G mutation and a heteroplasmic m.12258C > A variant (2.94%). MassARRAY also demonstrated advantages in terms of rapid turnaround time (approximately 8 h) and assay flexibility. In conclusion, MassARRAY offers a highly accurate and efficient alternative for detecting mtDNA mutations, with the added benefit of customizable probes. However, sequencing confirmation is recommended for broader mutation coverage.
    Keywords:  Mitochondrial diseases; Multiplex MALDI-TOF mass spectrometry; Multiplex ligation-dependent probe amplification; mtDNA
    DOI:  https://doi.org/10.1016/j.cca.2026.120820
  4. Neurology. 2026 Feb 10. 106(3): e214401
    Clinical and Genotypic Spectrum of Twinkle-Related Disorders: Insights From a Multinational Cohort Study.
    Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC)
       BACKGROUND AND OBJECTIVES: Twinkle, encoded by the TWNK gene, is a mitochondrial DNA helicase that unwinds the double helix of DNA during replication, playing a pivotal role in mitochondrial function. Twinkle-related disorders encompass a variety of genetic disorders characterized by mitochondrial dysfunction. Although several phenotypes have been described, the full clinical and molecular spectrum remains poorly defined. The aim of this study was to characterize the phenotypic and genotypic variability among multinational patients diagnosed with Twinkle-related disorders.
    METHODS: A retrospective cohort study was conducted in patients with Twinkle-related disorders at several specialized centers in Italy, France, Germany, Spain, Denmark, Hungary, and the United States, establishing the Twinkle-Related Disorders International Consortium for Trial Readiness (TReDIC). Data were collected from medical records, including clinical features, age at onset, disease progression, and results from genetic testing. Phenotypic categories included infantile-onset cerebellar ataxia, parkinsonism, primary mitochondrial myopathy (PMM), multisystem involvement, asymptomatic carriers, undetermined phenotypes, and other phenotypes. All patients' diagnoses were confirmed by genetic analysis, and their genetic variants were noted. Outcomes included prevalence of phenotypes, symptom chronology, and mutational patterns.
    RESULTS: The study included a total of 189 patients (116 female), with a mean age at symptom onset of 40.3 years. At the time of analysis, 70.4% were alive. PMM was the predominant syndrome (85.2%), and most common features were progressive external ophthalmoplegia (84.7%) and skeletal myopathy (55.6%), followed by hearing loss (17.5%) and psychiatric symptoms (15.3%). Most patients (76.8%) presented with neuromuscular symptoms, with fewer showing CNS (19.6%) or multiorgan (3.6%) features at onset; by more than 8 years from onset, these proportions shifted to 54.4%, 23.3%, and 23.3%, respectively. A total of 73 TWNK variants (16 novel) were found, mostly missense, clustered in functionally critical regions.
    DISCUSSION: This large multinational cohort analysis advances our understanding of Twinkle-related disorders by identifying mutational hotspots with clinical relevance and illustrating the broad phenotypic spectrum and progression patterns. In the context of such rare diseases, the formation of international collaborations, such as TReDIC, can enhance our understanding and support the design of upcoming clinical trials.
    DOI:  https://doi.org/10.1212/WNL.0000000000214401
  5. Bioanalysis. 2026 Jan 12. 1-13
    FALCON-qPCR: a new method for the quantification of oxidative lesions in mitochondrial DNA.
    Veronica Bazzani, Eve Harding, Szymon Balinski, Mara Equisoain Redin, Dario Alessi, Pierfrancesco Del Mestre, Walter Baratta, Daniela Cesselli, Antonio Paolo Beltrami, Michał Turek, Umberto Baccarani, Carlo Vascotto.
      Accurate quantification of oxidative mitochondrial DNA (mtDNA) lesions remains technically challenging due to the limitations of existing assays, which often require large sample inputs, multi-day workflows, and offer limited sensitivity. Here we introduce FALCON-qPCR (Fpg-assisted Long-PCR), a streamlined, high-sensitivity method for quantifying oxidative damage in mtDNA. FALCON-qPCR couples digestion with formamidopyrimidine [fapy]-DNA glycosylase (Fpg) to long-range PCR and qPCR-based normalization, enabling precise lesion quantification from as few as 10,000 cells (~300 ng total DNA) within a single day. The assay provides a robust dynamic range and reproducibility across diverse biological systems, including human cell lines, hepatocellular carcinoma biopsies, and Caenorhabditis elegans. Compared with established methods, FALCON-qPCR exhibits markedly higher sensitivity in detecting mtDNA damage induced by hydrogen peroxide, antimycin A, and rotenone. Its performance was further demonstrated in assessing mitochondrial toxicity of ruthenium-based compounds, highlighting its potential for pharmacological screening. By integrating enzymatic lesion recognition with quantitative amplification in a unified workflow, FALCON-qPCR eliminates the need for mitochondrial isolation. This methodological advance provides a rapid, accurate, and scalable platform for studying oxidative DNA damage, with broad applicability in mitochondrial research and translational toxicology.
    Keywords:  LongRange-PCR; Mitochondria; mitochondrial DNA damage; oxidative stress
    DOI:  https://doi.org/10.1080/17576180.2025.2608757
  6. Cell Mol Life Sci. 2026 Jan 12.
    A central role for PINK1 in governing local mitochondrial biogenesis and degradation in neurons.
    Marlena Helms, Angelika B Harbauer.
      Neurons have adapted the transport and positioning of mitochondria to fit their extended shape and high energy needs. To sustain mitochondrial function, neurons developed systems that allow local biogenesis and adaption to locally regulate mitochondrial form and function. Likewise, fine-tuned degradative systems are required to protect the neurons from mitochondrial dysfunction. Throughout both domains of mitostasis, the local synthesis of the mitochondrial damage-induced kinase PINK1 emerges as a central player. Along with other nuclear encoded mitochondrial proteins, its mRNA associates with mitochondria to sustain mitochondrial function locally. It also regulates mitochondrial degradation, via regulation of proteases, the generation of mitochondria-derived vesicles and mitophagy. In this review, we provide a general overview of the mechanisms governing mitochondrial health in neurons, with a special focus on the role of PINK1 in this endeavor.
    Keywords:  Local translation; Mitochondrial proteases; Mitophagy; mRNA transport
    DOI:  https://doi.org/10.1007/s00018-025-06054-4
  7. Redox Biol. 2026 Jan 09. pii: S2213-2317(26)00017-0. [Epub ahead of print]90 104019
    Intercellular mitochondrial transfer rewires redox signaling and metabolic plasticity: mechanisms, disease relevance and therapeutic frontiers.
    Jiahui Wang, Rongqing Li, Li Qian.
      Intercellular mitochondrial transfer is recognized as a central mechanism that shapes redox homeostasis, metabolic plasticity, and cellular resilience across multiple tissues. Through tunneling nanotubes (TNTs), extracellular vesicles (EVs), gap junction channels (GJCs), and cell fusion, mitochondria move between donor and recipient cells to restore bioenergetic capacity, buffer oxidative stress, and tune redox-sensitive signaling networks. Recent work has begun to clarify the regulatory framework governing donor-recipient specificity, cargo selection, and the stress-activated cues that trigger organelle exchange. Mitochondrial transfer also exerts distinct, context-dependent influences on disease trajectories. It mitigates injury in neurological damage, ischemia-reperfusion conditions, immune dysfunction, aging, and inflammatory pain, largely by reprogramming mitochondrial function and reactive oxygen species (ROS) dynamics. Conversely, in cancer, mitochondrial acquisition enhances metabolic flexibility, invasiveness, and resistance to therapy. Current therapeutic approaches, including mitochondrial transplantation, EV-based delivery systems, and mitochondria-enhanced immune cells, highlight the translational potential of manipulating mitochondrial exchange, yet face challenges such as mitochondrial fragility, inefficient targeting, and immunogenicity. Deeper mechanistic insight into how mitochondrial transfer remodels redox signaling and metabolic adaptation will be essential for converting this biological process into next-generation organelle-level interventions for redox-driven disorders.
    Keywords:  Extracellular vesicles (EVs); Immunometabolism; Mitochondrial therapeutics; Mitochondrial transfer; Tunneling nanotubes (TNTs)
    DOI:  https://doi.org/10.1016/j.redox.2026.104019
  8. Tissue Cell. 2026 Jan 08. pii: S0040-8166(26)00010-8. [Epub ahead of print]99 103318
    The dual regulation of mitophagy in myocardial injury: From molecular mechanisms to targeted therapies.
    Haiyan Yang, Lei Zhang, Haixia Qian.
      Cardiovascular diseases (CVDs) are the leading cause of death worldwide, far exceeding other diseases such as cancer. Myocardial injury is a key link in various CVDs; reducing myocardial injury is an effective means of preventing and treating CVDs. Mitochondrial dysfunction is the pathological basis of various CVDs. Mitophagy, as a process that selectively eliminates damaged or dysfunctional mitochondria, is of enormous significance in maintaining the normal function and structure of mitochondria in cardiomyocytes and alleviating myocardial injury. Therefore, this review systematically analyzes the role of mitophagy in myocardial injury, explores targeted intervention strategies, and hopes to provide a theoretical basis and effective therapeutic targets for clinical practice.
    Keywords:  Cardiovascular Diseases; Mitophagy; Molecular Mechanisms; Myocardial Injury
    DOI:  https://doi.org/10.1016/j.tice.2026.103318
  9. Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00002-X. [Epub ahead of print]
    MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
    Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard.
      Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments/augmented muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTs-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.002
  10. Am J Lifestyle Med. 2026 Jan 09. 15598276251415530
    Exercise and Brain Health: Expert Review.
    Cyrus Safaeipour, Dean Sherzai, Bashir Zikria.
      Preserving brain health is essential to maintaining quality of life and cognitive function with age. Exercise plays an essential role. Aerobic exercise such as running and cycling can enhance brain plasticity through increasing gray matter volume in the cerebellum and temporal lobe, as well as the density of connections in the brain's frontal and motor areas via upregulating brain-derived neurotrophic factor (BDNF) and serotonin systems. Anaerobic exercise, such as weightlifting, primarily increases gray matter volume in the basal ganglia and increases the density of connections in the posterior lobe of the cerebellum. In midlife, aerobic exercise can increase white matter integrity and cortical thickness in primary motor and somatosensory areas, while in older age it improves specific markers of cognitive function, such as episodic memory. With regards to neurodegenerative diseases, aerobic exercise has been linked to improved memory performance and reduced hippocampal atrophy in Alzheimer's disease. In Parkinson disease, aerobic exercise has shown to reduce brain atrophy, improve motor function and cognitive control, while anaerobic exercise improves motor performance and information processing. Overall, both aerobic and anaerobic exercises are integral and complementary to preserving brain health through effects on cognitive function and brain structure.
    Keywords:  aerobic exercise; anaerobic exercise; brain health; cognitive function; cognitive preservation
    DOI:  https://doi.org/10.1177/15598276251415530
  11. Neurology. 2026 Feb 10. 106(3): e214618
    What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
    Eduardo Benarroch.
      Mitochondrial dysfunction is a key pathogenic component of neurodegenerative disorders. Mitochondrial stress, created by accumulation of misfolded proteins, reactive oxygen species, and other mechanisms, triggers signals that promote changes in protein translation and gene transcription aimed at protecting and restoring mitochondrial function and maintaining cellular homeostasis. These quality control responses are the integrated stress response and the mitochondrial unfolded protein response. When triggered by mild mitochondrial stress, these adaptive responses promote mitohormesis, which enhances cell survival and lifespan. The exchange of information between mitochondria allows mitochondrial stress in specific tissues to initiate beneficial adaptations affecting mitochondrial populations in remote tissues and organs. Experimental and human observational studies indicate that approaches to trigger mitohormesis, such as physical exercise, have beneficial effects in neurodegenerative disorders.
    DOI:  https://doi.org/10.1212/WNL.0000000000214618
  12. NAR Mol Med. 2026 Jan;3(1): ugaf042
    The nuclear and mitochondrial genomes need to tango. How is their dance synchronized during development?
    Justin C St John.
      For quite some time, knowledge about mitochondria and the mitochondrial genome has been primarily limited to energy production. However, there is now increasing evidence that they have many important roles in cell function and that synergy between the nuclear and mitochondrial genomes is an essential prerequisite to developmental outcome. This review describes the mitochondrial genome and its contribution to overall cellular genomic content; and discusses mitochondrial DNA (mtDNA) inheritance. mtDNA homoplasmy and heteroplasmy are defined and distinctions between pathogenic and non-pathogenic rearrangements are drawn; how they are transmitted; and their effects on oocyte quality and developmental outcomes. This is followed by analysis of mtDNA replication and changes in mtDNA copy number during development; why they need to happen; and how they influence developmental outcomes. Changes to nuclear DNA methylation events are then discussed in the context of changes to mtDNA replication throughout development. This leads to the concept of 'genomic balance', which defines how cells at any stage of development require adjustments to both genomes to ensure successful cellular function and development; and how this process can be perturbed by some of the more invasive assisted reproductive technologies designed to treat infertility and mtDNA disease.
    DOI:  https://doi.org/10.1093/narmme/ugaf042
  13. Arrhythm Electrophysiol Rev. 2025 ;14 e34
    Cardiac Sympathetic Innervation and Ventricular Arrhythmias in Structural Heart Disease: Current Peripheral Neuromodulation Therapies and Emerging Therapeutic Targets.
    Léa Benabou, Marmar Vaseghi.
      Over the past several decades, substantial evidence has pointed to the role of the autonomic nervous system in the genesis and maintenance of ventricular arrhythmia. In particular, sympathetic activation has been shown to increase the risk of ventricular arrhythmia, particularly in the context of structural heart diseases, and is a key target of neuromodulatory therapies. Current peripheral sympathetic neuromodulatory approaches include temporary interventions, such as stellate ganglion block, proximal intercostal block, and thoracic epidural anaesthesia, as well as more definitive therapies, such as cardiac sympathetic denervation and renal denervation. Each of these approaches presents distinct strengths and limitations, as well as side effects that warrant careful consideration in clinical practice and highlight the need for more targeted strategies. Emerging interventions focusing on neuropeptide Y, sympathetic afferents ablation, high-frequency block of efferent nerves, and the restoration of sympathetic innervation after MI have shown promising potential. However, further research is needed to evaluate the feasibility and safety of these novel therapies prior to their implementation in patients with cardiovascular diseases.
    Keywords:  Autonomic nervous system; TRPV1; neuromodulation; neuropeptide Y; sympathetic; ventricular arrhythmia
    DOI:  https://doi.org/10.15420/aer.2025.24
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