bims-ripira 2026-03-22 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–03–22
eleven papers selected by
Martín Lopo

Vitamin D deficiency selectively exacerbates mitochondrial dysfunction in receptor-rich soleus muscle during disuse-induced atrophy.
The Effects of Vitamin K2 on Recovery from Muscle-Damaging Resistance Exercise in Young and Older Adults: The TAKEOVER Randomized Controlled Trial.
Mitochondrial DNA released from pyroptotic synovial macrophages via DDIT3-mediated mitophagy aggravates osteoarthritis progression.
Mitochondrial dysfunction and mitochondrial unfolded protein response (UPRmt): unravelling their roles in autism spectrum disorder pathogenesis.
Cell-free mitochondrial DNA (cf-mtDNA) in human body fluids: molecular characteristics, release mechanisms, and clinical translation-an updated review.
The cerebro-cerebellar system: Integrative roles in motor control, cognition, and neuropsychiatric disorders.
Bioenergetic impairment in schizophrenia: role of mitochondrial signaling in synaptic dysfunction - a systematic review.
Mitorubin, berberrubine-based compounds that improve mitochondrial function, exhibit cardioprotective effects against age-related cardiac dysfunction.
Mitochondrial DNA: Bridging cellular senescence and chronic inflammation in aging and beyond.
Quantitative imaging of mitochondrial redox conditions at the single-organelle level.
From clinical practice to mechanistic insights in ketogenic diets for epilepsy.

J Steroid Biochem Mol Biol. 2026 Mar 17. pii: S0960-0760(26)00065-8. [Epub ahead of print]260 106999

Vitamin D deficiency selectively exacerbates mitochondrial dysfunction in receptor-rich soleus muscle during disuse-induced atrophy.

Moe Matsumoto, Natsumi Yanagisawa, Kaoruko Iida.

  This study investigated the role of vitamin D (VD) in disuse skeletal muscle atrophy, with a particular focus on muscle type-specific differences. Male C57BL/6 J mice were fed either a standard or VD-deficient diet and subjected to hindlimb immobilization to induce disuse atrophy. The expression of vitamin D receptor (VDR) was analyzed across several skeletal muscles, and muscle fiber atrophy and mitochondrial function were evaluated. In addition, cultured C2C12 myotubes were used to assess the direct effects of VD on oxidative stress-induced mitochondrial dysfunction. VDR expression was markedly higher in the soleus (SOL) muscle than in other muscles at both mRNA and protein levels. VD deficiency selectively exacerbated immobilization-induced atrophy solely in the SOL muscle, characterized by a significant reduction in muscle fiber cross-sectional area and downregulation of mitochondria-related genes (Pgc1α, Cox1, Cox5b, Cytb, Sdha). Consistently, mitochondrial function, which was assessed based on succinate dehydrogenase activity, further decreased in the VD-deficient SOL muscle. In contrast, the gastrocnemius (GC) and tibialis anterior (TA) muscles showed no significant VD-dependent changes. In C2C12 myotubes, active VD [1,25(OH)₂VD₃] attenuated hydrogen peroxide-induced reductions in mitochondrial gene expression and mitochondrial DNA content, suggesting a direct protective role of VD in muscle cells. Taken together, these findings demonstrate that VD deficiency aggravates disuse muscle atrophy through impaired mitochondrial function, particularly in muscles with high VDR expression, such as the SOL. The study highlights muscle type-specific vulnerability to VD deficiency and suggests that VD supplementation can protect certain muscles from disuse-induced atrophy.

Keywords:  Disuse atrophy; Mitochondria; Muscle; Vitamin D

DOI:  https://doi.org/10.1016/j.jsbmb.2026.106999
Med Sci Sports Exerc. 2026 Apr 01. 58(4): 683-694

The Effects of Vitamin K2 on Recovery from Muscle-Damaging Resistance Exercise in Young and Older Adults: The TAKEOVER Randomized Controlled Trial.

Hannah Lithgow, Lynsey Johnston, Frederick Ho, Emma Dunning, Shinya Nakada, Carlos Celis-Morales, Angus M Hunter, Jennifer S Lees, Patrick B Mark, Terry J Quinn, Stuart R Gray.

   PURPOSE: Vitamin K2 supplementation has emerged as a strategy to enhance recovery and modulate postexercise physiological responses. This study aimed to assess the effects of vitamin K2 on recovery from muscle-damaging exercise in young and older adults.
METHODS: Healthy young (18-40 yr) and older (65+ yr) adults were randomly assigned to either vitamin K2 (menaquinone-7, MK-7, 240 μg/d) or placebo (cellulose) for 12 wk in this double-blind randomized controlled trial. Before and after supplementation, knee extensor maximal torque, functional ability, muscle soreness, and systemic blood markers of muscle damage and inflammation were measured before (0 h) and 3, 24, 48, and 72-h postexercise. Data were analyzed using regression and mixed models.
RESULTS: Seventy-one participants (35 young and 36 older) completed the study, with 12 wk of vitamin K2 supplementation increasing circulating MK-7 levels (P-value <0.001). There were no supplement × time effects for any variables. Significant supplement × time × older age interaction effects were noted for electromechanical delay (EMD) (P-value = 0.03), electromyography root mean square (RMS) (P-value = 0.01), interleukin-6 (IL-6) concentrations (P-value <0.001), and creatine kinase (CK) levels (P-value = 0.02). In older adults, after 12 wk, EMD appeared lower at all time points and RMS higher postexercise in the vitamin K2 group. No clear pattern in IL-6 or CK was observed, but at 72-h postexercise CK was lower in older adults in the vitamin K2 group.
CONCLUSIONS: Vitamin K2 supplementation had no effect on muscle strength, physical function, muscle soreness, or inflammatory responses in the recovery period after a bout of resistance exercise. Effects of supplementation were observed on EMD, RMS, IL-6, and CK by age and warrant further investigation.

Keywords:  INFLAMMATION; MUSCLE DAMAGE; RECOVERY; RESISTANCE EXERCISE; VITAMIN K2

DOI:  https://doi.org/10.1249/MSS.0000000000003901
J Orthop Translat. 2026 Jan;56 101036

Mitochondrial DNA released from pyroptotic synovial macrophages via DDIT3-mediated mitophagy aggravates osteoarthritis progression.

Chang Yang, Jin Ke, Qiongdong Xu, Wei Dong, Wenqian Yu, Yan Wang, Jiawei Wang.

   Objective: Emerging evidence has shown that inflammatory synovial macrophage and anabolism-impaired chondrocytes play essential roles in osteoarthritis (OA). The present work aims at uncovering the pathogenic mechanism of how the damage-associated molecular patterns (DAMPs) released from inflammatory synovial macrophage promote extracellular matrix (ECM) degradation of chondrocytes and developing feasible strategies to counter its detrimental effects.
Methods: We identified pyroptosis of synovial macrophages in the synovium of OA human and mouse. The effect and mechanism of mitochondrial DNA (mtDNA) released from pyroptotic synovial macrophage in ECM degradation of chondrocytes and cartilage degeneration was further explored in cellular and animal models. Finally, the ameliorative effect of folic acid-modified poly (lactic-co-glycolic acid) (PLGA) nanoparticles in OA was elucidated by in vivo experiments.
Results: Mitochondrial dysfunction in synovial macrophages leads to the release of mtDNA into the cytoplasm, which promotes macrophage pyroptosis, thereby facilitating extracellular release of mtDNA and creating an inflammatory microenvironment unfavorable to cartilage in OA. DDIT3 deficiency inhibits mtROS production by enhancing PINK1/Parkin-dependent mitophagy, which constraining the mtDNA release into the cytoplasm. The decreased cytosolic mtDNA, in turn, dampens macrophage pyroptosis. In vivo, DDIT3 deficiency significantly alleviates synovial inflammation and cartilage degeneration in OA progression, and targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles mimics the protective effects of DDIT3 deficiency against OA progression.
Conclusions: Our findings identified the pathological role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA, and demonstrated the efficacy of using folic acid-modified PLGA nanoparticles as a delivery for OA treatment.
The translational potential of this article: This study highlights the pivotal role of mtDNA released from pyroptotic synovial macrophages through DDIT3-mediated mitophagy in OA. Targeting inhibition of macrophage pyroptosis by folic acid-modified PLGA nanoparticles might serve as a potential therapeutic target for alleviating cartilage degeneration in OA.

Keywords:  Cartilage degeneration; DDIT3; Osteoarthritis; Pyroptotic macrophages; mtDNA release

DOI:  https://doi.org/10.1016/j.jot.2025.101036
Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00038-3. [Epub ahead of print] 102148

Mitochondrial dysfunction and mitochondrial unfolded protein response (UPRmt): unravelling their roles in autism spectrum disorder pathogenesis.

Merlin Jeejo, Mrudula Mathew, Kochupurackal P Mohanakumar, Usha Rajamma.

  Autism spectrum disorders (ASD) is a complex neurodevelopmental condition characterized by a gamut of impairments in social interaction, communication, and behaviour. Emerging evidence implicates mitochondrial dysfunction, manifested through disruptions in ATP synthesis, mitochondrial DNA (mtDNA) mutations, and heightened oxidative stress, as a significant contributor to the pathophysiology of ASD. Notably, individuals with ASD demonstrate a higher prevalence of mitochondrial disorders compared to the general population, suggesting a potential pathogenic link. However, the relationship between mitochondrial dysfunction and ASD is heterogeneous and varies among individuals, reflecting the disorder's intrinsic complexity. Recent interest in the Mitochondrial Unfolded Protein Response (UPRmt), which is activated in response to mitochondrial stress and misfolded proteins, underscores its critical role in maintaining mitochondrial integrity. Yet, its specific implications in ASD have been insufficiently investigated. This review aims to consolidate the current literature on UPRmt-related biomarkers in the context of ASD, elucidating how disruptions in this pathway may exacerbate mitochondrial dysfunction and contribute to ASD pathogenesis. In this narrative review, based on our literature search from academic databases such as PubMed, Scopus, Web of Science, and Google Scholar, and also grey literature, we present a conceptual framework to enhance our understanding of ASD pathophysiology that integrates mitochondrial stress, UPRmt activation, and neurodevelopmental outcomes. This review aims to expand the existing knowledge of mitochondrial contributions to ASD and identify new research dimensions to explore the mechanisms underlying UPRmt deregulation in ASD pathophysiology, thereby highlighting the potential therapeutic directions for targeting mitochondria-mediated UPRmt dysfunction in ASD.

Keywords:  Autism spectrum disorders; Gut-brain axis; Mitochondrial dysfunction; Mitochondrial unfolded protein response; Mitokine

DOI:  https://doi.org/10.1016/j.mito.2026.102148
Front Mol Biosci. 2026 ;13 1774015

Cell-free mitochondrial DNA (cf-mtDNA) in human body fluids: molecular characteristics, release mechanisms, and clinical translation-an updated review.

Yu Liu, Xixiang Ma, Qingmei Guan, Shunchang Zhou.

  Since its discovery, cell-free mitochondrial DNA (cf-mtDNA) has emerged as a promising non-invasive molecular marker for disease diagnosis and prognosis. However, the biological origins of cf-mtDNA remain incompletely understood, which limits its clinical applications. This review comprehensively summarizes the molecular characteristics, release mechanisms, and diagnostic applications of cf-mtDNA. By discussing standardization of cf-mtDNA detection methods, this review aims to provide theoretical foundations for clinical translation of this emerging biomarker.

Keywords:  body fluids; cf-mtDNA; molecular features; molecular markers; release mechanism

DOI:  https://doi.org/10.3389/fmolb.2026.1774015
IBRO Neurosci Rep. 2026 Jun;20 438-447

The cerebro-cerebellar system: Integrative roles in motor control, cognition, and neuropsychiatric disorders.

Mst Mohona Khatun, Mohammad Shahangir Biswas, Munna Kumar Podder, Rubait Hasan, Mst Ayesha Siddika.

  The cerebro-cerebellar system, a network of bidirectional loops between the cerebellum and cerebral cortex, is crucial for coordinating motor control, cognition, and emotion. Moving beyond its traditional role in motor coordination, contemporary research underscores the cerebellum's significant involvement in higher-order functions, including executive control, language, and social cognition. This review synthesizes current anatomical, functional, and clinical evidence to delineate the cerebellum's role in neuropsychiatric and neurodegenerative disorders such as schizophrenia, autism spectrum disorder (ASD), and ataxia. Unlike previous broad reviews, this article provides a structured framework that links cerebellar functional topography with disease-specific pathophysiological mechanisms. We particularly highlight the cellular substrates of cerebellar plasticity, such as Purkinje cell long-term depression (LTD). Our synthesis reveals that prior literature often lacks mechanistic depth and fails to integrate findings across structural, functional, and clinical domains. We conclude by proposing future research directions involving advanced neuroimaging, artificial intelligence, and targeted neuromodulation, thereby clarifying the cerebellum's integrative roles and underscoring its translational potential for novel therapeutic strategies.

Keywords:  Ataxia; Autism Spectrum Disorder; Cerebellum; Cerebral Cortex; Cerebro-cerebellar Loops; Long-Term Depression; Neuroimaging; Neuromodulation; Neuroplasticity; Schizophrenia

DOI:  https://doi.org/10.1016/j.ibneur.2026.03.001
Front Cell Dev Biol. 2026 ;14 1740079

Bioenergetic impairment in schizophrenia: role of mitochondrial signaling in synaptic dysfunction - a systematic review.

Valerio Ricci, Giovanni Martinotti, Alessio Mosca, Giuseppe Maina.

   Background: Mitochondrial dysfunction represents a critical pathophysiological mechanism in schizophrenia, potentially linking bioenergetic impairment to synaptic dysfunction and cognitive deficits. Converging evidence suggests that deficits in oxidative phosphorylation may drive the synaptic pathology contributing to treatment-resistant cognitive and negative symptoms.
Objective: To systematically review the evidence linking mitochondrial bioenergetic dysfunction to synaptic impairment in schizophrenia, examining structural, functional, and molecular mechanisms across multiple methodological approaches.
Methods: Following PRISMA guidelines, we searched PubMed/MEDLINE, Embase, PsycINFO, and Web of Science from 2000 to 2025 for original research studies investigating mitochondrial function and synaptic dysfunction in schizophrenia. Two independent reviewers screened 2,224 articles, with 29 studies meeting inclusion criteria. Quality was assessed using the Newcastle-Ottawa Scale (median score 7/9).
Results: Twenty-nine studies representing 2,847 participants demonstrated consistent mitochondrial dysfunction across postmortem (n = 10), neuroimaging (n = 8), and molecular/cellular (n = 11) investigations. Postmortem studies revealed reduced complex I (18%-35%) and complex IV activity (22%-28%) in prefrontal cortex, with concurrent synaptic density reductions (27%). Neuroimaging studies demonstrated 20%-22% reductions in ATP synthesis rates correlating with cognitive deficits (r = 0.48) and negative symptoms (r = -0.42). First-episode antipsychotic-naïve patients exhibited comparable bioenergetic abnormalities, indicating primary pathophysiology rather than medication effects. Molecular studies identified impaired calcium homeostasis, oxidative stress (27%-35% glutathione reductions in synaptic compartments), and novel pseudogene regulatory mechanisms perpetuating complex I deficits. Peripheral biomarkers including platelet complex I activity and cell-free mitochondrial DNA showed disease specificity and correlation with cognitive impairment. Substantial methodological heterogeneity precluded meta-analysis but provided complementary evidence across analytical levels.
Conclusion: Mitochondrial bioenergetic impairment represents a core, potentially modifiable pathophysiological mechanism driving synaptic dysfunction in schizophrenia. Regional specificity (prefrontal cortex, hippocampus) and cell-type selectivity (pyramidal neurons) provide mechanistic insights into cognitive symptom profiles. Early presence and progressive worsening suggest critical intervention windows. Mitochondrial-targeted therapies merit investigation as novel approaches for treatment-resistant cognitive and negative symptoms.

Keywords:  bioenergetics; first-episode psychosis; mitochondrial dysfunction; oxidative phosphorylation; schizophrenia; synaptic dysfunction

DOI:  https://doi.org/10.3389/fcell.2026.1740079
NPJ Aging. 2026 Mar 20.

Mitorubin, berberrubine-based compounds that improve mitochondrial function, exhibit cardioprotective effects against age-related cardiac dysfunction.

Michio Sato, Daishi Tanabu, Daisuke Torigoe, Tsuyoshi Kadomatsu, Keito Taniwaka, Yoshinobu Ogata, Isshin Shiiba, Yuiko Suzuki, Naoki Ito, Ryoko Inatome, Takeshi Tokuyama, Toshihiko Takeiwa, Satoshi Inoue, Eito Kanai, Takashi Hamano, Hiromi Hirata, Kayoko Kanamitsu, Hiroyuki Kusuhara, Akihito Yokosuka, Yoshihiro Mimaki, Hideki Abe, Yuichi Oike, Shigeru Yanagi.

Mitochondria play a central role in cellular energy metabolism and homeostasis, and their dysfunction is closely linked to the progression of age-related diseases. The mitochondrial ubiquitin ligase MITOL (also known as MARCHF5) is a key regulator of mitochondrial dynamics and function, and reduced MITOL expression in the mouse heart has been implicated in mitochondrial dysfunction and cardiac aging. In this study, we identified berberrubine as a compound that promotes MITOL expression and activates mitochondria. We further assembled a group of berberrubine-based compounds, including its quinoid form and a newly developed water-soluble derivative, and collectively named them "Mitorubin" as mitochondria-activating compounds with therapeutic potential. While conventional berberrubine has poor water solubility, the addition of acetic acid significantly improved its solubility, enabling formulation as a solution. Mitorubin enhanced MITOL expression in cultured cells, increased mitochondrial DNA content and expression of mitochondrial proteins, and promoted mitochondrial respiration. In a model of age-related cardiac dysfunction, oral administration of Mitorubin restored mitochondrial function, improved cardiac performance, suppressed myocardial hypertrophy, and alleviated pulmonary congestion. Moreover, Mitorubin did not shorten lifespan in aged mice and significantly extended lifespan in high-fat diet-fed mice, suggesting both safety and efficacy under chronic administration. These findings suggest that Mitorubin is a promising mitochondrial activator and may represent a novel therapeutic strategy for age-related diseases.

DOI: https://doi.org/10.1038/s41514-026-00366-w
Mutat Res Rev Mutat Res. 2026 Mar 17. pii: S1383-5742(26)00003-7. [Epub ahead of print]797 108587

Mitochondrial DNA: Bridging cellular senescence and chronic inflammation in aging and beyond.

Shimeng Wang, Fanglong Wu, Hongmei Zhou.

  Aging is a progressive and irreversible physiological process driven by a complex network of interrelated molecular and cellular mechanisms. Among these, cellular senescence and chronic inflammation, as two core hallmarks of aging, are interlinked and jointly promote the development and progression of aging. However, the precise molecular crosstalk between these two processes remains unclarified. Mitochondrial DNA (mtDNA), as the only cytoplasmic DNA, has recently emerged as a pivotal "bridge" linking cellular senescence and chronic inflammation through various mechanisms. Anchored on the unique characteristics of mtDNA, this review systematically elucidates its central roles in mitochondrial dysfunction and oxidative stress, with a particular emphasis on the dynamic changes of mtDNA within the cytosol and extracellular space that construct and amplify the cellular "inflammation-senescence" coupling network. Furthermore, we propose a conceptual framework linking mtDNA mutation/damage to the cellular senescence and the propagation of chronic inflammation. Finally, we discuss the therapeutic potential of targeting mtDNA dynamics and highlight key challenges and future directions in this emerging field, offering novel insights for mitigating aging and age-related diseases.

Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Mitochondrial DNA; Therapeutic intervention

DOI:  https://doi.org/10.1016/j.mrrev.2026.108587
Mitochondrion. 2026 Mar 13. pii: S1567-7249(26)00037-1. [Epub ahead of print]89 102147

Quantitative imaging of mitochondrial redox conditions at the single-organelle level.

Steffen Pöschel, Michael Müller.

  Mitochondria are morphologically and functionally heterogeneous and dynamically adapt to the current metabolic status of their hosting cell. Moreover, they are prominent sources but also sensitive targets of redox modulation and oxidative stress. Such subcellular ROS/redox signals are considered pivotal aspects in health and disease. Yet, their deciphering requires advanced optical tools. Here we took advantage of transgenic redox-indicator mice expressing a mitochondria-targeted reduction/oxidation-sensitive green fluorescent protein (roGFPm) in excitatory projection neurons. By excitation-ratiometric two-photon microscopy we quantified in acute brain slices the redox conditions of individual mitochondria. After developing adequate redox sensor calibrations and solving laser-mediated bleaching issues, we finally chose caudoputamen, which showed the most promising mitochondrial arrangement for our imaging approach. Confirming the reliability of single-mitochondria redox imaging, we characterized the interplay of redox state and mitochondrial morphology. In general, roGFPm was more oxidized in spherical than in filamentous mitochondria. Acute hypoxia reverted mitochondria to a more roundish shape and evoked a reducing shift. Furthermore, the fraction of spherical mitochondria increased with aging. Around postnatal day (pd)350, a significantly higher fraction of roundish mitochondria was present in females than in males. In addition, from pd150 on, female mice showed lower degrees of roGFPm oxidation than males. Both findings might be linked to estrogen levels, which decrease in female mice with reproductive senescence around pd350. In view of the pivotal role of mitochondria for cellular wellbeing and their involvement in various neuropathologies, the established single-organelle redox-imaging approach will foster further detailed studies.

Keywords:  2-photon microscopy; Aging; Hypoxia; Mitochondria; Reactive oxygen species; Redox imaging; roGFP

DOI:  https://doi.org/10.1016/j.mito.2026.102147
Lancet Neurol. 2026 Mar 11. pii: S1474-4422(26)00008-6. [Epub ahead of print]

From clinical practice to mechanistic insights in ketogenic diets for epilepsy.

Anna G Figueroa, Charuta N Joshi, Manisha N Patel.

Ketogenic diet therapies, including the classic ketogenic diet, modified Atkins diet, and low glycaemic index treatment, have shown effectiveness in controlling seizures, in part by shifting metabolism from glucose to ketone bodies. They improve mitochondrial function, reduce neuroinflammation, and modulate neurotransmitters. Ketogenic diet therapies also affect the gut microbiome, potentially impacting neurotransmitter balance in ways that contribute to seizure control. A classic ketogenic diet is effective yet restrictive, whereas the modified Atkins diet and low glycaemic index treatment offer greater flexibility, tolerability, and ease of implementation, particularly in resource-limited settings. Cochrane reviews and meta-analyses rank the certainty of randomised controlled trial evidence for ketogenic diet therapies as limited. Early initiation of ketogenic diet therapies, particularly in children or patients with metabolic epilepsies, improves seizure outcomes, potentially preventing further mitochondrial and neuronal damage and reducing the risk of developing resistance to antiseizure medications. Research using rigorous, large-scale comparative effectiveness study designs that accounts for differences in age, epilepsy type, dietary therapy modality, sociodemographic background, care delivery contexts, and that minimises performance and observation bias is needed to resolve remaining uncertainties regarding the efficacy and real-world challenges of ketogenic diet therapies in epilepsy.

DOI: https://doi.org/10.1016/S1474-4422(26)00008-6