bims-ripira 2026-06-14 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–06–14
seventeen papers selected by
Martín Lopo

Evaluating a Coenzyme Q10-Based Food for Special Medical Purpose, for Mitochondrial Diseases Management: An Open-Label, Pilot Trial.
Mitochondrial DNA-driven intercellular communication networks in post-infarction ventricular remodeling: the three-threshold model of cGAS-STING activation.
Tranexamic acid inhibits mitochondrial DNA release and reduces inflammatory response in an in vitro model of OGD/R-induced Caco-2 cell injury.
Biological Variation of Natriuretic Peptides and Other Cardiovascular Disease-Related Biomarkers: A Systematic Review and Meta-analysis.
Egg-Derived Bioactive Peptides Modulate LPS-Induced Acute Intestinal Immune Stress via the FPR2-Mitochondrial Axis.
Oculomotor phenotypes and longitudinal video-oculography dynamics in anti-GAD65 antibody-associated neurological syndromes: a case series and literature review.
Testicular origin of epigenetic inheritance independent of sperm mitochondrial DNA and epididymal exposure.
Targeting Sensory Neuropathies Through Neurotrophin-Based Approaches.
Prevalence and treatment of mitochondrial diabetes in Southwest Finland.
GDF15 Aggravates Sepsis-Induced Coagulopathy and is Associated with PI3K/AKT/mTOR Signaling Changes.
Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.
Mitochondrial capsules mitigate mitochondrial dysfunction.
Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease.
Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.
Mitophagy: an emerging therapeutic target in mitochondrial diseases.
The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.
Use of medium-chain triglycerides in paediatric patients with drug-resistant epilepsy without ketogenic therapy.

Int J Mol Sci. 2026 Jun 05. pii: 5127. [Epub ahead of print]27(11):

Evaluating a Coenzyme Q10-Based Food for Special Medical Purpose, for Mitochondrial Diseases Management: An Open-Label, Pilot Trial.

Lucia Chico, Piervito Lopriore, Giulia Cecchi, Adriana Meli, Clara Bernardini, Linda Balestrini, Maico Polzella, Vincenzo Montano, Michelangelo Mancuso.

  Primary mitochondrial diseases (PMD) are rare disorders with limited therapeutic options. Coenzyme Q10 (CoQ10) supplementation is widely used, although formulation differences can affect absorption and efficacy. This open-label pilot feasibility trial evaluated a food for special medical purposes (FSMP) containing high-dose CoQ10 (250 mg per capsule) in patients with PMD. Ten patients (mean age: 55.5 ± 8.6 years) were enrolled. Serum/plasma biomarkers, including CoQ10, fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), ferric-reducing antioxidant power (FRAP), total sulfhydryl groups (t-SH), and advanced oxidation protein products (AOPP), were assessed at baseline (T0, after ≥30 days of conventional ubidecarenone) and after 30 days of FSMP administration (T1). Fatigue severity scale (FSS) and 5-times sit-to-stand test (5xSST) were evaluated at both timepoints. FSMP was administered at 250 or 500 mg/day. Twenty sex- and age-matched healthy controls were included for CoQ10 comparison. Absolute CoQ10 concentrations remained stable overall at T1, with all patients maintaining levels above 390 ng/mL (100% vs. 60% at T0), although concentrations remained lower than in healthy controls (p < 0.01). Dose-normalized CoQ10 exposure was significantly higher with FSMP versus conventional ubidecarenone (p < 0.001, Cohen's d = 7.31). FGF21, GDF15, AOPP, and t-SH remained unchanged, whereas FRAP increased at T1 (p < 0.01). No significant changes were observed in 5xSST and FSS. Exploratory analyses indicated inter-individual variability in functional responses. FSMP was associated with higher dose-normalized systemic CoQ10 exposure, more consistent circulating CoQ10, and increased FRAP levels. Its simplified dosing regimen may support long-term adherence. Larger studies are warranted to validate these preliminary findings.

Keywords:  antioxidants; coenzyme Q10; food for special medical purposes; mitochondrial diseases

DOI:  https://doi.org/10.3390/ijms27115127
Front Immunol. 2026 ;17 1852079

Mitochondrial DNA-driven intercellular communication networks in post-infarction ventricular remodeling: the three-threshold model of cGAS-STING activation.

Chao Meng, Xiao Xia, Yiying Liu, Jun Li, Shiyi Tao, Xuanchun Huang, Yonghao Li.

  Mitochondrial DNA (mtDNA) has long been recognized as an intracellular damage-associated molecular pattern, but emerging evidence reveals its role as an intercellular messenger driving post-infarction ventricular remodeling. This review systematically elaborates the transition of mtDNA from an "intracellular DAMP" to an "intercellular messenger" and proposes a conceptual framework termed the "three-threshold model", which integrates existing evidence but requires direct experimental validation. The three thresholds are defined as the release threshold (mitophagy-controlled mtDNA leakage), the transmission threshold (efficiency of intercellular transfer), and the activation threshold (sensitivity of STING signaling). mtDNA is transferred between cells via four modes-naked mtDNA, Ambra1+ sEVs, mt-sEVs, and intact mitochondria-mediating inflammation, fibrosis, and vascular dysfunction, respectively. These pathological effects continuously lower all three thresholds through positive feedback loops, driving irreversible remodeling. Time-window-based combination strategies offer a new paradigm for precision intervention. This framework integrates the entire process from mtDNA generation to intercellular transfer and downstream signaling, providing a systematic basis for precision intervention in post-infarction remodeling. Importantly, several components of this model are based on preliminary or indirect evidence and await independent confirmation.

Keywords:  cGAS-STING pathway; mitochondrial DNA; myocardial infarction; three-threshold model; ventricular remodeling

DOI:  https://doi.org/10.3389/fimmu.2026.1852079
BMC Pharmacol Toxicol. 2026 Jun 06.

Tranexamic acid inhibits mitochondrial DNA release and reduces inflammatory response in an in vitro model of OGD/R-induced Caco-2 cell injury.

Ziyue Wang, Liman Huo, Hong Liu, Shuwei Shi, Rui Feng.

   BACKGROUND: Ischemia-reperfusion (I/R) injury of the intestine remains a challenging clinical issue, and there is currently no definitive treatment protocol. Tranexamic acid (TXA), an antifibrinolytic drug used in bleeding patients, has been shown in previous studies to protect the intestinal epithelial barrier, but the specific mechanism remains unclear. This study aimed to explore the molecular mechanisms by which TXA protects the intestinal barrier after intestinal I/R.
METHODS: The cell viability assay was assessed to verify the cytotoxicity of TXA toward Caco-2 cells. A Caco-2 cell oxygen-glucose deprivation-reperfusion (OGD/R) model was established. The transepithelial electrical resistance (TEER) of Caco-2 cell monolayers and FITC-dextran permeability assays were performed to assess the intestinal barrier function. The JC-1 fluorescent probe was used for assessment of mitochondrial membrane potential. Quantitative PCR (qPCR) was used to quantify mitochondrial DNA (mtDNA) released by Caco-2 cells, and enzyme-linked immunosorbent assay (ELISA) was employed to assess inflammatory factors.
RESULTS: TXA reversed OGD/R-induced decreases in TEER and increases in FITC-dextran permeability in Caco-2 cell monolayers. Microscopy images of the Caco-2 monolayer also support these results. Additionally, TXA enhanced mitochondrial membrane potential, suppressed mtDNA release and alleviated inflammatory responses.
CONCLUSIONS: TXA protects the intestinal barrier after intestinal I/R by enhancing mitochondrial membrane potential, inhibiting mtDNA release and reducing inflammation, suggesting its potential as a therapeutic agent for intestinal I/R injury.

Keywords:  Caco-2 cell; Inflammation; Intestine Ischemia-reperfusion; Mitochondrial DNA; Tranexamic acid

DOI:  https://doi.org/10.1186/s40360-026-01160-w
Clin Chem. 2026 Jun 11. pii: hvag051. [Epub ahead of print]

Biological Variation of Natriuretic Peptides and Other Cardiovascular Disease-Related Biomarkers: A Systematic Review and Meta-analysis.

Pilar Fernández-Calle, Jorge Díaz-Garzón, Bill Bartlett, Abdurrahman Coskun, Anna Carobene, Elisabeth González-Lao, Fernando Marqués-García, Berta Sufrate-Vergara, Isabel Moreno-Parro, Kornelia Galior, Denis İlhan Topcu, Sverre Sandberg, Aasne K Aarsand.

BACKGROUND: The clinical application of cardiovascular disease (CVD) biomarkers requires robust biological variation (BV) data to enable both interpretation of serial results and definition of appropriate analytical quality. A critical review and meta-analysis of eligible BV studies of natriuretic peptides and other CVD-related biomarkers was therefore undertaken, with a focus on differences observed in different states of health and the impact of sampling intervals on BV.
METHODS: BV studies of N-terminal pro-B-type natriuretic peptide (NT-proBNP), brain natriuretic peptide, N-terminal pro-A-type natriuretic peptide, galectin, copeptin, soluble suppression of tumorigenicity-2, and growth differentiation factor 15 were identified by a systematic literature review and assessed using the Biological Variation Data Critical Appraisal Checklist. A meta-analysis of eligible studies was used to derive within-subject (CVI) and between-subject BV estimates, which were used to calculate analytical performance specifications, indices of individuality, and reference change values.
RESULTS: Twenty-one studies were identified, only 3 of which achieved an A grade on the Biological Variation Data Critical Appraisal Checklist, indicating full checklist compliance. For NT-proBNP, meta-analysis-derived CVI estimates depended on sampling frequencies and study duration: <15 days (9.9%; 95% CI, 8.8-18.0) and >15 days (34.3%; 95% CI, 25.0-60.0). For the other biomarkers, from one to 5 BV studies were identified, reporting on different states of health and sampling intervals.
CONCLUSIONS: This systematic review provides quality-assessed BV data for natriuretic peptides and other CVD markers. Our results highlight the influence of sampling frequency on CVI for NT-proBNP, potentially impacting the intended use. Further BV studies applicable to multiple clinical scenarios are required.

DOI: https://doi.org/10.1093/clinchem/hvag051
J Agric Food Chem. 2026 Jun 10.

Egg-Derived Bioactive Peptides Modulate LPS-Induced Acute Intestinal Immune Stress via the FPR2-Mitochondrial Axis.

Jiao Li, Le Chen, Huifang Xiang, Yongchao Chen, Jun Fang, Sujuan Ding.

  The egg-derived tripeptides IRW and IQW have been widely reported to possess anti-inflammatory and -antioxidant effects. This study aims to investigate their mechanistic roles in modulating the LPS-induced acute intestinal immune stress. The findings indicated that IRW and IQW significantly alleviated the LPS-induced intestinal and mitochondrial damage. Notably, IRW and IQW significantly reduced the release of mitochondrial N-formyl peptides (mtNFPs) caused by mitochondrial damage, which could activate FPR2. Consistently, FPR2 expression in the intestinal tissue was suppressed following peptide treatment. In addition, IRW and IQW inhibited ERK1/2 phosphorylation, which is potentially linked to improved mitochondrial function and reduced FPR2 expression. Metabolic analysis revealed elevated aspartate and glutamine levels while decreasing l-serine levels, which favored mitochondrial function recovery, suggesting that IRW and IQW can regulate mitochondrial function through amino acid metabolism. Overall, these findings indicate that the alleviating effects of IRW and IQW on LPS-induced intestinal immune stress are associated with the FPR2-mitochondrial axis.

Keywords:  FPR2; MAPK-ERK1/2; egg-derived bioactive peptides; intestinal immune stress; metabolomics; mitochondria

DOI:  https://doi.org/10.1021/acs.jafc.6c01851
BMC Neurol. 2026 Jun 11.

Oculomotor phenotypes and longitudinal video-oculography dynamics in anti-GAD65 antibody-associated neurological syndromes: a case series and literature review.

Feifei Dai, Shilei Cui, Yanjun Guo, Jiawei Wang.

   BACKGROUND: Anti-glutamic acid decarboxylase (GAD) antibody-associated neurological syndromes encompass a heterogeneous group of immune-mediated disorders in which ocular involvement is increasingly recognized but remains insufficiently characterized. Data on clinical features, neuroimaging, and longitudinal ocular motor findings are limited.
METHODS: We retrospectively reviewed four patients diagnosed with anti-GAD antibody-associated neurological syndromes presenting with ocular manifestations at our center between 2019 and 2025. Clinical features, ocular motor findings, laboratory and neuroimaging results, treatment, and outcomes were collected. Longitudinal video-oculography (VOG) was analyzed in one patient. A literature review was performed to summarize reported ocular and vestibulo-ocular abnormalities.
RESULTS: All four patients (2 males, 2 females; onset age 53-68 years) exhibited ocular symptoms, three presented with ocular symptoms early in the disease course; however, in one case (Case 4), the temporal association between the initial ocular symptom and the final diagnosis remained uncertain. Diplopia, nystagmus, and ptosis were the predominant findings. Early brain and orbital Magnetic Resonance Imaging (MRI) were unremarkable, while cerebellar atrophy developed in one patient during relapse. All patients were positive for serum anti-GAD65 antibodies; one also had anti-titin antibodies with elevated creatine kinase(CK). VOG in one patient demonstrated worsening saccadic velocity and pursuit gain during relapse, consistent with cerebellar dysfunction. Literature review of 61 articles showed that diplopia and nystagmus were the most frequently reported features, with characteristic vestibulo-ocular abnormalities including multistep saccades and square-wave oscillations. Based on clinical and literature findings, we further identified recurrent oculomotor patterns across cases.
CONCLUSIONS: Ocular symptoms may represent early clinical features of anti-GAD antibody-associated neurological syndromes, although the temporal relationship may vary across patients and should be interpreted with caution in atypical cases. Downbeat nystagmus may serve as an early marker of cerebellar involvement. Longitudinal VOG provides objective insights into disease evolution. Importantly, we propose a structured oculomotor phenotype framework and highlight longitudinal VOG as a tool for tracking dynamic cerebellar dysfunction, which may facilitate earlier recognition and monitoring of disease progression.

Keywords:  GAD65; Ocular manifestations; Titin; Vestibulo-ocular motor; Video-oculography

DOI:  https://doi.org/10.1186/s12883-026-05014-0
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2611096123

Testicular origin of epigenetic inheritance independent of sperm mitochondrial DNA and epididymal exposure.

Zhuqing Wang, Yasuhiro Yamauchi, Sheng Chen, Huili Zheng, Monika A Ward, Wei Yan.

  Paternal epigenetic inheritance remains mechanistically unresolved. Recent studies propose that environmental exposures induce mitochondrial DNA (mtDNA)-dependent transcription in sperm during epididymal transit, altering small RNA content and offspring phenotypes. Here, we show that mature murine sperm are effectively devoid of mtDNA, precluding mtDNA-dependent transcription, and that sperm-borne mitochondrial RNAs originate during spermatogenesis. Testicular sperm transmitted diet-induced metabolic traits as efficiently as, and in most cohorts more efficiently than, epididymal sperm. These findings establish testicular inheritance independent of sperm mtDNA transcription and epididymal exposure.

Keywords:  epigenetic inheritance; mitochondrial DNA; small RNA; sperm epigenome

DOI:  https://doi.org/10.1073/pnas.2611096123
Cell Mol Neurobiol. 2026 Jun 08.

Targeting Sensory Neuropathies Through Neurotrophin-Based Approaches.

Veronica Mohamed Hizam, Di Prisco Stefania, Anna Pisani, Boccella Serena, Brandolini Laura, Claudio Grassi, Fabiola Paciello, Anna Rita Fetoni.

  Neurotrophins, including NGF, BDNF, and NT-3, are crucial regulators of neuronal survival, synaptic plasticity, and regeneration in sensory systems. Emerging evidence suggests that neurotrophin signaling may represent a common biological axis underlying both sensory neuron vulnerability and repair across auditory, visual, and olfactory systems. This review examines the roles of neurotrophins in maintaining neuronal integrity, promoting synaptic repair, and facilitating functional recovery in sensory pathways. We delved into the molecular mechanisms by which neurotrophins influence neuronal survival and plasticity, with a particular focus on cochlear synaptopathy, optic neuropathy, and olfactory dysfunction. Additionally, we compared neurotrophin-based therapies to emerging approaches, such as gene therapy, small molecules, and cell-based treatments, emphasizing their potential to complement and enhance existing strategies. Despite their therapeutic promise, several challenges persist in translating neurotrophin therapies to clinical practice, including issues related to delivery efficiency and pharmacokinetics. Overall, neurotrophin-based interventions, especially when integrated with complementary regenerative approaches, may offer an effective strategy for restoring sensory function and modifying disease progression, paving the way for future clinical applications.

Keywords:  Neuroprotection; Neurotrophins; Sensory neuropathies; Therapy

DOI:  https://doi.org/10.1007/s10571-026-01756-0
J Diabetes Metab Disord. 2026 Jun;25(1): 154

Prevalence and treatment of mitochondrial diabetes in Southwest Finland.

Nelli Rindell, Heidi Immonen, Mika H Martikainen.

   Purpose: Diabetes mellitus (DM) is a common manifestation of mitochondrial disease, typically associated with the mitochondrial DNA (mtDNA) variant m.3243A>G. We investigated the clinical features, treatment, and epidemiology of mitochondrial DM in the region of Southwest Finland.
Methods: Electronic medical records at Turku University Hospital were searched for patients assigned ICD-10 codes E13.0-E13.9 during 2000-2022. Among 1004 screened individuals, nine patients with genetically confirmed mitochondrial diabetes were identified. Eight additional genetically confirmed patients were included from an ongoing mitochondrial disease research project, resulting in a cohort of 17 patients. The clinical characteristics and DM treatment of the patients were obtained from medical records.
Results: We identified 17 patients with mitochondrial DM. Mean age at diagnosis of DM was 35 years (range 11 to 60 years). Most patients with mitochondrial DM had hearing impairment (14/17). Insulin treatment was typically initiated 3.5 years after the diagnosis of DM. Only six (35%) patients had HbA1c below 7.0% (53 mmol/mol). The prevalence of mitochondrial DM in the region of Southwest Finland in the end of 2022 was 2.7/100,000 and annual incidence during the study period 0.14/100,000.
Conclusions: The onset of non-autoimmune diabetes in young adult age, particularly when associated with hearing impairment, suggests possible mitochondrial DM. Recognition of mitochondrial diabetes is essential for optimal management and complication prevention.

Keywords:  Diabetes; Gene variant; Mitochondrial diabetes; Mitochondrial disease; Type 1 diabetes; Type 2 diabetes

DOI:  https://doi.org/10.1007/s40200-026-01964-x
Curr Mol Med. 2026 Jun 08.

GDF15 Aggravates Sepsis-Induced Coagulopathy and is Associated with PI3K/AKT/mTOR Signaling Changes.

Lihui Wang, Xiaoliang Ji, Qinglong Lu, Shimin Dong.

   INTRODUCTION: The study was designed to explore the role of Growth Differentiation Factor 15 (GDF15) and its underlying mechanisms in coagulation dysfunction, the inflammatory response, and multi-organ damage using a rat model of cecal ligation and puncture (CLP)-induced sepsis.
METHODS: A CLP-induced sepsis model was established in Sprague-Dawley rats. Adenovirus vectors were used to overexpress or knockdown GDF15. A PI3K inhibitor (LY294002) was administered to specific groups. Serum levels of GDF15, apoptosis markers (cleaved-caspase3), endothelial injury markers (syndecan-1, heparan sulfate), coagulation markers (D-dimer), inflammatory cytokines (IL-6, TNF-α), and PI3K/AKT/mTOR phosphorylation were measured by ELISA. Coagulation parameters and platelet counts were assessed. Organ damage was evaluated via H&E staining of the liver, heart, and kidneys.
RESULTS: GDF15 levels were significantly elevated in CLP rats. High GDF15 levels were associated with increased cleaved-caspase3, syndecan-1, heparan sulfate, Ddimer, IL-6, and TNF-α; prolonged APTT, PT, and TT; decreased platelet count and fibrinogen (FIB); aggravated multi-organ damage; and enhanced PI3K, AKT, and mTOR phosphorylation. Silencing GDF15 or inhibiting PI3K with LY294002 reversed these effects, whereas GDF15 overexpression exacerbated them. The detrimental effects of GDF15 overexpression were attenuated by co-administration of LY294002.
DISCUSSION: GDF15 exacerbates coagulopathy, inflammatory responses, and multiorgan damage in septic rats, likely by activating the PI3K/AKT/mTOR signaling pathway. These results establish GDF15 as a potential mediator of sepsis pathophysiology and a therapeutic target warranting further investigation.
CONCLUSION: The findings of this study suggest that GDF15 is associated with coagulation dysfunction, inflammatory responses, and multi-organ injury in septic rats, and these effects may involve modulation of the PI3K/AKT/mTOR signaling pathway. Regarding translational implications, GDF15 has potential as a biomarker, but human validation is required. It may represent a potential therapeutic target that warrants further investigation, and its clinical relevance requires confirmation in human studies. It is important to emphasize that these findings are derived from a preclinical rat model and may not directly translate to human sepsis.

Keywords:  CLP model; GDF15; PI3K/AKT/mTOR pathway; biomarker.; coagulopathy; inflammation; multi-organ damage; sepsis

DOI:  https://doi.org/10.2174/0115665240474141260519104154
Fundam Res. 2026 May;6(3): 1893-1912

Mitochondrial homeostasis in bone aging: Unraveling dysfunctional pathways and developing precision therapies.

Yu Zhang, Xishui Liu, Zijie Xiang, Yuqing Yang, Lei Xing, Yu Chen, Siming Zhang, Shixiang Zhao, Youzhi Hong, Yusen Qiao, Jiaxiang Bai.

  Mitochondria have complex functional and information-processing networks that play key roles in both health regulation and disease progression. However, the multiple properties and complex thresholds of mitochondrial dysfunction and quality control make the contribution of mitochondria to bone aging elusive. These factors prevent mitochondria from being among the most important precision therapies. Currently, many strategies that target mitochondrial homeostasis have entered clinical trials. In mitochondria, mitochondrial DNA (mtDNA) and its associated proteins are potential therapeutic agents for immunometabolic diseases and tissue injury, with the aim of enhancing mitochondrial function. Here, we comprehensively review the intrinsic mechanisms of mitochondrial dysfunction and quality control leading to bone aging and summarize current strategies for the treatment of skeletal aging disorders and the clinical translation of relevant agents in terms of unraveling dysfunctional pathways and developing precision therapies. In this review, we offer a general overview of the progress of clinical application in the treatment of skeletal senescence diseases, and we also provide prospects for the challenges associated with the role of mitochondrial dysfunction in bone senescence in clinical application and future trends in this field.

Keywords:  Bone aging; Clinical application; Mitochondrial DNA (mtDNA); Mitochondrial dysfunction; Precision therapy; Quality control

DOI:  https://doi.org/10.1016/j.fmre.2025.12.021
Nat Genet. 2026 Jun;58(6): 1200

Mitochondrial capsules mitigate mitochondrial dysfunction.

Chiara Anania.

DOI: https://doi.org/10.1038/s41588-026-02651-6
Int J Mol Sci. 2026 May 30. pii: 4966. [Epub ahead of print]27(11):

Sex Differences in Mitochondrial Function: Endocrine Regulation, Immunometabolic Signaling, and Implications for Health and Disease.

Hanna Bynum, Kristin S Edwards.

  Mitochondria are central regulators of cellular bioenergetics, redox balance, and signaling pathways that integrate metabolic and immune responses. Emerging evidence indicates that biological sex is an important determinant of mitochondrial function, in part through the regulatory effects of sex hormones on mitochondrial biogenesis, oxidative phosphorylation, reactive oxygen species production, and quality control mechanisms. Estrogen, testosterone, and progesterone differentially modulate mitochondrial dynamics, substrate utilization, antioxidant capacity, and immune signaling, resulting in distinct mitochondrial phenotypes that may influence disease susceptibility across the lifespan. In this review, we synthesize current knowledge on the mechanistic basis of sex differences in mitochondrial function and highlight mitochondria as key mediators linking endocrine signaling to immunometabolic regulation. We discuss how mitochondrial-derived signals, including mitochondrial reactive oxygen species, mitochondrial DNA release, and cardiolipin exposure, activate inflammatory pathways such as NF-κB, cGAS-STING, and NLRP3 inflammasome signaling. These pathways may contribute to chronic inflammation, gut barrier dysfunction, and systemic metabolic disruption. We further examine the impact of major endocrine transitions, including pregnancy, the postpartum period, menopause, and androgen imbalance in conditions such as polycystic ovary syndrome, on mitochondrial function and disease risk. Particular emphasis is placed on the gastrointestinal tract as a metabolically active and mitochondria-dependent interface, where mitochondrial dysfunction may contribute to epithelial barrier disruption, microbial dysbiosis, and systemic inflammation. Finally, we discuss emerging therapeutic strategies targeting mitochondrial function, including exercise, hormone-based therapies, mitochondria-targeted antioxidants, and interventions aimed at improving mitochondrial quality control. Understanding sex-specific mitochondrial regulation may provide a framework for improved endocrine stratification, mitochondrial phenotyping, and precision medicine approaches across diverse clinical contexts.

Keywords:  endocrine disorders; estrogen; immunometabolism; mitochondria; mitochondrial dynamics; mitochondrial reactive oxygen species; oxidative phosphorylation; sex differences; sex hormones; testosterone

DOI:  https://doi.org/10.3390/ijms27114966
Free Radic Biol Med. 2026 Jun 06. pii: S0891-5849(26)00857-9. [Epub ahead of print]253 749-769

Mitochondrial disease: mechanisms, signalling, and therapeutic opportunities.

Samantha Corrà, Luke Young, Anthony L Moore, Carlo Viscomi.

Mitochondria are central hubs of cellular metabolism and signalling, and their dysfunction underlies a broad spectrum of human diseases, including rare mitochondrial disorders as well as common neurodegenerative and metabolic conditions. Mitochondrial diseases are genetically heterogeneous disorders caused by mutations in nuclear or mitochondrial DNA that impair oxidative phosphorylation (OXPHOS), resulting in reduced ATP production and cellular energy failure. Despite a shared bioenergetic defect, these diseases display marked clinical variability, and the mechanisms underlying this heterogeneity remain poorly understood. At present, no curative therapies are available, although several metabolic and experimental approaches have shown promise in preclinical models. Mitochondrial dysfunction is commonly associated with altered redox homeostasis and increased production of reactive oxygen species (ROS), which can damage mitochondrial components, including mitochondrial DNA, and further impair respiratory chain function. At the same time, ROS also act as context-dependent signalling molecules, with effects that vary according to concentration, localization, and cell type complicating their interpretation in disease mechanisms and therapy development. In this review, we summarize current concepts in mitochondrial disease pathophysiology focusing on unresolved questions that limit mechanistic understanding and clinical translation. We critically evaluate the role of ROS in disease progression and signalling, discuss how the alternative oxidase (AOX) has emerged as a valuable experimental tool to dissect ROS-related mechanisms and reveal unexpected aspects of mitochondrial dysfunction and disease variability.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.06.013
Biochem J. 2026 Jul 08. 483(7): 1193-1220

Mitophagy: an emerging therapeutic target in mitochondrial diseases.

Brígida R Pinho, Michael R Duchen, Jorge M A Oliveira.

  Mitophagy is a crucial autophagic process that degrades dysfunctional or unnecessary mitochondria, thereby maintaining cellular homeostasis. Mitophagy occurs through both basal mitophagy and stress-induced pathways, highly regulated by a complex network of proteins. In mitochondrial diseases, which are genetic disorders lacking effective treatments, mitophagy is often defective or insufficient. This permits the accumulation of dysfunctional mitochondria that negatively impact cell homeostasis. While some experimental therapeutic strategies have enhanced mitophagy in mitochondrial disorders by targeting broadly acting signaling pathways, such as mTORC1 inhibition or AMPK activation, pharmacological approaches directly targeting the mitophagy process remain underexplored in these disorders. Given the growing understanding of mitophagy regulation, targeting key proteins involved in this process may offer novel therapeutic opportunities for mitochondrial diseases. Here, we explore the molecular mechanisms of mitophagy, examining distinct pathways and regulatory checkpoints that might present potential therapeutic targets. Additionally, we review recent studies evaluating the effects of mitophagy modulation in mitochondrial diseases.

Keywords:  autophagy; mitochondria; pathway; pharmacology; receptors; ubiquitins

DOI:  https://doi.org/10.1042/BCJ20260161
Int J Mol Sci. 2026 May 29. pii: 4932. [Epub ahead of print]27(11):

The Role of the Ketogenic Diet in Modulating Biochemical Pathophysiology in Psychiatric and Neurodegenerative Disorders.

Yoo Been Chang, James D Baleja.

  The ketogenic diet, a high-fat and low-carbohydrate diet, has potential therapeutic effects on various neurological and psychiatric disorders. The diet shifts the body's energy production in the form of adenosine triphosphate from using glucose to fats. The increased fatty acid β-oxidation results in the production of ketone bodies. This metabolic adaptation changes cellular bioenergetics, especially in the brain, which is highly reliant on energy metabolism. Schizophrenia, a psychotic disorder, and bipolar disorder, a mood disorder, are distinct psychiatric illnesses that can both involve disturbances in mood, cognition, and perception. These disturbances differ in prominence and clinical significance between the two conditions. Although the underlying mechanisms behind each disorder vary, they share some common pathophysiology, such as imbalances in the neurotransmitter system, mitochondrial dysfunction, and oxidative stress. Alzheimer's disease, a neurodegenerative disorder marked by progressive cognitive decline, shares similar cellular disruptions, along with additional pathological features such as neuroinflammation and neuronal death. Recent studies suggest that the ketogenic diet may exert therapeutic effects by modulating underlying biochemical pathways. Its ability to reduce oxidative stress, improve mitochondrial function, and stabilize neurotransmitter balance may help alleviate symptoms and potentially slow disease progression.

Keywords:  Alzheimer’s disease; bipolar disorder; brain energy metabolism; ketogenic diet; mitochondrial dysfunction; neurotransmitter dysregulation; oxidative stress; schizophrenia

DOI:  https://doi.org/10.3390/ijms27114932
Epilepsy Behav. 2026 Jun 12. pii: S1525-5050(26)00283-0. [Epub ahead of print]183 111162

Use of medium-chain triglycerides in paediatric patients with drug-resistant epilepsy without ketogenic therapy.

Rocío Viollaz, María Julia Alberti, Larissa de Clauser, José Francisco Vilavedra.

   OBJECTIVE: This study aimed to evaluate the efficacy of a Medium Chain Triglyceride (MCT) add-on treatment in children with drug-resistant epilepsy (DRE).
METHODS: We retrospectively reviewed 36 patients who received MCT add-on treatment using MCT oil (ratio C8:C10, 60:40) between June 2022 and May 2023 in our clinic. This treatment was proposed to patients before initiation of a ketogenic diet (KD), due to long waiting lists. After the completion of the MCT add-on phase patients were offered initiation of a KD.
RESULTS: Overall, 66.7% of patients responded to MCT add-on treatment. The average MCT dose was 0.7 ml/kg body weight. Seizure reduction did not differ based on etiology, type of epilepsy, dietary intervention or type of feeding. No correlation was observed between seizure reduction and age at therapy, number of concomitant antiseizure medications or MCT dose. By contrast, treatment duration was positively correlated with response. After the MCT add-on phase 63.8% of patients decided to follow the proposed KD for at least 3 months. Of those, 65.2% experienced a further reduction in monthly seizures.
SIGNIFICANCE: Our study shows that an MCT add-on treatment is feasible and effective in reducing seizures in paediatric patients with DRE, adding to existing evidence. Lower MCT doses might be beneficial to reduce the possibility of gastrointestinal side effects. The treatment may also serve as an introductory phase to KD, which in our cohort was associated with additional seizure reduction.

Keywords:  Dietary therapy; Drug-resistant epilepsy; Ketogenic diet; MCT; Paediatric epilepsy

DOI:  https://doi.org/10.1016/j.yebeh.2026.111162