bims-ripira 2026-06-07 papers

bims-ripira

Biomed News

on RRM2B MDMD in Adults

Issue of 2026–06–07
eleven papers selected by
Martín Lopo

Mutations Causative of CPEO Differentially Engage Innate Immunity Sensors.
Emerging therapeutic strategies for mitochondrial DNA-related diseases.
Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?
Glycine and N-acetylcysteine supplementation, with or without exercise, in brain health and functional aging: implications for sarcopenia and frailty in older adults.
Effect of six weeks ubiquinol supplementation on mitochondrial respiratory function and exercise capacity in healthy males.
Traditional Chinese medicine-derived monomers delay osteoarthritis progression by regulating mitochondrial homeostasis.
The Effects of Geranylgeraniol Supplementation on Testosterone in Middle-Aged Healthy Adults: An 18-Week, Single-Group Crossover Placebo-Controlled Trial.
POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.
Neither intracellular oxygen availability nor mitochondrial coupling explain lower oxidative capacity in older human vastus lateralis muscle in vivo.
Quantitative Analysis of murine C-terminal Alpha-1-Antitrypsin Peptides in experimental Sepsis and their Comparison with human Sepsis Peptide Biomarkers.
Vitamin D and resveratrol in sarcopenic obesity: a systematic review highlighting the gap in phenotype-defined randomized controlled trials.

bioRxiv. 2026 May 25. pii: 2026.05.24.727547. [Epub ahead of print]

Mutations Causative of CPEO Differentially Engage Innate Immunity Sensors.

Joshua Okletey, Megan Muench, Chenxiao Yu, Alessandra Maresca, Valerio Carelli, Marco Tigano.

Chronic Progressive External Ophthalmoplegia (CPEO) is a primary mitochondrial disorder (PMD) caused by mutations in nuclear genes encoding mitochondrial DNA (mtDNA) maintenance proteins. CPEO is characterized by mtDNA depletion and deletions, and patients primarily present with ocular and muscular features (isolated CPEO). However, additional encephalomyopathy, neurological complications, and Parkinsonism can drive a more severe disease form, CPEO-plus. The evolution from isolated CPEO to CPEO-plus remains poorly understood. Inflammatory and innate immune processes are emerging as strong disease modifiers and may underlie this heterogeneity. Instability of mitochondrial DNA is a major driver of organellar stress and release of mitochondrial contents into the cytosol. Mutations in several genes involved in mtDNA replication and maintenance have been implicated in triggering the escape of mitochondrial nucleic acids from the mitochondrial matrix. Once exposed to cytosolic innate immune sensors, mtDNA and mitochondrial double-stranded RNA (mt-dsRNA) act as potent immunogens, with more than 10 innate immune sensors capable of recognizing them. Therefore, mtDNA and mt-dsRNA release are likely pathological mechanisms in CPEO, yet the list of CPEO-related genes that can trigger inflammatory processes is far from complete. Here, we use patient-derived fibroblasts from individuals with CPEO carrying mutations in RNASEH1 and Twinkle, and provide - for the first time - evidence that their mutations drive innate immune activation through the release of different mitochondrial nucleic acids. RNASEH1 mutations lead to the accumulation and subsequent release of mt-dsRNA, while mtDNA remains protected. On the other hand, mutations in Twinkle cause the release of mtDNA without triggering mt-dsRNA production, or leakage. Supporting this notion, the POLRMT inhibitor IMT-1, and the STING inhibitor H-151, reduced interferon stimulated genes expression downstream of RNASEH1 and Twinkle mutations, respectively. Further, when we analyzed a unique compound patient line carrying mutations in both genes simultaneously, we detect both species of nucleic acids in its cytosol, indicating that both pathways can be engaged simultaneously in the same cell. Lastly, we show that cytosolic sensing triggers paracrine signaling to activate bystander microglia - the resident macrophages of the retina and brain - with potential implications to the neurological progression of CPEO. Overall, our findings reveal a new role for RNASEH1 and Twinkle in driving aberrant innate immunity and paracrine inflammation in CPEO. Our data support a model in which innate immunity is a universal feature of mutations causing mtDNA instability; yet different mutations engage distinct sensing pathways, and in complex scenarios multiple pathways can be triggered at the same time. Given the clinical heterogeneity observed in patients with PMDs, our findings that different signaling pathways are triggered in patient-specific manners might have direct implications for precision medicine approaches aimed at targeting specific innate immunity.

DOI: https://doi.org/10.64898/2026.05.24.727547
Cell Rep Med. 2026 Jun 02. pii: S2666-3791(26)00258-2. [Epub ahead of print] 102841

Emerging therapeutic strategies for mitochondrial DNA-related diseases.

Rubing Shi, Micol Falabella, Jana Aref, Michael G Hanna, Michal Minczuk, Carlo Viscomi, Robert D S Pitceathly.

  Primary mitochondrial diseases (PMDs) are among the most common inherited metabolic disorders, affecting approximately 1 in 4,300 individuals. They result from pathogenic variants in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that disrupt oxidative phosphorylation and lead to multisystem disease. Although advances in genomic testing have significantly improved diagnostic rates in PMDs, effective disease-modifying therapies remain limited. Therapeutic development increasingly focuses on mtDNA-targeted approaches because mtDNA variants are a major cause of disease and may offer opportunities for targeted intervention. Current strategies include allotopic expression, mitochondria-targeted nucleases, and next-generation base editors, which reduce or correct pathogenic mtDNA variants. Other emerging approaches include pharmacological modulation of heteroplasmy, reproductive techniques such as mitochondrial donation, and therapeutic strategies based on mitochondrial transplantation. This review summarizes advances in gene editing, pharmacological approaches, and reproductive and mitochondrial transplantation strategies for mtDNA-related PMDs, highlighting progress toward more targeted interventions.

Keywords:  gene therapy; mitochondrial DNA; mitochondrial replacement therapy; primary mitochondrial diseases

DOI:  https://doi.org/10.1016/j.xcrm.2026.102841
Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00152-X. [Epub ahead of print]38(6): 1079-1080

Is an emerging pharmacotherapeutic era for rare mitochondrial diseases here?

Jirair K Bedoyan, Jerry Vockley.

After decades without approved pharmacotherapies, mitochondrial disease care is shifting. Two FDA approvals emerged in 1 year, elamipretide (Forzinity) for Barth syndrome and deoxynucleoside therapy (Kygevvi) for TK2 deficiency, with another under review. Zink et al.1 suggest sildenafil (Viagra) could treat Leigh syndrome, highlighting drug repurposing for severe pediatric mitochondrial disease.

DOI: https://doi.org/10.1016/j.cmet.2026.04.014
Front Nutr. 2026 ;13 1775264

Glycine and N-acetylcysteine supplementation, with or without exercise, in brain health and functional aging: implications for sarcopenia and frailty in older adults.

Xiaolan Wang, Ruiliang Hou, Zhihao Chen, Xiaoyang Wang, Haoyu Wang.

  Aging is closely associated with oxidative stress, mitochondrial dysfunction, chronic inflammation, and progressive declines in muscle and cognitive function. Exercise is widely recognized as the most effective non-pharmacological strategy to counteract these processes; however, its benefits may be potentiated by targeted nutritional interventions. Glycine and N-acetylcysteine (NAC), both precursors of the antioxidant glutathione, have emerged as promising candidates for maintaining redox balance, supporting mitochondrial metabolism, and improving physiological resilience in older adults. Evidence on NAC suggests context-dependent effects, with supplementation improving glutathione availability, fatigue resistance, and exercise performance in individuals with low baseline glutathione, while results remain inconsistent in healthy populations. Glycine and its derivatives, such as glycine propionyl-L-carnitine, show potential to enhance anaerobic performance and reduce lactate accumulation, though findings are mixed and require confirmation in older cohorts. Increasingly, studies on combined glycine and NAC supplementation (GlyNAC) provide compelling proof-of-concept: clinical and preclinical trials demonstrate improvements in oxidative stress, mitochondrial dysfunction, insulin resistance, inflammation, muscle strength, cognition, and even lifespan extension in animal models. These results suggest that GlyNAC, especially when paired with exercise, may represent a novel paradigm to mitigate aging hallmarks and extend healthspan.

Keywords:  GlyNAC; N-acetylcysteine; aging; chronic inflammation; exercise; glycine; oxidative stress; sarcopenia

DOI:  https://doi.org/10.3389/fnut.2026.1775264
Eur J Appl Physiol. 2026 Jun 06.

Effect of six weeks ubiquinol supplementation on mitochondrial respiratory function and exercise capacity in healthy males.

Jarred P Acton, Nehal S Alsharif, Jack W Bond, Stuart P Cocksedge, Abbie G Mclellan, Donald L Peden, Mark P Funnell, Hannah F Dugdale, Lewis J James, Richard A Ferguson, Tom Clifford, Stephen J Bailey.

  Coenzyme Q10 (CoQ10) is an integral component of the mitochondrial electron transfer system. Most studies have administered the oxidised form of CoQ10 (ubiquinone) and observed no effects on mitochondrial respiratory function or endurance exercise performance. The reduced form of CoQ10, ubiquinol (UQH2), has greater bioavailability than ubiquinone, but the effects of UQH2 supplementation on mitochondrial respiratory function and exercise capacity are unclear. Fifty-four healthy, recreationally active males were randomised to receive either 300 mg·day- 1 UQH2 or placebo (PLA) for 6 weeks in a double-blind independent-group design. Before and after the supplementation period, skeletal muscle mitochondrial respiration variables and protein content of the mitochondrial leak proteins, adenine nucleotide translocase1 + 2 (ANT1 + 2) and uncoupling protein-3 (UCP-3), were assessed. In addition, participants completed a severe-intensity cycle test to exhaustion to assess time to the limit of tolerance (TLim) and oxygen uptake (V̇O2) kinetics. Compared to pre-supplementation and PLA, UQH2 supplementation increased plasma [CoQ10] (P < 0.05), and lowered inverse respiratory control ratio (Pre-PLA: 0.064 ± 0.034 vs. Post-PLA: 0.072 ± 0.026; Pre- UQH2: 0.073 ± 0.039 vs. Post-UQH2: 0.044 ± 0.019; P < 0.05), suggestive of improved oxidative phosphorylation coupling efficiency. There were no differences in ANT1 + 2 or UCP-3 protein content post-supplementation compared to pre-supplementation between groups (P > 0.05). End-exercise V̇O2, change in V̇O2 between 2 min and end-exercise, and TLim were not different between groups post-supplementation (P > 0.05). Six-weeks UQH2 supplementation increased plasma [CoQ10] and oxidative phosphorylation coupling efficiency, but did not alter mitochondrial leak proteins, TLim or V̇O2 kinetics during severe-intensity exercise in healthy, active males.

Keywords:  Coenzyme Q10; Dietary supplement; Exercise performance; Mitochondrial respiratory efficiency; V̇O2 kinetics

DOI:  https://doi.org/10.1007/s00421-026-06275-w
Front Cell Dev Biol. 2026 ;14 1845072

Traditional Chinese medicine-derived monomers delay osteoarthritis progression by regulating mitochondrial homeostasis.

Baohui Wang, Bo Dong.

  Osteoarthritis is a common degenerative disease characterized by the degeneration of articular cartilage, which also affects the synovium, subchondral bone, and the joint microenvironment. Currently, clinical treatment remains focused primarily on pain relief and symptom improvement, with a lack of disease-modifying strategies capable of effectively slowing disease progression. In recent years, the role of mitochondrial homeostasis imbalance in the pathogenesis and progression of osteoarthritis has gradually gained attention. Mitochondria not only participate in the energy supply of chondrocytes but are also closely associated with oxidative stress, mitochondrial dynamics, mitochondrial autophagy, apoptosis, cellular senescence, and extracellular matrix metabolism. In the osteoarthritis microenvironment, inflammatory stimuli, abnormal mechanical loading, and age-related stress disrupt mitochondrial function, leading to reactive oxygen species accumulation, membrane potential decline, and impaired energy metabolism, which in turn promote chondrocyte dysfunction and joint degeneration. A growing body of research indicates that single compounds derived from traditional Chinese medicine can exert protective effects by regulating mitochondrial homeostasis, thereby alleviating oxidative stress, improving energy metabolism, maintaining mitochondrial function, promoting moderate mitochondrial autophagy, and inhibiting chondrocyte apoptosis and senescence. Ultimately, these actions reduce inflammatory responses and matrix degradation, thereby delaying the progression of osteoarthritis. This article reviews the pathological role of mitochondrial homeostasis imbalance in osteoarthritis, summarizes recent research progress on TCM-derived monomers, and outlines current challenges and future directions.

Keywords:  TCM-derived monomers; chondrocytes; mitochondrial homeostasis; mitophagy; osteoarthritis

DOI:  https://doi.org/10.3389/fcell.2026.1845072
Integr Med (Encinitas). 2026 Apr;25(2): 12-19

The Effects of Geranylgeraniol Supplementation on Testosterone in Middle-Aged Healthy Adults: An 18-Week, Single-Group Crossover Placebo-Controlled Trial.

Michael Jurgelewicz, Christopher R D'Adamo, Christopher A Malaya.

Background: Geranylgeraniol (GG) is a naturally occurring isoprenoid that is involved in steroid hormone synthesis, the endogenous production of coenzyme Q10 (CoQ10), healthy muscle function, bone metabolism, and cellular energy production. Although preclinical research and a recent human study have indicated a potential role for GG in modulating testosterone levels, its effects in middle-aged adults remain unclear.
Aim: This study aimed to assess the effects of GG supplementation on testosterone status, coenzyme Q10 concentrations, and validated questionnaires of overall and sexual health in middle-aged healthy adults.
Method: This 18-week, single-group, crossover, placebo-controlled trial involved participants aged 40 to 65 years. The intervention consisted of 8 weeks of placebo followed by a 2-week washout and 8 weeks of GG supplementation (300 mg/day). Outcomes were assessed at baseline, Week 8 (after blinded placebo), Week 10 (post-washout), and Week 18 (after blinded intervention).
Results: Thirty-four participants completed the study. No significant changes were observed in total testosterone, free testosterone, or sex hormone binding globulin (all P > .05) in the full study sample or within the female subgroup. In the subgroup of men with lower baseline testosterone (<600 ng/dL, n = 8), total testosterone increased significantly following GG supplementation (mean difference = 28.44 ng/dL, 95% CI: 7.45-49.43, P = .015), with a large effect size (Cohen's d = 1.13), indicating a meaningful physiological response. Serum CoQ10 declined significantly during placebo (mean difference = -0.10 μg/mL, P = .03) but remained stable during GG supplementation (P = .9), suggesting a potential maintenance effect.
Conclusion: These results highlight GG as a promising natural strategy to support endogenous testosterone production and CoQ10 homeostasis in age-related declines. Further investigation in larger, targeted populations such as men with late-onset hypogonadism or individuals on statin therapy is warranted.

Keywords: annatto; coenzyme Q10; geranylgeraniol; hypogonadal; testosterone; ubiquinone
Mol Genet Metab Rep. 2026 Jun;47 101322

POLG-related disorders: Clinical and molecular Spectrum in the Saudi population.

Fuad Al Mutairi, Faisal Joueidi, Ziyad A Al Mutairi, Maha Alshalan, Wafaa Eyaid, Aziza M Mushiba, Malak AlGhamdi, Brahim Tabarki, Abdulaziz AlGhamdi, Ruqaiah AlTassan, Hamad Alzaidan, Abubakar Sharif, Hesham Aldhalaan, Muhammad Umair, Majid Alfadhel.

   Background: POLG-related disorders are a group of mitochondrial diseases caused by variants in the POLG gene, which is essential for mitochondrial DNA replication and repair. These disorders encompass a wide spectrum of clinical manifestations, ranging from severe, early-onset conditions to milder, adult-onset syndromes.
Methods: We conducted a retrospective study of 19 molecularly confirmed cases with POLG-related disorders from 16 unrelated families in six different referral centers. Clinical, radiological, and molecular analysis were performed following standard methods.
Results: Most of the patients in this study presented with variable neurological symptoms before the age of 12 years (80%); commonly, these symptoms included developmental delay and encephalopathy (63%), seizures (58%), ataxia and dysphagia (42% each). Molecular analysis revealed eight different disease-causing variants in the POLG gene. The most frequently observed variant was c.3286C > T; p.(Arg1096Cys). Notably, the POLG c.1957G > A; p.(Glu653Lys) variant has not been reported in the literature previously, and might impact protein folding and stability.
Conclusion: Despite the management of these conditions remaining largely supportive, advances in understanding the molecular mechanisms of POLG-related disorders offer promise for future therapeutic strategies targeting mitochondrial function and stability. This study highlights the complexity of POLG-related disorders and underscores the need for continued research into their pathophysiology and treatment.

Keywords:  Developmental delay; Mitochondrial depletion; Mitochondrial replication; Myopathy; POLG; Seizures

DOI:  https://doi.org/10.1016/j.ymgmr.2026.101322
J Physiol. 2026 Jun 02.

Neither intracellular oxygen availability nor mitochondrial coupling explain lower oxidative capacity in older human vastus lateralis muscle in vivo.

Luke R Arieta, Zoe H Smith, Rajakumar Nagarajan, Martin Meyerspeer, Jane A Kent.

  Skeletal muscle oxidative capacity is a useful in vivo marker of mitochondrial health and is generally lower in the knee-extensor muscles of older compared with younger adults. The causes of this lower oxidative capacity in older muscle are unclear. We used magnetic resonance spectroscopy to investigate the influence of intramyocellular oxygen availability and the coupling (P/O ratio) between mitochondrial respiration and ATP production on oxidative capacity in the knee-extensor muscles of 14 young and 10 older adults. Participants completed a 24-s contraction protocol followed by 10 min of recovery and 8 min of cuff occlusion while interleaved 31P and 1H spectroscopy data were acquired. Oxidative capacity was calculated as the rate constant of phosphocreatine recovery, and intramyocellular oxygen tension ( PO2${{P}_{{{{\mathrm{O}}}_2}}}$ ) was determined from the deoxymyoglobin signal. Critical PO2${{P}_{{{{\mathrm{O}}}_2}}}$ , the point at which respiration is limited owing to insufficient oxygen availability, and the P/O ratio were determined for each individual. Oxidative capacity was lower in older than younger muscles, whereas neither critical PO2${{P}_{{{{\mathrm{O}}}_2}}}$ nor the P/O ratio differed between groups. On average, PO2${{P}_{{{{\mathrm{O}}}_2}}}$ remained above the critical PO2${{P}_{{{{\mathrm{O}}}_2}}}$ throughout the protocol in both young and older muscle. Oxidative capacity was modestly related to PO2${{P}_{{{{\mathrm{O}}}_2}}}$ during recovery in young but not older muscle, and mitochondrial coupling was unrelated to oxidative capacity. These novel results do not support a primary role for limited oxygen availability or impaired mitochondrial coupling in the lower oxidative capacity of older knee-extensor muscles and suggest instead that other mechanisms, such as lower mitochondrial content, might be responsible. KEY POINTS: Knee-extensor muscle oxidative capacity is generally lower in older age, but the questions of whether this decline is attributable, in part, to insufficient oxygen availability or altered coupling between mitochondrial energy production and oxygen consumption remain open. Interleaved 31P and 1H magnetic resonance spectroscopy was used to measure intramyocellular phosphocreatine and deoxygenated myoglobin in vivo, respectively, in the knee-extensor muscles of young and older adults in response to a 24-s contraction protocol and 8 min of circulatory occlusion. Oxidative capacity was indeed lower in the older muscles, but intracellular oxygen availability during and after contractions was sufficient to support oxidative metabolism and did not differ in young and older muscles. Mitochondrial coupling did not differ by age and was unrelated to oxidative capacity. Thus, the lower knee-extensor muscle oxidative capacity in older age is not a result of inadequate intramyocellular oxygen availability or differences in mitochondrial coupling.

Keywords:  ATP; P/O ratio; ageing; cellular respiration; deoxymyoglobin; intracellular oxygen tension; knee extensors; phosphocreatine recovery

DOI:  https://doi.org/10.1113/JP291176
Biomarkers. 2026 Jun 01. 1-14

Quantitative Analysis of murine C-terminal Alpha-1-Antitrypsin Peptides in experimental Sepsis and their Comparison with human Sepsis Peptide Biomarkers.

Franziska Scherr, Na Liu, Ikebana Konwar, Michael Kiehntopf, Adrian T Press, Friedemann R Börner.

  The levels of alpha-1-antitrypsin (AAT) peptides could be used as prognostic biomarkers in critically ill patients, and peptide treatment has therapeutic efficiency in experimental sepsis. However, the regulation of AAT peptides in M. musculus is unknown, although they may be prerequisites for peptide-based therapies. This study aims to quantify murine AAT peptides and investigate their regulation during experimental sepsis.LC-MS/MS was used to quantify six AAT peptides from two murine AAT isoforms in plasma of septic mice.Peptide mC36-2 is the most abundant and significantly regulated murine AAT peptide, with approximately 20-fold higher level than in critically ill patients. In contrast, the upregulation of peptide C42 in septic patients is absent in mice; thus, it may represent a specific marker of human disease. Nevertheless, the increase and kinetics of mC36 during experimental sepsis reflect our observations in patients.In summary, the conserved upregulation of AAT peptides reflects important pathophysiological mechanisms of severe infections; thus, peptide levels can be used as predictive biomarkers in experimental and clinical sepsis. Although species-specific differences exist and need to be considered, quantification of AAT peptides might help to characterize individual immune responses and build the foundation for novel therapeutic approaches in pre-clinical and clinical research.

Keywords:  Alpha-1-antitrypsin peptides; LC-MS/MS; animal model; biomarker; sepsis

DOI:  https://doi.org/10.1080/1354750X.2026.2682420
Front Nutr. 2026 ;13 1818450

Vitamin D and resveratrol in sarcopenic obesity: a systematic review highlighting the gap in phenotype-defined randomized controlled trials.

Cristina Russo, Maria Stella Valle, Sofia Surdo, Michele Tuttobene, Maria Teresa Cambria, Lucia Malaguarnera.

   Background: Sarcopenic obesity (SO) is an inflammatory-metabolic condition characterized by the coexistence of excess adiposity and impaired skeletal muscle mass and function. Vitamin D and resveratrol modulate regulatory pathways implicated in SO pathophysiology, including NF-κB signaling, PGC-1α, mitochondrial regulation, and redox balance. Whether this mechanistic rationale has translated into phenotype-defined randomized clinical trials remains unclear.
Methods: We conducted a systematic dual-track search across PubMed, Scopus, and Web of Science to identify randomized controlled trials (RCTs) evaluating isolated vitamin D or resveratrol supplementation in adults with explicitly defined sarcopenic obesity or meeting implicit SO phenotype criteria, defined as the concurrent presence of adiposity and objective muscle impairment at baseline. Trials lacking confirmation of both components at enrollment were excluded. Risk of bias was assessed using Cochrane RoB 2.0.
Results: The search retrieved five records (PubMed n = 5; Scopus n = 0; Web of Science n = 0). Following full-text assessment, none met eligibility criteria requiring baseline confirmation of both adiposity and sarcopenia together with isolated vitamin D or resveratrol supplementation (n = 0). Retrieved RCTs in related populations did not simultaneously require adiposity and muscle impairment as enrollment criteria. As a result, no phenotype-defined interventional evidence specific to sarcopenic obesity was identified.
Conclusion: Despite compelling mechanistic convergence, randomized interventional evidence in strictly defined sarcopenic obesity populations is currently lacking. Future RCTs must adopt phenotype-defined enrollment strategies integrating adiposity, muscle dysfunction, and mechanistic endpoints to determine whether micronutrient signaling can meaningfully modify outcomes in SO.
Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261307248, identifier PROSPERO (CRD420261307248).

Keywords:  inflammation; mitochondrial dysfunction; precision nutrition; randomized controlled trials; resveratrol; sarcopenic obesity; vitamin D

DOI:  https://doi.org/10.3389/fnut.2026.1818450