bims-mistre Biomed News
on Mito stress
Issue of 2026–10–25
thirteen papers selected by
Ellen Siobhan Mitchell, MitoQ
  1. Estradiol-PGC-1 signaling in mitochondrial health: Implications for perimenopause and cardiovascular disease.
  2. Context-specific hypermetabolism in humans with mitochondrial defects.
  3. Exercise training and mitochondrial remodeling in aging skeletal muscle: A translational systematic review and meta-analysis.
  4. Metformin and caffeic acid phenethyl ester counteract hyperglycemia-induced endothelial dysfunction through growth differentiation factor 15 and heme oxygenase-1-associated signaling.
  5. Association of Serum GDF-15 with Bone and Muscle Parameters in Community-Dwelling Individuals.
  6. Synthesis, molecular dynamics, and functional analysis of mitochondria-targeted estrogens through estrogen receptors.
  7. Why diabetes matters in dementia studies: Failure to account for diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.
  8. Creatine and cognitive function: Why has physiological plausibility not translated into convincing clinical evidence?
  9. Running in reverse: Tau redirects mitochondrial electron flow toward neurodegeneration.
  10. Polystyrene nanoplastics impair mitochondrial function, quality control, and ER-mitochondria crosstalk in HeLa cells.
  11. The Mitochondrial-Derived Peptide MOTS-c Improves Bioenergetics in Aging-Associated Granulosa Cells and Oocytes.
  12. Mitochondria-targeted antioxidant Mito-Q induces granulosa cell apoptosis and impairs human pre-antral follicle growth in vitro.
  13. Methylmalonic Acid in Skeletal Aging and Osteoporosis: Linking Vitamin B12 Metabolism to Mitochondrial Dysfunction.
  1. Physiol Rep. 2026 Oct;pii: e71155. [Epub ahead of print]14(20):
    Estradiol-PGC-1 signaling in mitochondrial health: Implications for perimenopause and cardiovascular disease.
    Alyssa L Parten, Glenn C Rowe.
      Cardiovascular disease (CVD) is the leading cause of death in aging women. While CVD etiology is multifactorial, mitochondrial dysfunction, characterized by reduced content, impaired energy production, and increased oxidative stress, is an underlying contributor. These impairments reduce the ability of the heart and vasculature to support peripheral tissues. Estradiol, a key sex hormone with widespread physiological effects, supports mitochondrial function, lipid oxidation, vascular endothelial cell and smooth muscle function, and redox balance, contributing to its cardioprotective effects in women. Perimenopause is marked by hormonal variability and an overall decline in estradiol concentrations that may compromise mitochondrial quality and vascular function, increasing CVD risk. Mitochondrial quality and maintenance are largely controlled by the peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family of transcriptional coactivators. Impairments in PGC-1 isoform expression have been linked to cardiovascular and metabolic decline and may be exacerbated by estradiol loss during the menopause transition. However, the mechanisms by which estradiol signaling regulates PGC-1 isoforms, and how this interaction contributes to mitochondrial dysfunction and CVD development following menopause, have not been comprehensively described. Thus, this review aims to highlight current evidence on the individual and overlapping roles of estradiol and PGC-1 isoforms and examine how their interaction may contribute to the development of CVD following menopause.
    Keywords:  PGC‐1; cardiovascular; estradiol; estrogen; menopause; mitochondria
    DOI:  https://doi.org/10.14814/phy2.71155
  2. Cell Press Blue. 2026 Oct 07. pii: 100129. [Epub ahead of print]
    Context-specific hypermetabolism in humans with mitochondrial defects.
    Evan D Shaulson, Alexander J Sercel, Shannon Rausser, Samantha Leonard, Kathryn Whyte, Faris Zuraikat, Heather Seid, Qiuhan Huang, Alex Junker, Darshana Kapri, Mangesh Kurade, David Shire, Joanna Chen, Caroline Trumpff, Catherine Kelly, Natalia Bobba-Alves, Kris Englestad, Herman Pontzer, Wei Shen, Seth A Creasy, Edward L Melanson, Michael Rosenbaum, Marie-Pierre St-Onge, Dympna Gallagher, Michio Hirano, Martin Picard.
      Pathogenic mitochondrial DNA (mtDNA) defects test how impaired oxidative phosphorylation reshapes human energy expenditure. We studied adults with confirmed mtDNA defects (MitoD) and healthy controls using whole-room indirect calorimetry, doubly labeled water, quantitative magnetic resonance, actigraphy, autonomic monitoring, mood assessments, plasma inflammatory markers, and growth differentiation factor 15 (GDF15). Under behaviorally clamped conditions, fat-free mass-adjusted 24-h energy expenditure (24-h EE) was consistently higher in MitoD, with higher non-resting expenditure per unit wrist acceleration by day, and blunted sleep-related metabolic suppression at night. In contrast, free-living total daily energy expenditure (TDEE) was similar between groups despite lower physical activity in MitoD, consistent with behavioral compensation within a constrained energy budget. Plasma GDF15 was ~5-fold higher in MitoD and tracked with disease severity, systemic inflammation, fatigue, energetic burden, and lower habitual activity. These findings identify a persistent energetic burden in MitoD that is buffered in daily life and associated with elevated GDF15.
    Keywords:  GDF15; doubly labeled water; energy expenditure; fatigue; hypermetabolism; metabolic phenotyping; mitochondrial disease; resting energy expenditure; sickness behavior; whole-room indirect calorimetry
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100129
  3. Arch Gerontol Geriatr. 2026 Sep 30. pii: S0167-4943(26)00304-3. [Epub ahead of print]152 106435
    Exercise training and mitochondrial remodeling in aging skeletal muscle: A translational systematic review and meta-analysis.
    Farhan Yousaf, Sean Kao, Shahid Ishaq, Iqbal Ali Shah, Shin-Da Lee.
      Aging skeletal muscle shows impaired mitochondrial function, altered redox regulation, disrupted fusion-fission balance, and reduced mitochondrial turnover. This translational systematic synthesis and meta-analysis evaluated whether exercise training remodels mitochondrial and functional outcomes in aging muscle. PubMed, EMBASE, and Web of Science were searched to June 26, 2026 following PRISMA 2020. Twenty-eight studies involving aged exercise groups compared to sedentary groups were included. Outcomes covered oxidative stress, mitochondrial dynamics, mitophagy, mitochondrial biogenesis/function, skeletal muscle morphology, and physiological performance. Random-effects meta-analysis showed a significant improvement in VO₂max/VO₂peak after exercise training (SMD = 0.46, p < 0.001; I² = 0%), whereas pooled changes in citrate synthase (SMD = 0.18, p = 0.450) and BMI (SMD = -0.09, p = 0.557) were not significant. The directional synthesis showed that mitochondrial biogenesis and function were consistently responsive across species, particularly for OXPHOS proteins, mitochondrial volume density, ATPmax, and SIRT1/SIRT3 signaling. Human and rodent studies assessed different, only partly overlapping mitophagy and mitochondrial dynamics markers. Therefore, differences in pathway responsiveness across species cannot be separated from differences in which markers were measured. Exercise training and lifelong physical activity were associated with changes in mitochondrial biogenesis, dynamics, mitophagy-related signaling, and muscle function in aging skeletal muscle. The observed patterns varied by training protocol and study design, but indirect comparisons and heterogeneous outcome measures preclude conclusions about the superiority of any modality. Human and rodent findings should therefore be interpreted as complementary evidence rather than equivalent estimates of biological response.
    Keywords:  Aerobic exercise; Energy metabolism; Longevity; Sarcopenia
    DOI:  https://doi.org/10.1016/j.archger.2026.106435
  4. Biochem Biophys Rep. 2026 Dec;48 102826
    Metformin and caffeic acid phenethyl ester counteract hyperglycemia-induced endothelial dysfunction through growth differentiation factor 15 and heme oxygenase-1-associated signaling.
    Patrick Yan-Tyng Liu, Kang-Shuo Chang, Wei-Yin Lin, Horng-Heng Juang.
      Hyperglycemia disrupts the redox homeostasis of endothelial cells and impairs their angiogenic capacity. In our in vitro study, we examined the regulation of growth differentiation factor 15 (GDF15) and heme oxygenase-1 (HO-1) in cultured human umbilical vein endothelial cells (HUVECs) and human aortic endothelial cells (HAECs) under high glucose conditions. Our findings revealed that exposure to elevated glucose levels (30 mM) reduced GDF15 and HO-1 expression, increased reactive oxygen species (ROS) levels, and decreased endothelial proliferation and angiogenesis in vitro; importantly, mannitol did not replicate these effects. Notably, metformin effectively restored GDF15 expression and secretion, reversed glucose-induced changes in AKT and AMPKα1/2 phosphorylation, enhanced HO-1 expression, reduced ROS accumulation, and improved in vitro angiogenic capacity. Similarly, caffeic acid phenethyl ester (CAPE) elevated GDF15 and HO-1 levels, decreased ROS, and reinstated angiogenesis under glucose stress in vitro. Knockdown experiments indicated a co-expression and functional interaction between GDF15 and HO-1, although the directionality of the pathway remains to be established. These cell-based findings highlight the potential of GDF15-HO-1-associated signaling as a glucose-responsive mechanism of endothelial stress and warrant further in vivo validation.
    Keywords:  AKT; AMPK; Glucose; HAEC; HUVEC; Proliferation; ROS
    DOI:  https://doi.org/10.1016/j.bbrep.2026.102826
  5. Front Med (Lausanne). 2026 ;13 1920342
    Association of Serum GDF-15 with Bone and Muscle Parameters in Community-Dwelling Individuals.
    Nicia I Profili, Sokratis Makrogiannis, Roberto Castelli, Maria Benelli, Valeria Orrù, Michele Marongiu, Edoardo Fiorillo, Francesco Cucca, Alessandro P Delitala.
       Introduction: Muscle mass and bone mineral density decrease with aging, although following different patterns among males and females. Growth differentiation factor 15 (GDF-15) is a stress-induced cytokine and has emerged as a key biomarker for inflammation, tissue injury, and metabolic stress. We tested the association between GDF-15 and specific bone and muscle parameters in a large cohort of community-dwelling subjects.
    Methods: The SardiNIA survey included 4,842 subjects (2,795 females). All underwent a detailed medical visit and laboratory testing. Peripheral quantitative computed tomography at the tibia was performed to evaluate volumetric bone mineral density and bone microstructure as well as muscle mass.
    Results: Multivariate regression analysis showed that GDF-15 was negatively associated with cortical bone density (Beta -0.042, p < 0.001) in females. In males, total bone density and trabecular bone density at 4% site and cortical bone area at 38% site were negatively associated with GDF-15 levels (respectively, Beta -0.016, p = 0.027, Beta -0.014, p = 0.039, and Beta -0.022, p = 0.002). Multivariate regression analysis for muscle parameters showed that GDF-15 was negatively associated with muscle density (Beta -0.002 in females and males, p < 0.001 for all) and muscle area (Beta -0.338, p = 0.003, Beta -0.744, p < 0.001).
    Conclusions: Higher circulating GDF-15 levels were independently associated with lower volumetricBMD and poorer muscle parameters in both women and men. These findings support the potential role of GDF-15 as a biomarker of age-related musculoskeletal decline, although longitudinal studies are needed to determine whether GDF-15 contributes to the development of these changes or simply reflects the underlying biological processes.
    Keywords:  GDF-15; aging; bone mineral density; pQCT; sarcopenia
    DOI:  https://doi.org/10.3389/fmed.2026.1920342
  6. J Steroid Biochem Mol Biol. 2026 Oct 19. pii: S0960-0760(26)00204-9. [Epub ahead of print]266 107138
    Synthesis, molecular dynamics, and functional analysis of mitochondria-targeted estrogens through estrogen receptors.
    Geovanni Alberto Ruiz-Romero, Magdiel Orozco-Valdivia, Javier I Wong-Romero, Ricardo Alberto González-Sánchez, Sergio Andrés Águila, Aldo Moreno-Ulloa, Rafael Vazquez-Duhalt, Kanchan Chauhan, Carolina Álvarez-Delgado.
      Estrogens play an important role in regulating mitochondrial function and cellular metabolism. Most of the effects of estrogens are mediated by estrogen receptors α and β (ERα and ERβ), located in various cellular compartments, including the mitochondria. The aim of this study was to validate the mitochondrial accumulation of mitochondria-targeted estrogens and determine whether their biological effects are mediated by ERs. Two mitochondria-targeted estrogen derivatives, mitoE2 and mitoEE2, were synthesized by covalently coupling a triphenylphosphonium (TPP) moiety to 17β-estradiol (E2) and 17α-ethynylestradiol (EE2), respectively, and were structurally characterized. Mitochondrial and cytosolic accumulation in MCF-7 cells was quantified by high resolution mass spectrometry. Cell viability assays were performed to assess the cytocompatibility of TPP. To investigate the binding of mitochondria-targeted estrogens to ERs molecular dynamics simulations were performed. Functional assays were assessed in vitro in the MCF-7 cell line through Manganese-dependent Superoxide Dismutase (MnSOD) activity assays using selective ER antagonists, and by gene expression analyses of mitochondrial-encoded cytochrome c oxidase COX1 and nuclear-encoded COX4. Both mitoE2 and mitoEE2 preferentially accumulated in mitochondria compared with the cytosol. The molecular dynamic simulations showed a thermodynamically stable binding to the ligand-binding domain of ERα and ERβ. In vitro analyses revealed that ERβ selectively mediates the inhibition of MnSOD activity induced by mitoE2 and that mitochondria-targeted estrogens differentially modulate COX1 and COX4 expression in a time-dependent manner. In conclusion, this work contributes to understanding the molecular mechanisms underlying the effects of mitochondria-targeted estrogens on mitochondrial function. Our findings support the need for further investigation to determine their role as modulators of mitochondrial processes and provide a mechanistic basis for future studies in additional cellular and disease-specific models.
    Keywords:  Cytochrome c oxidase; Estrogen; Estrogen receptor; Mitochondria-targeted estrogen; Superoxide dismutase
    DOI:  https://doi.org/10.1016/j.jsbmb.2026.107138
  7. Alzheimers Dement. 2026 Oct;22(10): e71870
    Why diabetes matters in dementia studies: Failure to account for diabetes status masks regional mitochondrial DNA copy number changes in human hippocampus, amygdala, and cerebellum in Alzheimer's disease.
    Aakruti Kaikini, Anqi Shi, Paul Francis, Russell Swerdlow, Claire Troakes, Jaimee Kennedy, Alan Hodgkinson, Afshan N Malik.
       INTRODUCTION: Diabetes is a major risk factor for Alzheimer's disease (AD), and both diseases involve mitochondrial dysfunction. Changes in mitochondrial DNA (mtDNA) can influence energy metabolism, cellular signaling, and epigenetic programming, thereby affecting cellular health. We hypothesized that AD is associated with reduced mtDNA copy number (mtDNA-CN) in vulnerable brain regions, and that diabetes modifies these changes.
    METHODS: MtDNA-CN was quantified by absolute quantitative polymerase chain reaction (qPCR) in post-mortem hippocampus, amygdala, and cerebellum from cognitive controls (CCs), AD, and diabetes groups (CC+D, AD+D; N = 66-77).
    RESULTS: MtDNA-CN differed by region, being highest in amygdala, intermediate in hippocampus, and lowest in cerebellum (503, 421, and 160 copies/cell; p < 0.0001). Pooled analyses showed modestly lower mtDNA-CN in AD. However, inclusion of diabetes appeared to mask differences. Donors with diabetes (CC+D and AD+D combined) had higher mtDNA-CN than non-diabetic (CC and AD combined) in hippocampus (+37.5%; p = 0.0012), amygdala (+30.6%; p = 0.0057), and cerebellum (+48.5%; p = 0.0002). This diabetes-associated increase was also present within AD, where AD+D had higher mtDNA-CN than AD in all regions. Removal of diabetic donors showed that AD was associated with a 19%-30% lower mtDNA-CN, reaching significance in the amygdala and cerebellum after correction for multiple testing.
    DISCUSSION: We show that AD is associated with multiregional mtDNA-CN loss most clearly in donors without diabetes, whereas diabetes is associated with higher mtDNA-CN and can mask AD-related mitochondrial changes. The functional significance of higher mtDNA-CN in the diabetic brain remains unclear, but evidence that diabetes acts as an effect modifier has important implications for dementia studies.
    Keywords:  Alzheimer's disease; biobank; co‐morbidity; diabetes; mitochondrial DNA; post‐mortem brain
    DOI:  https://doi.org/10.1002/alz.71870
  8. Exp Physiol. 2026 Oct 23.
    Creatine and cognitive function: Why has physiological plausibility not translated into convincing clinical evidence?
    Marco Machado.
      Creatine is among the most extensively studied and widely used nutritional supplements in sports and exercise science. Over the past two decades, however, interest has expanded well beyond skeletal muscle, driven by growing recognition of the central role played by the creatine-phosphocreatine system in cerebral bioenergetics. Experimental evidence indicates that creatine contributes to neuronal energy homeostasis, mitochondrial function, membrane stability and potentially neuroprotection. This has fuelled growing enthusiasm for the idea that creatine supplementation might enhance cognitive function and benefit individuals with compromised cerebral metabolism. Yet, despite strong physiological plausibility, clinical findings remain inconsistent and often difficult to interpret. In this review, it is argued that the gap between proposed mechanisms and available clinical evidence reflects two distinct challenges: biological constraints on cerebral creatine availability after supplementation, and persistent methodological weaknesses in the clinical literature. We contend that the central challenge for the coming decade is not to identify new mechanisms of creatine action in the brain, but to establish, unequivocally, whether measurable changes in cerebral bioenergetics translate into meaningful cognitive benefit - whether as enhanced performance in healthy individuals or as clinically significant improvement in patient populations.
    Keywords:  blood–brain barrier; brain bioenergetics; cognitive function; creatine; magnetic resonance spectroscopy; phosphocreatine; translational physiology
    DOI:  https://doi.org/10.1113/EP094109
  9. Neuron. 2026 Oct 21. pii: S0896-6273(26)00693-8. [Epub ahead of print]114(20): 3731-3733
    Running in reverse: Tau redirects mitochondrial electron flow toward neurodegeneration.
    Ahmed Atwa, Marco A Perez, Nicholas M Kanaan.
      In this issue of Neuron, Li et al.1 show that tau enters mitochondria and binds NDUFS3 to regulate reverse electron transport (RET) in a phosphorylation-dependent manner. RET promotes tau phosphorylation, forming a self-perpetuating loop that is exacerbated with stress and tauopathy.
    DOI:  https://doi.org/10.1016/j.neuron.2026.09.010
  10. Front Toxicol. 2026 ;8 1907794
    Polystyrene nanoplastics impair mitochondrial function, quality control, and ER-mitochondria crosstalk in HeLa cells.
    Giuseppe Petito, Maria Teresa Gentile, Arianna Cuomo, Angelo Fusco, Sara Falvo, Maria Della Valle, Gianluca D'Abrosca, Carla Isernia, Roberto Fattorusso, Maria Emanuela Errico, Antonia Lanni, Gaetano Malgieri, Rosalba Senese.
       Introduction: Polystyrene nanoplastics (PS-NPs) represent persistent environmental contaminants derived from the degradation of plastic debris and are increasingly detected in biological systems, raising concerns regarding their potential effects on human health. Emerging evidence suggests that, following cellular internalization, PS-NPs can induce intracellular stress responses and interfere with mitochondrial homeostasis, highlighting mitochondria as key targets of nanoplastic-induced cellular dysfunction. This study aimed to investigate the effects of PS-NPs on mitochondrial function in HeLa cells. Particular attention was devoted to Mitochondrial Quality Control (MQC) pathways, including the mitochondrial Unfolded Protein Response (UPRmt), a stress-adaptive mechanism that remains poorly characterized in response to nanoplastic exposure in human cellular model. In addition, the study examined the functional crosstalk between the Endoplasmic Reticulum and mitochondria.
    Methods: HeLa cells were exposed to PS-NPs, and mitochondrial bioenergetics, oxidative stress, mitochondrial membrane potential, cellular ATP levels, extracellular lactate levels, and calcium homeostasis were assessed using functional assays. MQC-related pathways, including UPRmt, mitochondrial biogenesis, dynamics, autophagy/mitophagy, and ER stress responses, were evaluated through biochemical, molecular, and imaging approaches.
    Results: Our results demonstrate that PS-NP exposure induces mitochondrial dysfunction, characterized by impaired mitochondrial coupling, mitochondrial membrane depolarization, increased H2O2 levels in cell lysates, and altered cellular redox homeostasis. Moreover, PS-NPs disrupt MQC processes, leading to an imbalance in the mechanisms that maintain mitochondrial homeostasis, including modulation of UPRmt-associated proteins and dysregulation of ER-mitochondria communication via Mitochondria-Associated Membranes (MAMs).
    Conclusion: Collectively, these data advance our understanding of PS-NP toxicity by identifying alterations in MQC systems and ER-mitochondria crosstalk as key events in nanoplastic-induced cellular stress. These findings provide novel mechanistic insights into nanoplastic toxicity and highlight the potential impact of environmental PS-NP exposure on cellular homeostasis and human health.
    Keywords:  HeLa cells; mitochondria associated membranes (MAMs); mitochondrial dysfunction; mitochondrial unfolded protein response (UPRmt); nanoplastics (NPs); oxidative stress
    DOI:  https://doi.org/10.3389/ftox.2026.1907794
  11. Reprod Fertil. 2026 Oct 19. pii: RAF-26-0161. [Epub ahead of print]
    The Mitochondrial-Derived Peptide MOTS-c Improves Bioenergetics in Aging-Associated Granulosa Cells and Oocytes.
    Kuan-Hao Tsui, Shih-Hsuan Cheng, Li-Te Lin, Pei-Hsuan Lin, Boyang Wang, Zhi-Hong Wen, Chia-Jung Li.
       LAY SUMMARY: As women age, the quality of their eggs declines, which is a major contributor to age-related infertility. Eggs are supported by neighboring "helper" cells called granulosa cells, which act like a support crew that supplies the egg with the energy it needs to mature. These helper cells contain mitochondria, tiny energy-generating structures often called the cell's "powerhouses," and with age these powerhouses become less efficient, leaving eggs with less support than they need. This study tested whether MOTS-c, a small molecule naturally produced by mitochondria, could restore the function of these aging helper cells. In laboratory experiments using aged human granulosa cells and eggs from aged mice, MOTS-c boosted energy production and helped maintain cell structure, and was associated with improved egg maturation compared with untreated aged eggs, although treated eggs did not fully reach the maturation levels seen in young mice. These findings are from laboratory and animal experiments, not from women, and this study did not test whether MOTS-c affects fertilization, embryo development, or live birth. Further research is needed before any conclusions can be drawn about its relevance to human fertility.
    Keywords:  MOTS-c; granulosa cell metabolism; mitochondrial quality control; mitochondrial-derived peptide; oocyte bioenergetics; reproductive senescence
    DOI:  https://doi.org/10.1530/RAF-26-0161
  12. Mol Hum Reprod. 2026 Oct 23. pii: gaag062. [Epub ahead of print]
    Mitochondria-targeted antioxidant Mito-Q induces granulosa cell apoptosis and impairs human pre-antral follicle growth in vitro.
    Cristina Subiran Adrados, Jesus Cadenas, Lise Bürgel Christensen, Mette Honnes Tanvig, Lotte Berdiin Colmorn, Tanni Borgbo, Lea Bejstrup Jensen, Stine Gry Kristensen.
      The development of in vitro systems capable of supporting early human folliculogenesis holds significant promise for fertility preservation, particularly for patients who cannot undergo ovarian tissue transplantation. Mitochondria-targeted antioxidants have shown beneficial effects in later stages of oocyte maturation, but their impact during early folliculogenesis remains unclear. This study aimed to investigate the effects of the mitochondrial-targeted antioxidant Mito-Q on early-stage human follicles. Using human ovarian tissue and isolated pre-antral follicles obtained from women undergoing fertility preservation, two complementary in vitro models were established. Ovarian cortex fragments were cultured for up to 14 days, and isolated pre-antral follicles were maintained in three-dimensional culture for 8 days. Following an initial comparison of the oxidised and reduced forms, the reduced form was selected for further experiments. Outcomes included follicle density and morphology, apoptosis, cytotoxicity, growth, survival, and gene expression. Mito-Q did not improve follicle survival or overall follicle density. Instead, increasing concentrations were associated with a significant increase in apoptosis in granulosa cells within ovarian tissue and reduced growth of isolated pre-antral follicles. These effects were accompanied by changes in the expression of mitochondrial stress-related genes, suggesting activation of cellular stress responses without functional benefit for follicle development. The findings indicate that mitochondrial antioxidant supplementation does not universally benefit early folliculogenesis and may be detrimental at higher concentrations. These results highlight the importance of stage-specific approaches to redox modulation and suggest that careful optimisation of antioxidant strategies is required to improve in vitro follicle development and fertility preservation outcomes.
    Keywords:   in vitro ; MitoQ; Oxidative stress; ovarian tissue; pre-antral follicle; primordial follicles
    DOI:  https://doi.org/10.1093/molehr/gaag062
  13. Calcif Tissue Int. 2026 Oct 20. pii: 165. [Epub ahead of print]117(1):
    Methylmalonic Acid in Skeletal Aging and Osteoporosis: Linking Vitamin B12 Metabolism to Mitochondrial Dysfunction.
    Ting Ji, Tengbo Pei, Jian Yang, Ting Wan, Yang Zhang, Xin Ma, Meng He, Tianyan Gu, Rongzeng Lu, Wentao Guo.
      Methylmalonic acid (MMA) is a functional marker of vitamin B12 insufficiency and an emerging metabolic factor associated with skeletal aging and osteoporosis. This review synthesizes epidemiological, experimental, and mechanistic evidence linking the vitamin B12-MMA axis to impaired bone homeostasis. Population studies associate elevated circulating MMA with lower bone mineral density, higher odds of osteoporosis, and lower knee extensor strength, while disturbed vitamin B12 metabolism has also been linked to altered bone turnover. Experimental MMA exposure and models of methylmalonyl-CoA mutase (MMUT) deficiency reveal context-dependent abnormalities in mitochondrial respiration, energy metabolism, redox balance, and quality control. These findings provide a rationale for investigating skeletal effects, but the broader consequences of vitamin B12 deficiency and inherited metabolic defects should be distinguished from direct MMA actions in bone cells. Concurrent homocysteine accumulation and reduced S-adenosylmethionine availability may further impair collagen cross-linking, epigenetic regulation, and skeletal remodeling. These pathways support a metabolic-mitochondrial framework in which functional vitamin B12 deficiency contributes to bone loss through coordinated effects on bioenergetics, redox balance, cell fate, and extracellular matrix quality. MMA may therefore complement vitamin B12, homocysteine, renal function, and conventional bone markers in the assessment of skeletal metabolic risk. Prospective human studies, bone-specific mechanistic experiments, and intervention trials are needed to establish causality, clinically useful thresholds, and the skeletal benefits of correcting vitamin B12 deficiency or targeting mitochondrial dysfunction.
    Keywords:  Methylmalonic acid; Mitochondrial dysfunction; Osteoporosis; Skeletal aging; Vitamin B12 deficiency
    DOI:  https://doi.org/10.1007/s00223-026-01622-7
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