bims-mistre 2026-04-05 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–04–05
twenty-two papers selected by
Ellen Siobhan Mitchell, MitoQ

Growth differentiation factor 15 (GDF-15) as an emerging biomarker for cardiovascular and kidney diseases, a therapeutic target in cancer and a potential biomarker for preeclampsia.
NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.
Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
Mitochondrial connection to Alzheimer's disease and heart failure.
BPM31510 Increases the CoQ Pool in Chemically Induced CoQ-Deficient Cells, CoQ-Deficient Patient Fibroblasts, and in Metabolically Active Murine Tissues.
Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.
Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.
Peripheral Mitochondrial Energetics are Associated with Cortical Neurophysiological Alterations in Alzheimer's Disease.
Probiotic potential of Parabacteroides johnsonii in mitigating age-related ovarian functional decline.
Mitochondrial signals in the bloodstream: Peripheral signature of mitochondrial dysfunction in mental health. A systematic review.
Within-individual changes in mitochondrial DNA copy number across the life course and links to individual performance.
Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans.
Age at Menopause and Trajectories of Multimorbidity Progression to Mortality: A Multi-State Analysis of UK Biobank Data.
Exercise training induces mitochondrial biogenesis, while high-fat diet increases the ability of mitochondria to use long and short-chain fatty acids.
Oxidative Stress and Antioxidant Status in Premenopausal and Postmenopausal Women: A Comparative Cross-sectional Study.
ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.
Reprogramming the mitochondrial-circadian energy code with incretins.
Procyanidin capsules attenuate PI3K/AKT-mediated mitochondrial dysfunction and accelerate skin wound healing in diabetic mice.
Mitochondrial translational control in cardiovascular diseases: from mechanisms to therapies.
Redox regulation in aging muscles: exercise as a key modulator to combat sarcopenia and frailty.
Research progress on the relationship between mitochondrial dysfunction and inflammatory response in brain cells following traumatic brain injury: A review.

Front Pharmacol. 2026 ;17 1779087

Growth differentiation factor 15 (GDF-15) as an emerging biomarker for cardiovascular and kidney diseases, a therapeutic target in cancer and a potential biomarker for preeclampsia.

Daniela A Pereira, Carla S Ceron, Ricardo C Cavalli, Valeria C Sandrim, Marcelo R Luizon.



Keywords:  cancer; cardiovascular diseases; endothelial dysfunction; genetic polymorphisms; growth differentiation factor 15; kidney diseases; nitric oxide; preeclampsia

DOI:  https://doi.org/10.3389/fphar.2026.1779087
Front Biosci (Landmark Ed). 2026 Mar 19. 31(3): 49714

NAD+ Homeostasis and Mitochondrial Modifiability: Resilience in Alzheimer's Disease.

George B Stefano.

  Alzheimer's disease (AD) is increasingly associated with mitochondrial dysfunction and disrupted metabolism. Thus, the maintenance of nicotinamide adenine dinucleotide (NAD+) homeostasis is proposed as a potential therapeutic strategy. Toward this end, we suggest that AD-related mitochondrial dysfunction might be viewed as a regulatable, redox-dependent vulnerability rather than an inherently degenerative and irreversible process. This perspective advances an evolutionary model in which NAD+-mediated redox systems represent a conserved regulatory axis, and that destabilization of this axis during aging may increase susceptibility to degeneration. Here, we assess the potential of a therapeutic approach that combines this understanding of mitochondrial energy metabolism with results from preclinical studies demonstrating the impact of pharmacologic correction of NAD+ homeostasis (e.g., P7C3-A20) as contextual motivation. We explicitly elevate redox balance, rather than absolute NAD+ abundance, as the mechanistically dominant variable that shapes mitochondrial resilience, inflammatory tone, and neurovascular stability. Accordingly, the key unresolved issue is whether specific physiologic benefits might accrue from increased NAD+ availability per se or rather, the restoration of the NAD+/NADH redox ratio, with important implications for the interpretation of the results of directed metabolic interventions. Within this framework, metabolic failure in AD can be understood as an upstream permissive condition that explains, rather than replaces, canonical amyloid-β and tau-associated pathologies. While extended human lifespan may expose late-life vulnerabilities in otherwise conserved metabolic systems, claims of causal primacy, disease reversibility, and cross-neurodegenerative generalization remain premature, underscoring the need for redox-resolved, genetic, and clinical validation.

Keywords:  Alzheimer’s disease; cognition; evolution; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammatory diseases; nicotinamide adenine dinucleotide

DOI:  https://doi.org/10.31083/FBL49714
Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2508286123

Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.

Esther García-Domínguez, Cristina García-Domínguez, José Luis Cabrera-Alarcón, María Del Mar Muñoz-Hernández, Pablo Hernansanz-Agustín, Andrea Curtabbi, Julio Domenech-Fernandez, Enrique Calvo, Jesús Vázquez, Antonio L Serrano, Pura Muñoz-Cánoves, Gloria Olaso-González, José Antonio Enríquez, María Carmen Gómez-Cabrera.

  Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.

Keywords:  frailty; health span; mitochondrial function; proteomics; sarcopenia

DOI:  https://doi.org/10.1073/pnas.2508286123
Curr Opin Physiol. 2025 Jun;pii: 100830. [Epub ahead of print]44

Mitochondrial connection to Alzheimer's disease and heart failure.

Anupriya Sinha, Natasha Jaiswal, Pooja Jadiya, Dhanendra Tomar.

The brain and heart are intricately linked, with dysfunction in one organ often affecting the other. Cardiovascular diseases (CVDs), particularly heart failure, impair cerebral blood flow, contributing to cognitive decline and increasing dementia risk. Conversely, Alzheimer's disease (AD), marked by amyloid-beta plaques and tau tangles, impacts cardiac function. A shared mechanism between AD and CVDs is mitochondrial dysfunction, which disrupts energy production and oxidative balance, worsening both neurodegeneration and heart health. This interdependence underscores the potential for mitochondria-targeted therapies to address both conditions. With an aging population facing rising incidences of AD and CVDs, understanding these interconnected pathways and the central role of mitochondria could inform new therapeutic strategies and improve outcomes in both neurodegenerative and cardiovascular diseases.

DOI: https://doi.org/10.1016/j.cophys.2025.100830
FASEB J. 2026 Apr 15. 40(7): e71737

BPM31510 Increases the CoQ Pool in Chemically Induced CoQ-Deficient Cells, CoQ-Deficient Patient Fibroblasts, and in Metabolically Active Murine Tissues.

Juan J Aristizabal-Henao, Sarah R Wessel, Sylwia A Stopka, Srada Karmacharya, Devon Van Cura, Alba Pesini, Kelsey R Nickerson, Kashni Grover, Oksana Zavidij, Archna Ravi, Andressa L Mota, Kenneth M Rosen, Maria-Dorothea Nastke, Megan K Cox, Niven R Narain, Vijay Modur, Catarina M Quinzii, Stephane Gesta, Michael A Kiebish.

  Coenzyme Q10 (CoQ10) is a lipid-soluble redox cofactor essential for mitochondrial electron transport, membrane stabilization, and antioxidant defense in its reduced form. Broad clinical utility has been hampered by poor oral bioavailability and low tissue uptake using nutraceutical formulations. BPM31510 is a novel pharmaceutical nanotechnology formulated with oxidized CoQ10 as a lipid nanoparticle designed to enhance systemic exposure and mitochondrial concentration. Using UHPLC-MS/MS, we quantified oxidized CoQ10, reduced CoQ10, and oxidized CoQ9 in BPM31510- and CoQ10-treated SH-SY5Y neuroblastoma cells following para-aminobenzoic acid (PABA)-induced CoQ deficiency. BPM31510 significantly increased all three analytes and raised ATP content in SH-SY5Y cells more effectively than solubilized CoQ10. In patient-derived fibroblasts with PDSS2, COQ2, or COQ8A mutations, BPM31510 outperformed nutraceutical formulations in enriching CoQ10 levels. In vivo, C57BL/6J mice received BPM31510 (10 or 50 mg/kg, intraperitoneal) or oral CoQ10 twice daily for 14 days. BPM31510 substantially increased oxidized and reduced CoQ10 in plasma, liver, heart, and adipose tissue, enhancing the overall CoQ pool relative to oral CoQ10. MALDI mass spectrometry imaging confirmed oxidized CoQ10 accumulation in myocardial tissue beyond the vasculature, consistent with UHPLC-MS/MS findings. These results demonstrate that BPM31510 targets bioactive CoQ10 to metabolically active tissues, overcoming limitations of oral supplementation, and may provide therapeutic benefit for primary and secondary CoQ10 deficiencies and other mitochondrial or metabolic disorders marked by impaired redox balance and energy homeostasis.

Keywords:  CoQ10 deficiency; mass spectrometry; mitochondrial disease; quinomics

DOI:  https://doi.org/10.1096/fj.202503629RR
Aging Cell. 2026 Apr;25(4): e70452

Targeting Mitochondrial Stress Responses: Terbinafine and Miglustat as Novel Lifespan and Healthspan Modulators.

Amélia Lalou, Ioanna Daskalaki, Ilias Gkikas, Sandra Rodríguez-López, Jean-David Morel, Giorgia Benegiamo, Adrien Faure, Arwen W Gao, Joaquim Barmaz, Qi Wang, Terytty Yang Li, Feng Gao, Danaé Broustail, Kristina Schoonjans, Giovanni D'Angelo, Johan Auwerx.

  Mitochondria are central to cellular homeostasis and play a critical role in aging and age-related disorders, making them promising therapeutical targets. Here, we identify terbinafine and miglustat as novel mitochondrial stress inducers that extend lifespan and improve healthspan in Caenorhabditis elegans. Through a two-step screening, we found that both compounds activate the mitochondrial stress response (MSR) and exhibit distinct mechanisms of action. Terbinafine and miglustat robustly activated the mitochondrial unfolded protein response (UPRmt) mediator ATFS-1, upregulated MSR pathways, and modulated mitochondrial function across species, similarly to doxycycline. Interestingly, both compounds also engaged the insulin/IGF-1 signaling (IIS) pathway in C. elegans, revealing an integrated stress response involving coordinated action of ATFS-1 and the FOXO transcription factor DAF-16, distinct from canonical IIS activation. Experiments in human HEK293T cells confirmed the translational potential, with both compounds inducing mitochondrial stress and modulating mitochondrial function in mammalian systems. This study highlights the potential of harnessing the MSR to promote longevity and mitigate age-related functional decline. The identification of terbinafine and miglustat as mitochondrial stressors paves the way for novel anti-aging therapies.

Keywords:   Caenorhabditis elegans ; aging; doxycycline; drug repositioning; longevity; miglustat; mitochondria; terbinafine

DOI:  https://doi.org/10.1111/acel.70452
medRxiv. 2026 Mar 25. pii: 2026.03.23.26348537. [Epub ahead of print]

Saliva cell-free mitochondrial DNA (cf-mtDNA) as a dynamic biomarker of stress and emotion in daily life: Evidence from two independent repeated-measures studies.

Lauren Petri, Sun Ah Lee, David Shire, Samantha Leonard, Alexander Behnke, Jody Greaney, Lacy Alexander, David M Almeida, Martin Picard, Caroline Trumpff.

The present study analyzes the impact of naturalistic stress and emotions on saliva cell-free mitochondrial DNA (cf-mtDNA) in daily life across two independent cohorts with different temporal resolutions. Study 1 examined the interaction between daily stress and major depressive disorder (MDD) on cf-mtDNA in young adults (n= 18, 8 MDD, 10 controls) across four days. For individuals with MDD, stress exposure was associated with a 68% reduction in cf-mtDNA. A higher number or greater severity of stressors also reduced cf-mtDNA by 24 to 27%. Study 2 extended this framework by implementing a finer temporal resolution, measuring saliva and affective states every hour, up to 20 times per day for 2 days (n = 25). Negative emotions, including stress and frustration, were associated with reductions in cf-mtDNA of 15%, whereas positive emotions, such as happiness and calm, predicted increases of up to 28%. The strength and direction of the effects were person- and context-dependent. These findings suggest that cf-mtDNA does not exhibit a uniform stress response in daily life. Instead, it reflects dynamic signaling shaped by timing, emotional context, and diagnostic status. This work demonstrates that interpreting cf-mtDNA as a stress biomarker in real-world settings requires modeling timing and heterogeneity of effects.
Highlights: Saliva cf-mtDNA dynamically tracks with psychosocial experience in real-world contexts.Daily stress was associated with marked cf-mtDNA reductions in MDD, revealing stress-contingent vulnerability.Higher stressor load was associated with dose-dependent suppression of cf-mtDNA.At the hourly level, negative emotions predicted lower cf-mtDNA, whereas positive emotions predicted higher levels.cf-mtDNA showed greater sensitivity to psychosocial experience than cf-nDNA, supporting the notion that mitochondrial DNA release is regulated beyond passive cell death.

DOI: https://doi.org/10.64898/2026.03.23.26348537
medRxiv. 2026 Mar 27. pii: 2026.03.25.26349329. [Epub ahead of print]

Peripheral Mitochondrial Energetics are Associated with Cortical Neurophysiological Alterations in Alzheimer's Disease.

Sean L Kriwokon, Santiago I Flores-Alonso, Brianne A Kent, Tony W Wilson, Rachel K Spooner, Alex I Wiesman.

Alzheimer's disease is associated with both mitochondrial dysfunction and altered neurophysiological signalling. Peripheral measures of mitochondrial respiration have been established as effective predictors of mitochondrial function in the healthy brain, and more recently, of altered brain signalling in clinical groups. Here, we sought to assess whether peripheral mitochondrial energetics are associated with altered neural signalling in Alzheimer's disease. We collected task-free magnetoencephalography (MEG) from individuals on the Alzheimer's disease continuum (69.21 [6.91] years; n = 38) and cognitively normal older adults (72.20 [4.73] years; n = 20). Each participant also provided a blood sample for analysis of mitochondrial respiration using the Seahorse XF96 Analyzer. We used region-wise linear models to test the relationship between ATP-linked mitochondrial respiration and Alzheimer's disease-associated neurophysiological changes. We found that mitochondrial respiration linked to ATP production is associated with altered alpha and theta band cortical rhythms in Alzheimer's disease (α: p FDR < 0.05, r = -0.7; θ: p FDR < 0.05, r = -0.6). We then tested colocalization of mitochondria-neurophysiological relationships with a human brain atlas of respiratory capacity and found that brain regions with lower mitochondrial respiratory capacity exhibit a stronger relationship between aperiodic signalling and peripheral ATP-linked respiration ( p FDR = 0.003, r = 0.35). Our findings suggest that peripheral blood measures of mitochondrial function can offer insight into the neurophysiological alterations associated with energetic changes in Alzheimer's disease and warrant further investigation into the translational potential of joint neuronal-mitochondrial markers of neurological diseases of aging.

DOI: https://doi.org/10.64898/2026.03.25.26349329
J Genet Genomics. 2026 Apr 01. pii: S1673-8527(26)00111-6. [Epub ahead of print]

Probiotic potential of Parabacteroides johnsonii in mitigating age-related ovarian functional decline.

Dan-Yang Wang, Yin-Wei Wang, Ke-Chun Yu, Xuan Yang, Jun Ma, Bo-Han Li, Ya-Ling Peng, Xin-Yin Deng, Zhen-Xia Chen, Ling Wang.

  The gut microbiota is increasingly recognized as a regulator of reproductive health, yet its role in ovarian aging remains unclear. Here, we combine Mendelian randomization (MR) analysis with experimental validation to investigate the causal relationship between gut microbiota and ovarian aging. MR analysis identifies four microbial taxa significantly associated with age at natural menopause. In mouse models, germ-free mice exhibit accelerated ovarian functional decline, including reduced ovarian reserve and impaired folliculogenesis. Fecal microbiota transplantation (FMT) from young donors alleviates ovarian aging phenotypes, whereas FMT from aged donors exacerbates functional decline. Metagenomic analysis reveals species-level differences between young and ovarian-aging mice, with Parabacteroides johnsonii (P. johnsonii) enriched in young mice. Administration of P. johnsonii to middle-aged mice improves ovarian reserve, reduces follicular atresia, enhances granulosa cell proliferation, and decreases systemic inflammation. These findings highlight a causal role of the gut microbiota in ovarian aging and support microbiota-targeted interventions as a potential strategy to preserve ovarian function.

Keywords:  Fecal microbiota transplantation; Gut microbiota; Mendelian randomization; Ovarian aging; Parabacteroides johnsonii; Probiotic intervention

DOI:  https://doi.org/10.1016/j.jgg.2026.03.023
Neurosci Biobehav Rev. 2026 Mar 30. pii: S0149-7634(26)00127-2. [Epub ahead of print]186 106670

Mitochondrial signals in the bloodstream: Peripheral signature of mitochondrial dysfunction in mental health. A systematic review.

Inés Lucía Fernández-Pech, María Fernández-Guillén, Cristina Morente-Montilla, Benedicto Crespo-Facorro, Celia Martín-Cuevas.

  Psychiatric disorders are characterized by marked clinical heterogeneity, overlapping symptom dimensions, and the persistent lack of objective biomarkers. Liquid biopsy has emerged as a promising, non-invasive strategy to identify peripheral molecular signatures that may inform diagnosis and treatment monitoring. Given the central involvement of mitochondrial dysfunction in psychiatric pathophysiology, circulating cell-free mitochondrial DNA (ccf-mtDNA) has attracted increasing interest as a candidate biomarker. Following PRISMA 2020 guidelines, this systematic review synthesized evidence on ccf-mtDNA alterations in bipolar disorder (BD), depressive disorders (DD), and schizophrenia (SCZ). Findings in BD were heterogeneous: several studies reported elevated ccf-mtDNA, particularly in unmedicated individuals and those with cognitive deficits, whereas others observed no differences or even decreased levels compared with healthy controls (HC). In DD, evidence more consistently indicated increased ccf-mtDNA, especially in unmedicated or late-life depression, where higher levels correlated with symptom severity, frailty, and inflammatory indices. These data support ccf-mtDNA as a peripheral marker of mitochondrial and inflammatory dysregulation in DD. Conversely, most studies in SCZ reported no significant differences relative to HC; however, elevated ccf-mtDNA levels observed in cognitively impaired subgroups and in patients exhibiting alterations in brain bioenergetics point to underlying clinical and biological heterogeneity. Collectively, current evidence implicates ccf-mtDNA as a putative biomarker of mitochondrial dysfunction in psychiatry, with greater translational potential in DD and BD. Nonetheless, methodological heterogeneity, small sample sizes, and cross-sectional designs underscore the need for standardized, longitudinal investigations to establish its diagnostic and prognostic validity.

Keywords:  bipolar disorder; circulating cell-free mitochondrial DNA (ccf-mtDNA); cognition; depressive disorder; liquid biopsy; neuroinflammation; schizophrenia

DOI:  https://doi.org/10.1016/j.neubiorev.2026.106670
Biol Lett. 2026 Apr 01. pii: 20250521. [Epub ahead of print]22(4):

Within-individual changes in mitochondrial DNA copy number across the life course and links to individual performance.

Pablo Salmón, Miguel Hernandez-Gonzalez, Winnie Boner, Edward R Ivimey-Cook, Pat Monaghan.

  Ageing is characterized by complex biological processes reflected in cellular and molecular changes. Mitochondria, which are crucial for energy production and cellular homeostasis, are particularly vulnerable to age-related deterioration. The number of copies of mitochondrial DNA (mtDNAcn) varies across and within tissues in response to energetic activity and mtDNA integrity, and is related to health and physical performance. Age-related changes in mtDNAcn can be difficult to study due to differential survival of phenotypes into older ages, but studies of changes in mtDNAcn within individuals are very limited. In this study, we investigated changes in red blood cell mtDNAcn across the life course within individual zebra finches (Taeniopygia guttata), a well-established avian model, from the nestling stage into old age. Our findings revealed a pronounced decline in relative mtDNAcn during post-natal development, followed by comparative stability throughout adulthood. This pattern was remarkably consistent among individuals. We found no significant relationship between variation in mtDNAcn and growth during the nestling period. However, based on measurements of disturbed take-off speed in late adulthood, we found that individuals with higher physical performance at that stage had higher relative mtDNAcn, suggesting a link between variation in individual bioenergetics and biological state.

Keywords:  ageing; birds; flight performance; life history; mitochondria; within-individual

DOI:  https://doi.org/10.1098/rsbl.2025.0521
Front Endocrinol (Lausanne). 2026 ;17 1797525

Metformin increases glycolysis and the stress-induced cytokine GDF15 but not FGF21 in humans.

Kristoffer J Kolnes, Pauline M Møller, Rikke Kruse, Mette Marie H Christensen, Rasmus Kjøbsted, Martin Hey-Mogensen, Birgitte Andersen, Aase Handberg, Kurt Højlund.

   Background: Metformin lowers glucose by acting on the liver and the gastrointestinal tract and may reduce body weight by increasing circulating levels of the stress-induced cytokine GDF15. The tissue responsible for the release of GDF15 and whether this is paralleled by the induction of another, mainly liver derived, stress-responsive cytokine, FGF21, remains unclear.
Objective: We examined the effect of metformin on GDF15 and FGF21 in humans and in intestinal cells in vitro.
Methods: In a randomized, cross-over trial, 34 healthy individuals completed a 42-h fast twice, either with or without prior treatment with metformin for a week. Glucose metabolism was assessed using [3-3H]-glucose and indirect calorimetry and blood samples were drawn for the analysis of plasma metformin and serum GDF15 and FGF21. The effects of metformin on the expression and secretion of GDF15 and FGF21, and on mitochondrial respiration and glycolysis were examined in human intestinal epithelial cells (Caco-2).
Results: Metformin increased glucose utilization (p=8.9x10-13) due to increased glycolysis (p=7.6x10-13) in vivo. This was accompanied by increased serum GDF15 (1004±61 vs 607±89 ng/ml; p<0.001), whereas serum FGF21 (146±30 vs 156±29 ng/ml; p=0.65) was unaltered. The change in serum GDF15 did not correlate with plasma metformin levels. In vitro, metformin markedly increased mRNA levels and secretion of GDF15, whereas FGF21 levels were not detectable in Caco-2 cells or media. Moreover, metformin dose-dependently inhibited mitochondrial respiration and increased glycolysis in vitro.
Conclusions: The metformin-induced increase in serum GDF15, but not the liver-derived FGF21, in humans is consistent with the actions of metformin in human intestinal cells in vitro. These findings corroborate with recent studies demonstrating the gastrointestinal tract is an important site of metformin action.
Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT01400191.

Keywords:  FGF21; GDF15; glycolysis; intestine; metformin; mitochondrial respiration

DOI:  https://doi.org/10.3389/fendo.2026.1797525
BJOG. 2026 Apr 04.

Age at Menopause and Trajectories of Multimorbidity Progression to Mortality: A Multi-State Analysis of UK Biobank Data.

Min Li, Tianyu Liu, Haibo Zhou, Xinyue Yu, Hanhan Wang, Lixin Zheng, Zhongran Wang, Xu Han, Xiyun Ren, Xiangfeng Lu, Wenjing Tian.

   OBJECTIVE: To investigate whether age at menopause is associated with the trajectory of multimorbidity progression.
DESIGN: A retrospective cohort study.
SETTING: The UK Biobank.
POPULATION: 121 017 postmenopausal women aged 40-69 years with complete baseline and menopausal data.
METHODS: Cox proportional hazards models were used to explore the associations between menopausal age and both multimorbidity and mortality. Multi-state models were further employed to evaluate the association of menopausal age with transitions from a health state to the first chronic disease (FCD), to multimorbidity, and to mortality from each state.
MAIN OUTCOME MEASURES: Multimorbidity (defined as ≥ 2 of 35 chronic conditions) and mortality.
RESULTS: Over a median follow-up period of 8.6 years, 86 821 women developed the FCD, 42237 multimorbidity, and 10 527 participants died. In the multi-state models analysis, from health to FCD, compared with women who experienced menopause after age 50 years, the risks increased by 32%, 14%, and 3% among women with premature, early, and relatively early menopause, respectively (HR = 1.32, 95% CI: 1.28-1.36; HR = 1.14, 95% CI: 1.11-1.17; HR = 1.03, 95% CI: 1.01-1.05). Similarly, for the transition from FCD to multimorbidity, the risks increased by 22% (HR = 1.22, 95% CI: 1.17-1.27), 13% (HR = 1.13, 95% CI: 1.09-1.16), and 6% (HR = 1.06, 95% CI: 1.03-1.08), respectively.
CONCLUSIONS: Earlier menopause was associated with an increased risk of multimorbidity and mortality, mainly affecting two trajectories, from health to FCD and FCD to multimorbidity.

Keywords:  UK biobank cohort; age at menopause; menopausal age; multimorbidity progression; multi‐state model; postmenopausal women

DOI:  https://doi.org/10.1111/1471-0528.70235
J Physiol. 2026 Apr 03.

Exercise training induces mitochondrial biogenesis, while high-fat diet increases the ability of mitochondria to use long and short-chain fatty acids.

Jessica L Dowling, Rachel M Handy, Nicole M Notaro, Sara M Frangos, David J Dyck, Graham P Holloway.

  Short-chain fatty acids (SCFAs), derived from peroxisomal metabolism and the gut microbiota, have been proposed as key substrates to support mitochondrial oxidative phosphorylation (OXPHOS) in extrahepatic tissues such as skeletal muscle. However, the extent to which mitochondria can oxidize SCFAs (acetate, propionate and butyrate) and the ability of exercise training and a high-fat diet (HFD) to modulate this process remains unclear. Here, we show that SCFA-supported respiration in skeletal muscle is relatively limited (18 ± 6 nmol min-1 mg-1), accounting for only ∼7% of maximal carbohydrate (pyruvate: 252 ± 41 nmol min-1 mg-1) and ∼14% of LCFA (palmitoylcarnitine)-linked respiration. Despite this low capacity, the intrinsic mitochondrial ability to oxidize palmitoylcarnitine, acetate and butyrate increased (P < 0.05: +50%) following HFD consumption, suggesting HFD rewires mitochondria to optimize lipid oxidation. By contrast, exercise training prevented these HFD-induced intrinsic mitochondrial responses. Although intrinsic changes are biologically relevant, skeletal muscle adaptation to metabolic stress also involves mitochondrial biogenesis and an expansion of the mitochondrial proteome. Proteomic analysis and citrate synthase activity revealed that, although HFD independently did not alter mitochondrial protein abundance, exercise training increased mitochondrial proteins, a response amplified in the presence of a HFD. Consequently, although exercise did not directly enhance mitochondrial SCFA-supported respiration, the combined effect of HFD and exercise predicted a greater overall capacity for SCFA oxidation because of increased mitochondrial abundance. Collectively, although SCFAs contribute minimally to mitochondrial respiration in skeletal muscle, combined HFD and exercise synergistically enhance overall OXPHOS capacity across diverse substrates, including SCFAs, primarily through increased mitochondrial protein abundance rather than intrinsic mitochondrial remodelling. KEY POINTS: Peroxisome and gut derived short-chain fatty acids (SCFA) have been proposed as an alternative metabolic fuel source to support skeletal muscle oxidative phosphorylation. The capacity and adaptability of mitochondrial SCFA oxidation remains unknown. SCFA-supported mitochondrial respiration is limited (<15%) compared to carbohydrate (pyruvate) and long-chain fatty acid linked substrates. High-fat feeding increased the intrinsic capacity of mitochondria to utilize palmitoylcarnitine, acetate and butyrate- effects prevented by 4 weeks of exercise training. Combined high-fat diet and exercise training increased skeletal muscle mitochondrial protein content in an additive manner, increasing oxidative capacity and ability to utilize both long- and SCFAs as a fuel source.

Keywords:  exercise; high‐fat diet; mitochondria; short‐chain fatty acids; skeletal muscle

DOI:  https://doi.org/10.1113/JP289545
Niger J Clin Pract. 2026 Mar 01. 29(3): 298-302

Oxidative Stress and Antioxidant Status in Premenopausal and Postmenopausal Women: A Comparative Cross-sectional Study.

S Cakina, E Sevinc-Postacı, E Pek, B Karabıyık, F Beyazit.

   BACKGROUND: Menopause is a physiological transition associated with hormonal changes and age-related systemic alterations. Emerging evidence suggests that oxidative balance may be disrupted during this period, although the extent and pattern of oxidative stress (OS) in menopausal women remain incompletely defined.
AIM: To compare OS markers and antioxidant parameters between premenopausal and postmenopausal women.
METHODS: This cross-sectional study included 100 women: 50 premenopausal (aged 18-45 years) and 50 postmenopausal (aged 45-65 years). Serum levels of arylesterase (ARE), paraoxonase (PON), thiols, total antioxidant status (TAS), and total oxidant status were measured using spectrophotometric methods. The OS index was calculated from total oxidant and antioxidant status. Statistical analysis was performed using SPSS version 25.0, with P < 0.05 considered statistically significant.
RESULTS: Total oxidant status and OS index were significantly higher in postmenopausal women compared with premenopausal women. In contrast, antioxidant parameters-including PON, ARE, TAS, and thiol levels-were significantly lower in the postmenopausal group (P < 0.05).
CONCLUSION: Menopause is associated with increased OS and reduced antioxidant capacity. This altered redox balance may contribute to the heightened risk of age-related conditions observed in postmenopausal women and highlights the potential value of monitoring OS markers during the menopausal transition.

Keywords:  Antioxidant enzymes; biomarker; lipid peroxidation; menopause; oxidative stress

DOI:  https://doi.org/10.4103/njcp.njcp_511_25
Aging (Albany NY). 2026 Mar 27. 18(1): 213-233

ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.

Victoria C Sanfrancesco, David A Hood.

  In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response

DOI:  https://doi.org/10.18632/aging.206365
Philos Trans R Soc Lond B Biol Sci. 2026 Apr 02. pii: 20250079. [Epub ahead of print]381(1947):

Rethinking mitochondrial heteroplasmy: selection, conflict and adaptation.

Jade R Kannangara, Hansong Ma, Damian K Dowling.

  Mitochondrial DNA (mtDNA) variation is increasingly recognized for its role in shaping evolutionary changes at the species and population levels. Yet, its evolutionary relevance within individuals remains less explored. Eukaryotic cells typically carry multiple copies of mtDNA. When these copies differ in sequence, heteroplasmy arises-a form of intra-organismal genetic diversity with potentially profound biological implications. To elucidate the evolutionary significance of heteroplasmy in animals, we first review how natural selection shapes adaptive mtDNA dynamics at broader biological levels, via cases of mito-nuclear coadaptation, environmental-mediated and sex-specific selection and balancing selection. We then explore whether analogous selective pressures may operate at the intra-individual level. Heteroplasmy introduces the potential for multi-level selection-from the genome to the organism-potentially yielding synergistic or antagonistic evolutionary outcomes. This framework encompasses both the selfish transmission of certain mtDNA variants and emerging evidence for adaptive shifts in heteroplasmy levels under environmental stress. These findings are supported by theoretical models suggesting that paternal mtDNA transmission-historically viewed as a stochastic anomaly-may confer adaptive benefits under specific ecological and evolutionary contexts by introducing intra-individual mtDNA diversity. Collectively, these insights suggest that heteroplasmy may act as an underappreciated reservoir of adaptive potential, enhancing the evolutionary capacity of organisms in a changing world. This article is part of the theme issue 'Evolutionary genetics of mitochondria: on diverse and common evolutionary constraints across eukarya'.

Keywords:  adaptation; adaptive; environmental change; evolution; heteroplasmy; mito-nuclear; mitochondria; mtDNA; selfish; selfish drive

DOI:  https://doi.org/10.1098/rstb.2025.0079
Trends Endocrinol Metab. 2026 Mar 31. pii: S1043-2760(26)00046-9. [Epub ahead of print]

Reprogramming the mitochondrial-circadian energy code with incretins.

Enzo Nisoli, Maurizio Ragni, Chiara Ruocco, Alessandra Valerio.

  Mitochondrial dysfunction, circadian disruption, and the accumulation of senescent cells converge to impair metabolic flexibility, a unifying phenotype of obesity and aging. We frame obesity as a nutrient-driven and aging as a time-driven expression of a disrupted mitochondrial-circadian energy code, with shared outputs: impaired substrate switching and flattened energy rhythms. This opinion argues that restoring code integrity, indexed clinically by gains in metabolic flexibility, should guide therapy. Beyond appetite and glycemia, GLP-1 (glucagon-like peptide-1) and dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) agonists may enhance mitochondrial efficiency, support circadian alignment, and temper prosenescent signaling across target tissues (muscle, liver, adipose, islets, and brain). We outline how node-specific and combination strategies (senolytics/senomorphics, mitophagy/NAD+ support, and chrono-entrainment) could reprogram systemic energy coordination, improve durability of response, and delay age-related metabolic decline.

Keywords:  GLP-1 receptor agonists; GLP-1/GIP dual agonists; circadian rhythms; metabolic flexibility; mitochondrial dysfunction; senescence

DOI:  https://doi.org/10.1016/j.tem.2026.02.011
Mater Today Bio. 2026 Jun;38 103029

Procyanidin capsules attenuate PI3K/AKT-mediated mitochondrial dysfunction and accelerate skin wound healing in diabetic mice.

Yifan Ping, Jiaying Wang, Shaoyin Wei, Wen Tong, Wanhang Li, Junxin Ren, Siyi Wang, Xinyi Yao, Liyang Zheng, Zelin Cao, Dong Yang, Cuie Wen, Shengbin Huang, Shufan Zhao.

  Hyperglycemia-induced oxidative stress considerably hinders healing of diabetic wounds, primarily due to mitochondrial dysfunction. This pathology leads to an excessive production of reactive oxygen species (ROS), disrupts respiratory chain function, and impairs energy metabolism. This study introduces procyanidin (PC) capsules designed to target the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. The PC capsules demonstrate a sustained ability to scavenge radicals, thereby directly lowering ROS levels and specifically activating the PI3K/AKT pathway. Through this activation, the capsules restore mitochondrial function by reducing mitochondrial reactive oxygen species, stabilizing mitochondrial membrane potential, and restoring energy production. Additionally, cell experiments reveal that the capsules significantly boost the migration of fibroblasts and enhance the angiogenic activity of endothelial cells, indicating the protective effects of PC on crucial cell functions involved in wound healing. In a chronic skin wound model of diabetic mice, the PC capsules are found to accelerate wound closure by promoting collagen deposition, suppressing excessive inflammation, and minimizing mitochondrial oxidative damage. Using the PI3K inhibitor LY294002, we further verified that the pro-migratory and pro-angiogenic effects of PC capsules are largely dependent on the PI3K/AKT signaling pathway. Our novel findings suggest that PC capsules stimulate PI3K/AKT-mediated repair of mitochondrial function, presenting a potential therapeutic approach for treating refractory diabetic wounds.

Keywords:  Diabetes mellitus; Mitochondrial dysfunction; Oxidative stress; PI3K/AKT; Procyanidin capsules; Wound healing

DOI:  https://doi.org/10.1016/j.mtbio.2026.103029
Redox Biol. 2026 Mar 26. pii: S2213-2317(26)00141-2. [Epub ahead of print]92 104143

Mitochondrial translational control in cardiovascular diseases: from mechanisms to therapies.

Yunong Deng, Ningning Guo, Die Li, Zhihua Wang.

  Mitochondria orchestrate cardiac metabolic homeostasis, and their dysfunction constitutes a fundamental mechanism driving cardiovascular diseases (CVDs). During eukaryotic evolution, most of the mitochondrial genes required for oxidative phosphorylation (OXPHOS) function have been transferred to the nuclear genome, except for 13 genes coding for core subunits of the OXPHOS machinery. The translational regulation of these 13 genes inside mitochondria is precisely and dynamically regulated according to the external environment under diverse metabolic conditions. However, our understanding of these biological processes in CVDs remains limited. This review summarizes recent advances in the regulatory processes of mitochondrial translation, highlighting mitoribosome biogenesis, dynamic tRNA epitranscriptomic modifications, and coupling between translation and inner-membrane assembly. We additionally integrate emerging upstream regulatory mechanisms, including redox and metabolite-sensitive signaling, mitoepigenetic remodeling, and mitochondria-localized microRNA (mitomiR)-mediated control of mitochondrial RNA fate, which collectively tune translational output under stress. Moreover, this review delineates how these processes are dysregulated in major cardiovascular pathologies, including ischemia-reperfusion (I/R) injury, cardiac hypertrophy, heart failure (HF), and inherited cardiomyopathies. Emerging therapeutic strategies designed to restore translational fidelity and throughput, ranging from pharmacological interventions and metabolic tuning to precise mitochondrial gene editing, are also discussed. By repositioning mitochondrial translation from a passive marker of injury to a druggable control node, this review offers a new paradigm for targeting mitochondrial translation to preserve myocardial resilience and treat CVDs.

Keywords:  Cardiovascular diseases; Mitochondrial translation; Mitoribosome; OXPHOS; tRNA modification

DOI:  https://doi.org/10.1016/j.redox.2026.104143
Front Cell Dev Biol. 2026 ;14 1772623

Redox regulation in aging muscles: exercise as a key modulator to combat sarcopenia and frailty.

Hua Guo, Xueqin Jiang, Wang Zhiming, Yang Gui, Zhanguo Su.

   Background and Context: Aging is characterized by progressive decline in skeletal muscle function, which can lead to sarcopenia (loss of muscle mass and strength) and frailty (increased vulnerability to stressors), with oxidative stress-arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses-playing a central role. This narrative review synthesizes evidence on how exercise modulates redox homeostasis to mitigate these conditions in older adults.
Objectives: To explore the sources and consequences of oxidative stress in aging muscle, examine exercise's role in restoring redox balance, evaluate its impact on sarcopenia and frailty, and identify relevant biomarkers and future research directions. We achieve this by exploring key sources through representative studies, examining molecular mechanisms via pathway analyses, evaluating intervention effects using RCTs and meta-analyses, and identifying biomarkers and gaps through critical synthesis.
Methods: This narrative review involved a comprehensive literature search in databases such as PubMed, Web of Science, and Scopus, focusing on studies from 2000 to 2025 on oxidative stress, exercise, sarcopenia, and frailty in adults aged 60+. Inclusion criteria prioritized peer-reviewed articles, meta-analyses, and RCTs; exclusion applied to non-English or irrelevant studies. Over 100 articles were selected qualitatively for synthesis.
Key Findings: Aerobic and resistance exercises reduce oxidant markers (e.g., MDA decreased by 10%-20% in meta-analyses) and enhance antioxidants (e.g., SOD increased by 15%-30%), upregulating pathways like Nrf2, AMPK, and PGC-1α. Multicomponent programs improve muscle strength (e.g., 20%-40% gains in RCTs) and frailty scores (e.g., reductions in Fried Frailty Phenotype by 1-2 points). However, heterogeneous responses exist, with some studies showing neutral effects on certain markers.
Conclusion: Exercise emerges as a non-pharmacological intervention to attenuate oxidative stress-driven muscle aging, promoting healthy aging. Future studies should focus on personalized regimens and long-term biomarkers for clinical translation.

Keywords:  antioxidant defense; exercise; mitochondrial biogenesis; muscle aging; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2026.1772623
Exp Neurol. 2026 Mar 31. pii: S0014-4886(26)00115-9. [Epub ahead of print] 115752

Research progress on the relationship between mitochondrial dysfunction and inflammatory response in brain cells following traumatic brain injury: A review.

Shuhong Wang, Lili Shi, Yin Tian, Jin Wu, Fujian Guo, Anyong Yu.

  Traumatic brain injury (TBI) initiates a complex secondary injury cascade, within which the bidirectional crosstalk between mitochondrial dysfunction and neuroinflammation forms a self-amplifying vicious cycle, termed the "mitochondria-inflammation axis." This axis is increasingly recognized as a core mechanism driving progressive neural damage. Following TBI, impaired mitochondria not only cause bioenergetic failure but also release copious damage-associated molecular patterns (mtDNA, etc.) and reactive oxygen species (ROS), which potently activate innate immune platforms such as the NLRP3 inflammasome and NF-κB signaling. Conversely, the ensuing inflammatory milieu further aggravates mitochondrial damage through oxidative stress and disruption of quality control, creating a feed-forward loop. This review systematically synthesizes recent advances in understanding this axis, highlighting novel concepts like immunometabolic reprogramming of microglia and intercellular mitochondrial transfer. Furthermore, we critically evaluate emerging therapeutic strategies aimed at breaking this cycle, including mitochondria-targeted antioxidants, precise immunomodulators, and pioneering mitochondrial transplantation. By integrating evidence from multi-omics studies and diverse models, this review provides a unified conceptual framework for understanding TBI pathophysiology and illuminates promising avenues for future translational research.

Keywords:  Immunometabolism; Mitochondria-inflammation axis; Mitochondrial dysfunction; Neuroinflammation; Traumatic brain injury

DOI:  https://doi.org/10.1016/j.expneurol.2026.115752