bims-mistre 2026-07-05 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–07–05
nineteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Delayed molecular aging, preservation of energy metabolism and enhanced exercise response in exercise-trained human muscle.
The microbiota-mitochondria axis: linking metabolic dysfunction to neurodegeneration.
Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications.
Enhancing effects of diphenyl diselenide and β-hydroxy β-methylbutyrate combined with exercise on neuroprotection, memory, mitochondrial function, muscle function, and inflammation regulation in older adults and age-related diseases.
Energy beats: Daily and circadian rhythms in mitochondrial biology.
The effects of menopausal hormone therapy on cardiovascular disease, cancer, cognition and depression in younger women: A systematic review.
Inflammatory, metabolic, and vascular pathways linking cardiorespiratory fitness to cognition: Results from the IGNITE study.
Moderate NEFA reprogram early follicular development and oocyte competence: evidence for a targetable redox mechanism.
Hormone Therapy is Associated with Better Cognitive Performance in Postmenopausal Women: Insights from the National Health and Nutrition Examination Survey (NHANES).
The role of mitochondria in the gut-kidney axis: implications for kidney health.
Endothelial mitochondrial homeostasis in the development and progression of atherosclerosis.
Valerenic acid attenuates chronic stress-exacerbated metabolic dysfunction-associated steatotic liver disease via the estrogen receptor α-GDF15 axis.
Chronic hyperinsulinemia accelerates adipose senescence via mitochondrial dysfunction and cGAS-STING signalling.
Maximal fat oxidation assessment in active postmenopausal females: A novel relative power FATmax test.
Sirtuin 3 alleviates ovarian granulosa cell senescence through regulating mitochondrial quality control.
Lifestyle-associated blood metabolic pathways and functional performance in cognitive aging.
Palmitate drives mitochondrial and ER stress through disruption of the CD73-Adenosine axis.
PGC-1α-Nrf2 Signaling Imbalance Mediates Doxorubicin-Induced Mitochondrial Dysfunction and Cardiac Injury.
Mitochondria as Integrative Regulators of Ferroptosis in the Female Reproductive System.

Nat Aging. 2026 Jul 03.

Delayed molecular aging, preservation of energy metabolism and enhanced exercise response in exercise-trained human muscle.

Georges E Janssens, Maria M Trętowicz, Lotte Grevendonk, Marit Kotte, Angelique Scantlebery, Bauke V Schomakers, Michel van Weeghel, Jill Hermans, Martin A T Vervaart, Eric J M Wever, Simone W Denis, Aldo Jongejan, Gajja S Salomons, Frédéric M Vaz, Patrick Schrauwen, Joris Hoeks, Riekelt H Houtkooper.

Exercise is fundamental to healthy aging, yet how it mitigates age-related molecular changes and how fitness level shapes exercise responses remain unclear. To address these questions, we performed transcriptomics, lipidomics and metabolomics on skeletal muscle of young and older adults with differing physical function, both before and after an acute bout of submaximal exercise. At baseline, older adults exhibited reduced expression of genes associated with cellular respiration and energy metabolism compared to young adults with comparable activity levels. Here we found that 50% of these age-related differences were absent in trained older adults, resulting in profiles resembling those of young adults. Although all participants displayed transcriptional immune and stress responses upon acute exercise, the magnitude of these responses in older adults was positively correlated with their physical fitness. Integrated multiomic analyses further revealed links among mitochondrial respiration, lipid metabolism, stress responses and NAD+ biology. These findings demonstrate that sustained physical training transforms age-related molecular profiles and provide a molecular atlas for study of fitness-dependent aging mechanisms.

DOI: https://doi.org/10.1038/s43587-026-01150-x
Metab Brain Dis. 2026 Jun 29. pii: 146. [Epub ahead of print]41(1):

The microbiota-mitochondria axis: linking metabolic dysfunction to neurodegeneration.

Sedighe Yosefi, Ali Babaeizad, Seyed Soheil Tabibian, Aisa Bahar, Majid Eslami.

  The interplay between gut microbiota and mitochondria represents a dynamic relationship that profoundly impacts host physiology, ranging from maintaining intestinal homeostasis to regulating systemic metabolic and neurological functions. Microbial metabolites such as short-chain-fatty-acids, bile acids, and amino acid derivatives serve as pivotal modulators of mitochondrial bioenergetics, oxidative stress management, and fission-fusion processes. These interactions are vital for preserving epithelial integrity, supporting energy metabolism, shaping immune responses, and managing inflammatory signaling pathways. Disruptions within this microbiota-mitochondria axis are associated with various pathologies, including non-alcoholic fatty liver disease, obesity, type 2 diabetes, and chronic inflammatory conditions like inflammatory bowel disease. Additionally, growing evidence connects gut dysbiosis and mitochondrial dysfunction to neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, highlighting the importance of this bidirectional relationship in maintaining neuronal health. On a mechanistic level, pathways involving AMPK, sirtuins, and PGC-1α govern mitochondrial biogenesis and adaptive responses to microbial signals. Dysregulation of these pathways can heighten oxidative stress, hinder mitophagy, and contribute to systemic inflammation. Emerging therapeutic strategies aim to target this axis through dietary modifications, probiotics and engineered microbes, FMT, and mitochondria-specific pharmacological treatments. These interventions focus on restoring metabolic stability, enhance resilience against oxidative damage, and slowing disease progression. By integrating insights from fields such as metabolism, immunology, and neuroscience, this review positions the microbiota-mitochondria axis as a critical area of focus in biomedical research. A deeper understanding of this communication network offers promising opportunities for precision therapies aimed at addressing metabolic, inflammatory, and neurodegenerative diseases.

Keywords:  Gut microbiota; Inflammation; Metabolic disorders; Mitochondria; Neurodegeneration; Therapeutic strategies

DOI:  https://doi.org/10.1007/s11011-026-01914-9
Mol Psychiatry. 2026 Jul 03.

Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications.

Yu Wang, Ji-Tao Li, Lin-Lin Zhu, Yan-Kun Wu, Yun-Ai Su, Tian-Mei Si.

Despite its high prevalence, the precise mechanisms underlying major depressive disorder (MDD) remain incompletely understood. Growing evidence identifies mitochondrial dysfunction, including abnormalities in mitochondrial DNA, impaired bioenergetics, disrupted quality control, and redox imbalance, as a central pathological feature of MDD. Beyond deficits in energy production, mitochondria function as upstream regulators of neuroinflammation. Mitochondria derived damage associated molecular patterns and excessive reactive oxygen species activate innate immune signaling, while inflammatory challenges in turn compromise mitochondrial integrity. This bidirectional and self-reinforcing interaction between mitochondrial dysfunction and inflammation may contribute to disease onset, progression, and clinical heterogeneity. Preclinical and clinical studies indicate that conventional antidepressants gradually restore mitochondrial function while suppressing oxidative and inflammatory stress, whereas rapid-acting agents such as ketamine induce acute metabolic reprogramming and mitophagy, enabling swift functional recovery. Mechanistically distinct interventions, including mitochondria targeted antioxidants, metabolic modulators, and psychedelic compounds, further highlight the therapeutic potential of targeting mitochondrial pathways. By integrating current evidence, this review delineates mitochondrial-inflammation crosstalk in MDD and supports mitochondrial regulation as a promising target for novel antidepressant strategies.

DOI: https://doi.org/10.1038/s41380-026-03732-y
Front Nutr. 2026 ;13 1770666

Enhancing effects of diphenyl diselenide and β-hydroxy β-methylbutyrate combined with exercise on neuroprotection, memory, mitochondrial function, muscle function, and inflammation regulation in older adults and age-related diseases.

Ranran Huang, Wendan Pang.

  Aging and age-associated pathologies are characterized by a gradual deterioration in cognitive abilities, neuroprotective mechanisms, mitochondrial efficacy, skeletal muscle mass, and overall functional capacity, frequently aggravated by oxidative stress and persistent inflammation. Physical exercise is extensively acknowledged for its role in ameliorating these age-related detriments; however, its effectiveness may be further enhanced through specific nutritional supplementation. Diphenyl diselenide (PhSe₂) represents a selenium-derived compound endowed with significant antioxidant and anti-inflammatory capabilities, whereas β-hydroxy β-methylbutyrate (HMB) serves as a metabolite of leucine that is recognized for its ability to augment muscle mass, strength, and protein synthesis. This review consolidates contemporary findings regarding the synergistic effects of PhSe₂ and HMB supplementation, in conjunction with exercise interventions, within aging models and age-related disorders. The amalgamation of these compounds with organized physical activity seemingly intensifies neuroprotective mechanisms, enhances cognitive performance, optimizes mitochondrial functionality, modulates inflammatory cytokines, and sustains skeletal muscle mass and functional capabilities. Mechanistically, these advantages are facilitated through the modulation of oxidative stress pathways, mitochondrial biogenesis, anti-apoptotic signaling, and the turnover of muscle proteins. Collectively, PhSe₂ and HMB, in conjunction with exercise, constitute a promising multi-targeted approach aimed at mitigating age-related physiological decline and promoting healthy aging. Additional preclinical and clinical investigations are necessary to optimize dosage, timing, and long-term efficacy within elderly populations and individuals suffering from age-associated disorders.

Keywords:  cognitive function; diphenyl diselenide; exercise; physical outcomes; β-hydroxy β-methylbutyrate

DOI:  https://doi.org/10.3389/fnut.2026.1770666
Mitochondrion. 2026 Jun 27. pii: S1567-7249(26)00081-4. [Epub ahead of print] 102191

Energy beats: Daily and circadian rhythms in mitochondrial biology.

Nadia Ceccato, Milena Damulewicz, Gabriella Margherita Mazzotta.

  Circadian rhythms orchestrate a wide array of behavioral and physiological functions, coordinating cellular and organismal processes on an approximately 24-h cycle through an intrinsic timekeeping system. Among the many processes subject to this temporal regulation, mitochondrial function has emerged as a critical and dynamic target of circadian control. Mitochondria, far from being static organelles, undergo continuous morphological remodeling through cycles of fusion and fission, collectively termed mitochondrial dynamics, that are essential for maintaining metabolic homeostasis, energy production, and cellular quality control. Disruptions in circadian rhythmicity, such as those arising from sleep disturbances or irregular feeding patterns, have been associated with impaired glucose tolerance, insulin resistance, and increased risk of metabolic syndrome, diabetes, and cardiovascular disease. Emerging evidence suggests that the circadian clock and mitochondrial dynamics are engaged in a bidirectional interplay, whereby clock-controlled gene expression shapes mitochondrial morphology and function, while mitochondrial metabolic states in turn feedback to influence circadian timing. This review explores the evolutionary origins of mitochondrial rhythmicity, synthesizes current evidence on how the circadian clock regulates mitochondrial dynamics, and examines the physiological and pathological implications of their interconnection. A particular focus is placed on how disruptions in this circadian-mitochondrial axis may contribute to the development of common diseases, including neurodegenerative disorders, metabolic diseases, and cancer, highlighting novel avenues for chronobiologically informed therapeutic strategies.

Keywords:  Circadian clock; Circadian misalignment; Clock-mitochondria interplay; Mitochondrial rhythmicity

DOI:  https://doi.org/10.1016/j.mito.2026.102191
JRSM Open. 2026 Jun;17(6): 20542704261455970

The effects of menopausal hormone therapy on cardiovascular disease, cancer, cognition and depression in younger women: A systematic review.

Patricia A Bencivenga, Natalie Fort, Adriane Fugh-Berman, Anthony R Scialli.

   Objective: The Women's Health Initiative (WHI), a randomized controlled trial, found no overall health benefit of menopausal hormone therapy. Our objective was to evaluate the hypothesis that initiating hormonal therapy prior to age 60 or within a few years after the last menstrual period provides health benefits in menopausal women.
Design: A search was conducted in MEDLINE, Scopus, and ClinicalTrials.gov from inception until August 26, 2025. Randomized controlled trials in which at least one arm was a pharmaceutical oestrogen and one arm was a placebo were included. We required studies to present clinical health outcomes.
Setting: Systematic review.
Participants: Menopausal women age 60 or younger or within a short time of the last menstrual period, as defined by individual study authors.
Main outcome measures: Studies were categorized based on primary endpoints, namely cardiovascular disease, cancer, depression, and cognition. Risk of bias was assessed using a standard tool. The reliability of conclusions was assessed using the core GRADE method.
Results: Thirty-one papers, reporting on seventeen randomized controlled trials, met eligibility criteria. Menopausal hormone therapy in young menopausal women was not shown to have beneficial effects on cardiovascular disease, cancer, depression, or cognition with the exception of some cardiovascular endpoints in women on oestrogen alone in the WHI, a finding not confirmed in other randomized controlled trials and not confirmed in women with vasomotor symptoms.
Conclusions: Menopausal hormone therapy in young menopausal women has not been shown in randomized controlled trials to have beneficial effects on cardiovascular disease, cancer, depression, or cognition.

Keywords:  Menopause; cancer; cardiovascular disease; cognition; depression; hormone therapy; perimenopause; systematic review; timing hypothesis

DOI:  https://doi.org/10.1177/20542704261455970
Brain Behav Immun Health. 2026 Aug;55 101291

Inflammatory, metabolic, and vascular pathways linking cardiorespiratory fitness to cognition: Results from the IGNITE study.

Patricio Solis-Urra, Kelsey R Sewell, Audrey M Collins, Chaeryon Kang, Haiqing Huang, George Grove, Lu Wan, Amani M Norling, Arthur F Kramer, Edward McAuley, Jeffrey M Burns, Charles H Hillman, Eric D Vidoni, Anna L Marsland, M Ilyas Kamboh, Amanda Szabo-Reed, Renee J Rogers, Daniel E Forman, Sandra A Billinger, John M Jakicic, Kirk I Erickson, Lauren E Oberlin.

Objectives: This study examined whether peripheral biological pathways including inflammation, insulin resistance, and arterial stiffness, partially explain the link between cardiorespiratory fitness (CRF) and cognitive function in older adults.
Methods: In a cross-sectional sample of cognitively unimpaired older adults (N = 648, 71% female, M age = 69.88 ± 3.75 years), participants completed a comprehensive cognitive battery assessing executive function (EF)/Attentional control, episodic memory, processing speed, working memory, and visuospatial abilities. CRF was measured using a maximal graded exercise test performed on a motorized treadmill. Peripheral biomarkers included low-grade systemic inflammation (Interleukin-6; IL-6), insulin resistance (Homeostatic Model Assessment for Insulin Resistance; HOMA-IR) and arterial stiffness (carotid-femoral pulse wave velocity; cfPWV). Parallel mediation models, adjusted for age, sex, APOE4 carriage, body fat percentage, study site and years of education, tested whether these biomarkers statistically mediated associations between CRF and cognitive performance.
Results: IL-6 emerged as a consistent significant mediator of the relationship between CRF and EF, episodic memory, visuospatial processing and working memory. HOMA-IR statistically mediated the association between CRF and both EF and processing speed. In contrast, cfPWV did not statistically mediate an association between CRF and performance in any cognitive domain.
Conclusion: These findings suggest that low-grade systemic inflammation broadly mediates the relationship between CRF and cognitive function, while metabolic pathways show more domain-specific associations. Together, these results highlight the need for understanding the plural, yet distinct, biological mechanisms by which higher CRF relates to better cognitive performance, with the goal of identifying potential targets for interventions aimed at preserving cognitive health in older adulthood.

DOI: https://doi.org/10.1016/j.bbih.2026.101291
Front Nutr. 2026 ;13 1840637

Moderate NEFA reprogram early follicular development and oocyte competence: evidence for a targetable redox mechanism.

Camila Rojo-Fleming, Chiara Di Berardino, Alessia Peserico, Angelo Canciello, Chiara Camerano Spelta Rapini, Gianna Sacchetti, Giulia Capacchietti, Veronica D'Antonio, Donato Angelino, Mauro Serafini, Sebastián Cánovas, Barbara Barboni.

   Introduction: Elevated circulating non-esterified fatty acids (NEFA), a hallmark of metabolic stress and negative energy balance, are increasingly associated with reduced female fertility. While most studies focus on late oocyte maturation, metabolic disturbances during follicular growth, particularly during the preantral - early antral transition, a critical window for establishing oocyte developmental competence may already impair oocyte quality. Here, we investigated whether sustained, physiologically buffered NEFA elevation during this stage affects oocyte developmental competence.
Methods: Preantral follicles were cultured for 18 days in a three-dimensional ovine in vitro folliculogenesis system under physiological (70 μM) or moderately elevated (140 μM) NEFA conditions, with defined fatty acid composition and albumin buffering. The cytoprotective effects of the antioxidants Trolox and resveratrol were also evaluated.
Results: Chronic exposure to moderately elevated NEFA induced a pro-oxidant follicular microenvironment, characterized by reactive oxygen species (ROS) accumulation and oxidative DNA damage, including increased 8-OHdG and mtDNA D-loop oxidation. This stress impaired cumulus cell function and somatic-oocyte communication, reduced oocyte mtDNA copy number and mitochondrial activity, and compromised meiotic and developmental competence despite preserved follicular growth. Antioxidant treatment with Trolox restored mitochondrial function, normalized cumulus activity, and rescued blastocyst development, partially reversing the NEFA-induced phenotype.
Discussion: Prolonged moderate NEFA elevation during early folliculogenesis impairs oocyte competence despite preserved follicular morphology, identifying chronic lipotoxicity and redox imbalance as early and clinically relevant determinants of impaired fertility.

Keywords:  antioxidant rescue; early folliculogenesis; lipotoxicity; mitochondrial dysfunction; non-esterified fatty acids (NEFA); oocyte developmental competence; oxidative stress; trolox

DOI:  https://doi.org/10.3389/fnut.2026.1840637
Ann Geriatr Med Res. 2026 Jun;30(2): 236-245

Hormone Therapy is Associated with Better Cognitive Performance in Postmenopausal Women: Insights from the National Health and Nutrition Examination Survey (NHANES).

Paula Amado-Riveros, Efrain Riveros-Perez.

   BACKGROUND: Alzheimer's disease is more prevalent among females. Estrogens influence brain metabolism and function, and low blood levels before, during, and after menopause may be associated with cognitive decline in later years. Here, we investigate the association between hormone therapy and reproductive lifespan with cognitive performance using a nationally representative sample from the National Health and Nutrition Examination Survey (NHANES) database.
METHODS: This cross-sectional study included 1,374 eligible women aged 60 years or older from the NHANES database. Cognitive performance was assessed using the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) word learning subtest, the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Univariate analysis and multivariate logistic regression were employed to evaluate the association between hormone therapy, reproductive span, and cognitive performance. Restricted cubic spline curves were used to assess the relationship between age as a continuous variable and cognitive performance.
RESULTS: After adjusting for age, race, and educational level, hormone therapy was significantly associated with word recall, digit symbol, and animal fluency cognitive performance (p < 0.05). The reproductive span was associated with word recall performance (p = 0.027) but not with digit symbol or animal fluency. The age-related cognitive decline is attenuated by hormone therapy with maximum effect between 65 and 70 years for all dimensions.
CONCLUSION: There is a positive association between hormone therapy and cognitive performance in postmenopausal women, particularly in age groups with the steeper decline. In addition, there is no significant association between reproductive span and cognitive function.

Keywords:  Aging; Cognition; Cognitive dysfunction; Hormone replacement therapy; Postmenopause

DOI:  https://doi.org/10.4235/agmr.25.0180
Front Pharmacol. 2026 ;17 1851705

The role of mitochondria in the gut-kidney axis: implications for kidney health.

Qin Hu, Hua Jin, Lan Hu, Xu Li.

  Mitochondria, multifunctional organelles that regulate cellular energy metabolism and signaling pathways, play a pivotal role in maintaining the physiological functions of the gut and kidneys, as well as influencing the progression of chronic kidney disease (CKD). Through the gut-kidney crosstalk, gut microbiota modulate gut and renal pathophysiology and also influence mitochondrial activity in intestinal and renal cells. This review explores the regulatory roles of mitochondria in preserving epithelial barrier integrity, regulating intestinal metabolism, and maintaining gut microbiota homeostasis. It also examines the contributions of mitochondrial biogenesis, dynamics, autophagy abnormalities, and mitochondrial DNA (mtDNA) damage to renal pathological progression. Moreover, we highlight the bidirectional interactions between intestinal and renal mitochondria via the microbiota-mitochondria-kidney axis and mechanisms involving inflammation, oxidative stress, and ferroptosis. Therefore, targeting mitochondrial regulation through non-pharmacological interventions such as dietary adjustments, probiotic supplementation and fecal microbiota transplantation (FMT) emerges as a promising therapeutic strategy for maintaining renal health by optimizing mitochondrial function. In conclusion, elucidating the mechanisms of mitochondrial involvement in the gut-kidney axis will lay the foundation for novel therapeutic approaches to CKD and other gut-kidney axis-related disorders.

Keywords:  chronic kidney disease; gut microbiota; gut-kidney axis; kidney disease; mitochondria

DOI:  https://doi.org/10.3389/fphar.2026.1851705
Front Cardiovasc Med. 2026 ;13 1813122

Endothelial mitochondrial homeostasis in the development and progression of atherosclerosis.

Naznin Sultana Remex, Md Sakil Miah, Tamjid Islam, Richa Aishwarya, Md Hasif Sinha, Proma Dhar, Cyrine Ben Dhaou, A Wayne Orr, Md Shenuarin Bhuiyan.

  Vascular endothelial cells (ECs) play a critical role in vascular functional homeostasis, and endothelial dysfunction activates signaling pathways that drive the development and progression of atherosclerosis. Mitochondria in ECs play an essential signaling role in regulating redox balance, calcium signaling, metabolic signaling, and inflammatory responses. Disruption of mitochondrial functional homeostasis by atherogenic stimuli leads to excessive mitochondrial reactive oxygen species production, altered mitochondrial dynamics, defective mitophagy, and mitochondrial DNA damage. These mitochondrial defects in ECs reduce nitric oxide bioavailability through eNOS uncoupling, destabilize endothelial junctional complexes, and promote endothelial activation. Additionally, damaged mitochondria release mitochondrial danger-associated molecular patterns contributing to the activation of inflammation and redox-sensitive signaling pathways in ECs. In this review, we delineated the mechanistic links between endothelial mitochondrial dysfunction and the pathological features of atherosclerosis. We highlight the contribution of mitochondrial signaling to the regulation of oxidative stress, innate immune activation, and endothelial barrier disruption. We also discussed emerging therapeutic strategies targeting mitochondria-associated signaling pathways, including modulation of mitochondrial dynamics, mitophagy, redox signaling, and mitochondria-targeted drug delivery. Together, we provide insights into the role of endothelial mitochondria in atherosclerotic disease progression and compelling targets for mechanism-based therapeutic intervention.

Keywords:  atherrosclerosis; endothelial cell; endothelial dysfunction; mitochondria; mitochondrial signaling pathway

DOI:  https://doi.org/10.3389/fcvm.2026.1813122
Eur J Pharmacol. 2026 Jul 01. pii: S0014-2999(26)00588-1. [Epub ahead of print]1030 179106

Valerenic acid attenuates chronic stress-exacerbated metabolic dysfunction-associated steatotic liver disease via the estrogen receptor α-GDF15 axis.

Xingli Wu, Yuzi Jiang, Junmin Wang, Simin Gu, Yanping Wang, Ning Li, Chunmei Qian, Hongming Nie, Yiyuan Zheng, Yong Li.

  The incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) has been rising annually. Meanwhile, with intensifying societal pressure, there has been a parallel surge in the prevalence of psychological disorders. The coexistence of these conditions creates a complex comorbidity, leading to heightened metabolic and cardiovascular risks, and posing challenges to traditional therapeutic approaches. Valerenic acid, a natural compound derived from the roots of Valeriana officinalis, exhibits sedative, anxiolytic, anti-inflammatory, and antioxidant effects, which may offer a promising therapeutic intervention for MASLD complicated by stress. The present study aims to experimentally evaluate the therapeutic effects of valerenic acid as well as to explore its pharmacological mechanisms, thereby providing evidence for its clinical application. Both male and female C57BL/6J mice were utilized in this study. A Western diet was employed to induce MASLD, while moderate, intermittent, and prolonged restraint stress was applied to simulate chronic stress, whereas valerenic acid was orally gavaged to assess its therapeutic efficacy. The outcomes revealed that, in both sexes, the initial phase of restraint stress induced concurrent reductions in food intake and body weight; however, following an adaptation period, persistent chronic stress paradoxically resulted in escalation of both food consumption and weight gain. Intervention with valerenic acid effectively attenuated stress-induced fluctuations in feeding behavior and body weight. Furthermore, estrogen receptor α was identified as a key target of valerenic acid, which regulated the pivotal immunometabolic mediator growth differentiation factor 15, thereby suppressing appetite while ameliorating hepatic inflammatory pathology.

Keywords:  Appetite suppression; Chronic stress; Metabolic dysfunction-associated steatotic liver disease; Valerenic acid

DOI:  https://doi.org/10.1016/j.ejphar.2026.179106
J Endocrinol. 2026 Jun 29. pii: JOE-25-0367. [Epub ahead of print]

Chronic hyperinsulinemia accelerates adipose senescence via mitochondrial dysfunction and cGAS-STING signalling.

Astha Singh, Nilesh Khandelwal, Prashant Rai, Vinita Kushwaha, Sanchita Gupta, Ravi Kumar, Rishabh Mishra, Pradeep Tiwari, Raj Kumar Mishra, Sandeep Kumar Mathur, Anil Nilkanth Gaikwad.

  Prediabetes and Type 2 Diabetes represent major global health challenges and have escalated to pandemic levels. Adipose tissue functions as a critical endocrine organ, playing a central role in maintaining glucose homeostasis during fasting, feeding, and stress responses. In this study, we demonstrated that prolonged chronic hyperinsulinemic stress increases the burden of senescent adipocytes, accompanied by activation of the cGAS-STING signalling pathway. Chronic hyperinsulinemia-induced insulin-resistant 3T3-L1 and human mesenchymal stem cell-derived adipocytes exhibited elevated senescence-associated phenotypes, mitochondrial dysfunction and impaired cellular energetics. Notably, we found that mitochondrial DNA leakage triggered the cGAS-STING pathway in insulin-resistant adipocytes and mouse models. Temporal analysis revealed that mitochondrial dysfunction was detectable at earlier stages of chronic insulin exposure, preceding activation of the cGAS-STING pathway and senescence-associated markers, supporting a progressive model of cellular dysfunction. This phenomenon was also observed in adipose depots of individuals with Type 2 diabetes, underscoring the translational relevance of our findings. Targeting cGAS or STING, either pharmacologically or through genetic silencing, significantly reduced inflammatory and senescence-related features in hyperinsulinemia-induced insulin-resistant 3T3-L1 adipocytes. Furthermore, attenuation of senescence treatment with the combination of Dasatinib and Quercetin alleviated mitochondrial stress and associated adipose dysfunction. Collectively, our findings support a model in which prolonged hyperinsulinemic stress induces early mitochondrial dysfunction, followed by activation of cGAS-STING signalling and the subsequent emergence of adipocyte senescence-associated phenotypes, contributing to adipose tissue dysfunction in insulin resistance and Type 2 Diabetes.

Keywords:  Adipose tissue; Chronic hyperinsulinemia; Mitochondrial dysfunction; Senescence; cGAS-STING pathway

DOI:  https://doi.org/10.1530/JOE-25-0367
Physiol Rep. 2026 Jul;14(13): e70991

Maximal fat oxidation assessment in active postmenopausal females: A novel relative power FATmax test.

Jordi Monferrer-Marín, Ainoa Roldán, Jørn Wulff Helge, Cristina Blasco-Lafarga.

  This study compared a novel relative-to-body-mass FATmax test (RFT; 0.15 W/kg/4 min from 0.45 W/kg) with a traditional absolute power FATmax test (AFT; 10 W/3min15sec from 30 W) in postmenopausal females. The aim was to determine whether the RFT protocol would improve fat oxidation kinetics during exercise, in females with lower maximal fat oxidation (MFO). It was hypothesized that the longer duration and the lower workload increments would result in higher fat oxidation values than AFT. Seventeen active postmenopausal females (69.2 ± 5.1 years) performed both protocols in a randomized order and were divided into above (H-MFO) or below (L-MFO) 0.3 g/min MFO. Groups were equal in age and body composition. Overall, time to MFO was delayed during the RFT protocol (765 ± 621 vs. 401 ± 262 s) without MFO differences. Both groups displayed longer time to MFO in RFT, whilst significantly only for L-MFO (420 ± 280 s vs. 317 ± 232). Although no statistical differences, moderate effect sizes were observed in the L-MFO group during RFT for both MFO (0.22 ± 0.04 vs. 0.19 ± 0.06 g/min, d = 0.65) and VO2 (12.8 ± 3.8 vs. 15.4 ± 5.5 mL/min/kg, d = -0.53). RFT may improve the determination of substrate oxidation kinetics in postmenopausal females with reduced fat oxidation capacity, while facilitating complementary analyses requiring longer recordings and stability (efficiency and Heart Rate Variability).

Keywords:  aging; energy expenditure; metabolic flexibility; relative power; respiratory exchange

DOI:  https://doi.org/10.14814/phy2.70991
Theriogenology. 2026 Jun 25. pii: S0093-691X(26)00244-X. [Epub ahead of print]264 118054

Sirtuin 3 alleviates ovarian granulosa cell senescence through regulating mitochondrial quality control.

Jingmiao Shi, Ziling Zhao, Fuguo Wang, Yongju Zhao, Zhongquan Zhao, Dejun Xu.

  Cellular senescence-triggered irreversible proliferative arrest leads to follicular atresia and suppressed dominant follicle selection. Mitochondrial sirtuin 3 (SIRT3) contributes substantially to mitochondrial function, yet the exact molecular mechanisms underlying its regulation of granulosa cell senescence remain largely elusive.‌ Here, single-cell transcriptomic profiling in goats revealed that the downregulation of SIRT3, together with cellular senescence and mitochondrial dysfunction, are the hallmark features of granulosa cells in aged ovarian follicles. Knockdown of SIRT3 led to cellular senescence, which was characterized by proliferative arrest, cell cycle dysregulation and DNA damage accumulation. Importantly, SIRT3 knockdown aggravated mitochondrial dysfunction, as evidenced by impaired mitophagy, elevated reactive oxygen species (ROS) and increased mitochondrial fragmentation. SIRT3 overexpression alleviated etoposide-induced senescence by restoring mitophagy and mitochondrial function. Transcriptomic profiling further confirmed the predominant involvement of SIRT3 in mitochondrial regulatory pathways. Collectively, our results reveal that SIRT3 alleviates granulosa cell senescence through the regulation of mitochondrial quality control, which is critical for sustaining physiological follicular development.

Keywords:  Goat; Mitochondrial dysfunction; Mitophagy; SIRT3

DOI:  https://doi.org/10.1016/j.theriogenology.2026.118054
Sci Rep. 2026 Jun 28.

Lifestyle-associated blood metabolic pathways and functional performance in cognitive aging.

Yirui Chen, Hongxin Gui, Kai Ma, Ziyi Zhang, Tieniu Zhao, Mengyang Wang.

  Functional decline is a major clinical feature of Alzheimer's disease (AD), yet the blood metabolic pathways associated with lifestyle factors and multidimensional functional performance across cognitive stages remain incompletely characterized. We applied a pathway-level blood metabolomics framework to harmonized, de-identified data from aging and dementia-related cohort resources spanning cognitively normal aging (CN), mild cognitive impairment (MCI), and AD. Metabolites were mapped to curated pathways and summarized into pathway activity scores across five domains: energy metabolism, amino acid metabolism, lipid metabolism, inflammation/oxidative stress, and microbiome-linked metabolism. We evaluated associations among physical activity, diet quality, pathway activity scores, and functional outcomes, including activities of daily living, gait speed, grip strength, global cognition, composite function, and frailty. To summarize pathway patterns jointly associated with physical activity and diet quality, we derived a lifestyle-modulated metabolic pathway score (LMPS) using elastic net regression with cross-validation, out-of-fold score estimation, and bootstrap stability assessment. Lifestyle-associated pathway activity showed coordinated patterns across metabolic domains and was associated with functional performance across cognitive groups. Higher LMPS values were associated with better physical and cognitive function and lower frailty, with graded differences observed across CN, MCI, and AD. Internal robustness analyses indicated greater stability at the pathway-domain level than at the individual-pathway coefficient level. Sensitivity analyses adjusting for cognitive group attenuated but did not eliminate the directionally consistent associations between LMPS and major functional outcomes. Convergent pathway patterns involved mitochondrial energy metabolism, lipid remodeling, inflammatory regulation, and microbiome-related metabolism. Pathway-level blood metabolomics identified lifestyle-associated metabolic patterns related to multidimensional functional outcomes across the cognitive aging spectrum. LMPS provides a data-driven summary of lifestyle-associated pathway variation in this cohort and may help generate hypotheses about metabolic correlates of functional performance. Independent and longitudinal validation will be required to determine its reproducibility, temporal relevance, and translational utility.

Keywords:  Alzheimer’s disease; Blood metabolomics; Diet quality; Frailty; Functional decline; Lifestyle exposures; Pathway-level analysis; Physical activity

DOI:  https://doi.org/10.1038/s41598-026-58782-7
Res Sq. 2026 Jun 15. pii: rs.3.rs-9902042. [Epub ahead of print]

Palmitate drives mitochondrial and ER stress through disruption of the CD73-Adenosine axis.

Shantiece Dawson, Sonia Batan, Nina Adams, Sergei Bombin, Erivan S Ramos-Junior, Ana Carolina Morandini.

Background Metabolic disorders associated with elevated saturated fatty acids are linked to chronic inflammatory diseases, including periodontitis, yet the mechanisms connecting lipotoxic stress to gingival inflammation remain unclear. This study investigated how palmitate-induced metabolic stress affects purinergic signaling, mitochondrial function, and endoplasmic reticulum (ER) stress in murine gingival fibroblasts (mGF), and whether adenosine modulates these effects. Methods mGF were treated with BSA control, palmitate, IL-1β, or palmitate plus IL-1β, followed by bulk RNA sequencing, Seahorse metabolic analysis, biochemical assays, and transmission electron microscopy. Results Palmitate suppressed expression of key adenosine-generating ectoenzymes and purinergic signaling genes, including Cd73 (Nt5e), Cd39 (Entpd1), Adk, Ada, and adenosine receptors. Concurrently, palmitate amplified IL-1β-induced inflammatory mediators such as Cxcl1, Cxcl2, Cxcl5, Ccl2, and Il6. Gene ontology analysis demonstrated enrichment of pathways related to innate immune activation, oxidative stress, mitochondrial dysfunction, ER stress, and purine metabolism. Palmitate also induced intracellular lipid accumulation and mitochondrial dysfunction, evidenced by reduced NAD+/NADH ratio, increased mitochondrial reactive oxygen species (ROS), elevated protein oxidation, and increased proton leak despite enhanced electron transport chain protein expression. Ultrastructural analyses revealed swollen mitochondria, ER expansion, and increased ER-mitochondrial associations. Mechanistically, palmitate activated the Perk-eIF2α-Atf4 ER stress pathway, increasing phosphorylation of Perk and eIF2α and elevating Atf4 expression. Extracellular adenosine attenuated mitochondrial ROS accumulation, reversed Perk and Atf4 activation, improved mitochondrial respiration, and preserved ER and mitochondrial ultrastructure. Conclusions Palmitate disrupts the Cd73-adenosine axis while promoting mitochondrial dysfunction, oxidative stress, and Perk-mediated ER stress in gingival fibroblasts. Adenosine signaling protects against lipotoxic-induced ER stress, highlighting the Cd73-adenosine pathway as a potential therapeutic target in metabolically driven periodontal inflammation.

DOI: https://doi.org/10.21203/rs.3.rs-9902042/v1
J Biochem Mol Toxicol. 2026 Jul;40(7): e71013

PGC-1α-Nrf2 Signaling Imbalance Mediates Doxorubicin-Induced Mitochondrial Dysfunction and Cardiac Injury.

Shaohuan Qian, Yue Guan, Zhuoya Yao, Jian Zhu, Wei Zhang.

  Doxorubicin (DOX)-induced cardiotoxicity is characterized by mitochondrial dysfunction and oxidative stress; however, the mechanistic interplay between mitochondrial metabolic regulation and antioxidant defense remains unclear. In this study, Transcriptomic analysis, in vitro human iPSC-derived cardiomyocytes, and DOX-induced murine models were used to investigate the functional interaction between peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and nuclear factor erythroid 2-related factor 2 (Nrf2). Pharmacological activation, gene knockdown, and histological approaches were employed to dissect pathway interdependence. DOX suppressed oxidative phosphorylation, tricarboxylic acid cycle, and mitochondrial biogenesis pathways while activating Nrf2-mediated antioxidant responses, indicating functional uncoupling. PGC-1alpha activation restored mitochondrial respiration and reduced oxidative stress, whereas its deficiency aggravated mitochondrial collapse. Notably, Nrf2-mediated antioxidant protection was significantly attenuated under PGC-1alpha deficiency, demonstrating dependence on mitochondrial integrity. In vivo, combined activation of PGC-1alpha and Nrf2 more effectively improved mitochondrial function, reduced oxidative injury, and preserved cardiac structure and function compared with single interventions. These findings indicate that DOX-induced cardiotoxicity involves functional decoupling between antioxidant responses and mitochondrial metabolism. PGC-1alpha maintains mitochondrial homeostasis and enables effective Nrf2-mediated defense, suggesting that targeting the PGC-1alpha/Nrf2 axis represents a promising therapeutic strategy for DOX-induced cardiac injury.

Keywords:  Nrf2; PGC‐1α; cardiotoxicity; doxorubicin; mitochondrial dysfunction

DOI:  https://doi.org/10.1002/jbt.71013
Biol Reprod. 2026 Jun 27. pii: ioag132. [Epub ahead of print]

Mitochondria as Integrative Regulators of Ferroptosis in the Female Reproductive System.

Isil Yenigun, Nazli Ece Huner, Aylin Yaba.

  Mitochondrial function is fundamental to female reproductive physiology, supporting follicular development, oocyte maturation, and endometrial remodeling. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has recently emerged as a potential contributor to reproductive dysfunction under conditions of mitochondrial impairment and oxidative stress. This review examines how mitochondrial quality-control (MQC) mechanisms-including biogenesis, dynamics, iron handling, and redox regulation-modulate ferroptotic sensitivity across female reproductive tissues. We highlight cell type-specific differences, ranging from ferroptosis-associated granulosa cell loss during follicular atresia to sublethal ferroptotic stress affecting oocyte competence and tightly restrained ferroptosis during decidualization and implantation. By integrating experimental and clinical evidence, we propose that mitochondrial regulation of ferroptosis acts as a context-dependent modulator of reproductive function rather than a uniform cell death pathway. Understanding this interplay provides new insight into ovarian aging, infertility, and uterine receptivity, with implications for reproductive medicine.

Keywords:  Ferroptosis; infertility; mitochondria; ovary; oxidative stress; uterus

DOI:  https://doi.org/10.1093/biolre/ioag132