bims-mistre 2026-01-18 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–01–18
seventeen papers selected by
Ellen Siobhan Mitchell, MitoQ

What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?
GDF-15 as an integrative cardiometabolic biomarker.
DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization.
TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.
Astaxanthin improves myogenicity of aged skeletal muscle progenitor cells in a sexually dimorphic manner.
MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
Reduced ATP-to-phosphocreatine ratios in neuropsychiatric post-COVID condition: Evidence from 31P magnetic resonance spectroscopy.
SIRT3 attenuates AGEs-induced senescence in human granulosa cells through enhancing mitophagy.
The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans.
Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.
SOD1 deficiency drives ferroptosis-linked oxidative and reproductive aging, mitigated by ginseng root extract.
Menopause, cognition, and Alzheimer's disease risk.
GDF11/TGFBR1 Activation Is Essential for the Antidepressant-like Effect of H₂S: Role of Suppressing the hippocampal cascade of necroptosis-neuroinflammation-Kynurenine Pathway Disorder.
Mitochondrial fission during mitophagy requires both inner and outer mitofissins.
Whole-grain black rice diet rewires the single-cell transcriptomic landscape of age-related ovarian decline in mice.
Nobiletin Ameliorates Skeletal Muscle Performance in D-Galactose-Induced Aging Mice by Boosting Aerobic Metabolism.
Mitochondrial DNA 6mA Methylation by METTL4 Drives Neuroinflammation via cGAS-STING Activation in Vascular Cognitive Impairment.

Neurology. 2026 Feb 10. 106(3): e214618

What Are the Roles of Mitochondrial Stress Responses and Mitohormesis in Neurodegenerative Disorders?

Eduardo Benarroch.

Mitochondrial dysfunction is a key pathogenic component of neurodegenerative disorders. Mitochondrial stress, created by accumulation of misfolded proteins, reactive oxygen species, and other mechanisms, triggers signals that promote changes in protein translation and gene transcription aimed at protecting and restoring mitochondrial function and maintaining cellular homeostasis. These quality control responses are the integrated stress response and the mitochondrial unfolded protein response. When triggered by mild mitochondrial stress, these adaptive responses promote mitohormesis, which enhances cell survival and lifespan. The exchange of information between mitochondria allows mitochondrial stress in specific tissues to initiate beneficial adaptations affecting mitochondrial populations in remote tissues and organs. Experimental and human observational studies indicate that approaches to trigger mitohormesis, such as physical exercise, have beneficial effects in neurodegenerative disorders.

DOI: https://doi.org/10.1212/WNL.0000000000214618
Clin Chim Acta. 2026 Jan 13. pii: S0009-8981(26)00021-5. [Epub ahead of print] 120839

GDF-15 as an integrative cardiometabolic biomarker.

Obaid Afzal, Muhammad Afzal, Nawaid Hussain Khan, Ali Altharawi, Mubarak A Alamri, Manal A Alossaimi, Abdulmalik S A Altamimi, Pavan Goud.

  Growth Differentiation Factor 15 (GDF-15) is a stress-inducible cytokine that is abundantly expressed in cardiomyocytes, adipose tissue, macrophages, endothelial cells, and vascular smooth muscle cells. The levels of this biomarker increase in response to tissue injury, inflammation, and metabolic stress and are elevated in the presence of primary cardiometabolic diseases, such as type 2 diabetes, obesity, hypertension, atherosclerosis, heart failure, and chronic kidney disease. This is articulated in a clinical chemistry narrative review, which elucidates why GDF-15 can be characterized as an integrative biomarker. This characterization is due to the shared pathophysiological processes of metabolic stress, inflammation, oxidative/mitochondrial stress, and tissue injury across these conditions, as well as its clinical applications in risk assessment, prognosis, and monitoring. We also briefly present modern methods to measure circulating GDF-15 (primarily immunoassays, with new mass-spectrometry techniques being developed) and note that inter-assay variability and assay standardization are considered to be the major impediments to clinical application. The most significant determinants of biological variability (age, sex, renal function, genetic variation, and comorbidities), by which reference intervals and longitudinal interpretation are affected, are also highlighted. Increased GDF-15 is consistently associated with poor outcomes in diabetes, obesity, hypertension, heart failure, and atherosclerosis, such as cardiovascular events, kidney failure, and death. Nonetheless, prognostic cutoffs have been proposed variably across studies, populations, and measurement platforms. Therefore, these thresholds should be approached with caution until harmonized assays and clinically validated decision limits established through prospective studies are available. GDF-15 is a powerful integrative biomarker of metabolic stress, inflammation, and tissue injury in cardiometabolic diseases. Its introduction into clinical practice may enhance early risk stratification, personalize therapeutic interventions and monitor disease progression. Future studies should focus on optimizing the standardization of assays, developing evidence-based reference intervals (and reference change values), and elucidating clinically practical decision limits and therapeutic implications of the GDF-15 pathway in the treatment of cardiometabolic diseases.

Keywords:  Analytical verification; Biological variation; Cardiometabolic diseases; GDF-15; Integrative biomarker; Obesity; Type 2 diabetes

DOI:  https://doi.org/10.1016/j.cca.2026.120839
Biochem Pharmacol. 2026 Jan 14. pii: S0006-2952(26)00040-7. [Epub ahead of print] 117709

DNMT1 knockdown mitigates sepsis-induced myocardial dysfunction by preventing TFAM-mediated mitochondrial DNA cytosolic escape and subsequent cGAS-STING to regulate macrophage M2 polarization.

Min Li, Yang Liu, Kuo Qu, Yu Zhang, Hailing Yang.

  Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication of sepsis and correlates with high mortality. The study investigated the effect of inhibiting DNA methyltransferase 1 (DNMT1) on SIMD and its potential mechanism. In this study, an SIMD mouse model was established using lipopolysaccharide (LPS). Two weeks before modeling, mice were intraperitoneally injected with the DNMT1 inhibitor decitabine or Vehicle. Pretreatment with the DNMT1 inhibitor decitabine in SIMD mice improved survival, cardiac function, and reduced cardiomyocyte apoptosis. In LPS-stimulated RAW264.7 macrophages, DNMT1 knockdown promoted M2 polarization while suppressing M1 polarization, and reduced apoptosis in cardiomyocytes cultured with conditioned media. Mechanistically, DNMT1 depletion upregulated mitochondrial transcription factor A (TFAM) by reducing DNA methylation modification, which alleviated mitochondrial dysfunction and limited mitochondrial DNA (mtDNA) release into the cytosol. This subsequently inactivated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. TFAM downregulation reversed the improvement in mitochondrial function achieved by DNMT1 knockdown, while cGAS upregulation averted DNMT1 knockdown-inhibited mtDNA cytosolic escape-mediated cGAS-STING. In vivo validation confirmed this mechanism. Collectively, DNMT1 regulates mitochondrial dysfunction and cytosolic mtDNA release by modulating TFAM promoter DNA methylation, thereby activating the cGAS-STING pathway, further influencing macrophage polarization and cardiomyocyte apoptosis, and ultimately exacerbating SIMD.

Keywords:  Cyclic GMP-AMP synthase; DNA methyltransferase 1; Mitochondrial DNA; Mitochondrial transfer; Sepsis-induced myocardial dysfunction; Stimulator of interferon genes

DOI:  https://doi.org/10.1016/j.bcp.2026.117709
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00023-7. [Epub ahead of print]

TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.

Yixiao Xu, Yishun Gong, Jiafa Zhong, Binghong Gao.

   OBJECTIVE: Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.
METHODS: A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H2O2 emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.
RESULTS: In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.
CONCLUSION: TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.

Keywords:  TRPV1; active heat acclimation; mitochondrial turnover; oxidative phosphorylation; skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.015
NPJ Aging. 2026 Jan 10.

Astaxanthin improves myogenicity of aged skeletal muscle progenitor cells in a sexually dimorphic manner.

Zachary Clemens, Jagruti Kosaraju, Lauren Weaver, Catharine Lasher, Jesse Zhang, Karen Hecht, Kai Wang, Allison C Bean, Amrita Sahu.

Age-related declines in skeletal muscle health are a major contributor to reduced mobility and development of sarcopenia in the elderly, yet effective interventions to prevent or reverse these declines are not fully optimized. Nutritional strategies to support muscle health in aging populations may be beneficial for improving muscle strength and function. In this study, we explored the effects of astaxanthin (AX), a naturally occurring antioxidant, on aged human muscle progenitor cells (hMPCs). Our findings reveal that AX enhanced proliferation and myogenic commitment of aged hMPCs, with a more pronounced effect in male hMPCs compared to female hMPCs. This dimorphism may be linked to differences in reactive oxygen species (ROS)-scavenging and effects on mitochondrial function. Other hallmarks of aging including DNA damage and cellular senescence showed differing effects of AX treatment. However, NRF2 and SIRT3 increased with AX treatment in both male and female hMPCs. This was accompanied by increased SIRT3 mitochondrial expression in males but not females, suggesting the NRF2-SIRT3 axis as a key driver of myogenicity and potential source of sexual dimorphism in response to AX. These results suggest sex-specific effects of AX in modulating aged hMPC behavior and pose a potential therapeutic strategy for combating age-related muscle decline.

DOI: https://doi.org/10.1038/s41514-025-00325-x
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00002-X. [Epub ahead of print]

MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.

Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard.

Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments/augmented muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTs-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.01.002
Biol Psychiatry. 2026 Jan 10. pii: S0006-3223(26)00021-1. [Epub ahead of print]

Reduced ATP-to-phosphocreatine ratios in neuropsychiatric post-COVID condition: Evidence from 31P magnetic resonance spectroscopy.

Wolfgang Weber-Fahr, Sandra Dommke, Markus Sack, Nabil Alzein, Robert Becker, Traute Demirakca, Gabriele Ende, Claudia Schilling.

   BACKGROUND: Post-COVID condition (PCCo) affects 5-10% of individuals following SARS-CoV-2 infection, with cognitive disturbances being a major feature. Central hypotheses regarding its pathophysiology include disturbed cell energy metabolism and oxidative stress pointing to mitochondrial dysfunction. However, brain energy metabolism remains unexplored.
METHODS: We investigated cerebral high-energy phosphate metabolism in 27 PCCo patients and 23 fully recovered controls using whole-brain 31P-MRSI at 3T. ATP/PCr ratios were quantified throughout the brain and analyzed with voxel-based and regional statistics including correlations with neuropsychological performance (Montreal Cognitive Assessment and Trail Making Test Part B). Statistical analysis employed voxel-wise comparisons with age as covariate, followed by region-of-interest analysis of cingulate cortex subdivisions.
RESULTS: PCCo patients showed a significant cluster of reduced ATP/PCr ratios centered on the cingulate cortex. Regional analysis revealed consistent reductions across anterior (ACC), mid- (MCC), and posterior (PCC) cingulate cortices. Lower ATP/PCr ratios in the ACC specifically correlated with poorer cognitive performance. Exploratory analyses revealed a trend toward higher intracellular pH in the MCC with significant negative correlation between pH and ATP/PCr observed only in patients, suggesting disease-specific alterations in pH regulation and bioenergetic homeostasis. Subgroup analysis showed similar metabolic alterations in PCCo patients meeting ME/CFS criteria.
CONCLUSIONS: Our study provides first in vivo evidence of impaired brain energy metabolism in PCCo, with anterior cingulate dysfunction directly linked to cognitive impairment. The observed pH-ATP/PCr relationship suggests broader disruption of cellular bioenergetic regulation. These findings support mitochondrial dysfunction as a key pathophysiological mechanism and may inform targeted therapeutic strategies.

Keywords:  (6): 31P-MRS; ATP; brain energy metabolism; cingulate cortex; mitochondrial dysfunction; post-COVID condition

DOI:  https://doi.org/10.1016/j.biopsych.2026.01.004
Cell Biol Toxicol. 2026 Jan 13.

SIRT3 attenuates AGEs-induced senescence in human granulosa cells through enhancing mitophagy.

Shuhang Li, Mingge Tang, Sihui Zhu, Zhiguo Zhang, Yunxia Cao, Rufeng Xue.

  Age-related decreases in follicle numbers and oocyte quality are major contributors to the decline in female fertility, which is associated with increased infertility rates. Emerging evidence suggests that targeting granulosa cell senescence could delay ovarian aging and depletion of the ovarian reserve, highlighting the potential for therapeutic interventions focused on granulosa cells. Advanced glycation end products (AGEs) accumulate with age and result in oxidative stress in the follicular microenvironment, but their direct impact on human granulosa cell (hGC) senescence and the fundamental processes are still mostly unknown. In this study, we found that AGEs treatment significantly exacerbated hGC senescence, impaired mitochondrial function, and suppressed mitophagy in a concentration-dependent manner. Importantly, these deficits were lessened by urolithin A-induced mitophagy activation, whereas Cyclosporine A-induced mitophagy inhibition had the reverse consequences. In addition, silencing Sirtuin 3 (SIRT3) or PINK1 further aggravated these adverse effects, while SIRT3 overexpression attenuated senescence and restored mitochondrial function by enhancing mitophagy. Furthermore, SIRT3 overexpression promoted the synthesis of estradiol-17β and progesterone, key hormones for ovarian function. Our findings demonstrated that AGEs induced hGC senescence by disrupting mitochondrial function and inhibiting mitophagy, with SIRT3 playing a protective role. Enhancing mitophagy by targeting SIRT3 may be a promising treatment approach to counteract age-related declines in female fertility.

Keywords:  Advanced glycation end products; Cellular senescence; Human granulosa cells; Mitophagy; Sirtuin 3

DOI:  https://doi.org/10.1007/s10565-026-10138-7
Nat Metab. 2026 Jan 15.

The differential impact of three different NAD+ boosters on circulatory NAD and microbial metabolism in humans.

Stefan Christen, Karine Redeuil, Laurence Goulet, Maria-Pilar Giner, Isabelle Breton, Riccardo Rota, Adrien Frézal, Atiye Nazari, Pieter Van den Abbeele, Jean-Philippe Godin, Sophie Nutten, Bernard Cuenoud.

Nicotinamide adenine dinucleotide (NAD(H)) and its phosphorylated form NADP(H) are vitamin B3-derived redox cofactors essential for numerous metabolic reactions and protein modifications. Various health conditions are associated with disturbances in NAD+ homeostasis. To restore NAD+ levels, the main biosynthetic pathways have been targeted, with nicotinamide (Nam), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) being the most prominent boosters. However, while many preclinical studies have examined the effects of these precursors, a direct comparison in humans is lacking, and recent rodent research suggests that the NAD+-boosting effects of NR and NMN may depend on their microbial conversion to nicotinic acid (NA), a mechanism not yet confirmed in humans. Here we show in a randomized, open-label, placebo-controlled study in 65 healthy participants that 14 days of supplementation with NR and NMN, but not Nam, comparably increases circulatory NAD+ concentrations in healthy adults. Unlike the chronic effect, only Nam acutely and transiently affects the whole-blood NAD+ metabolome. Using ex vivo fermentation with human microbiota, we identify that NR and NMN give rise to NA and specifically enhance microbial growth and metabolism. We further demonstrate ex vivo in whole blood that NA is a potent NAD+ booster, while NMN, NR and Nam are not. Ultimately, we propose a gut-dependent model for the modes of action of the three NAD+ precursors with NR and NMN elevating circulatory NAD+ via the Preiss-Handler pathway, while rapidly absorbed Nam acutely affects NAD+ levels via the salvage pathway. Overall, these results indicate a dual effect of NR and NMN and their microbially produced metabolite NA: a sustained increase in systemic NAD+ levels and a potent modulator of gut health. ClinicalTrials.gov identifier: NCT05517122 .

DOI: https://doi.org/10.1038/s42255-025-01421-8
BMB Rep. 2026 Jan 12. pii: 6696. [Epub ahead of print]

Stress Granules as a Central Hub Linking Organelle Stress, Aging, and Neurodegeneration.

Hyun-Ji Ham, Jin-A Lee.

Stress granules (SGs) are dynamic cytoplasmic assemblies composed of RNAs and proteins that form in response to cellular stress, serving to halt translation and protect cellular integrity. In neurons, SGs mediate adaptive, pro-survival responses to acute stress; however, their dysregulation has been increasingly associated with both aging and neurodegenerative diseases. Aging neurons frequently exhibit changes in SG dynamics - with an increased propensity to form SGs while displaying reduced efficiency in their clearance - resulting in persistent granules that can facilitate the accumulation of pathological protein aggregates (e.g., TDP-43 or tau). Aberrant SG formation and defective clearance mechanisms are implicated in the pathogenesis of key neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), and Parkinson's disease (PD). Recent findings have shown that SGs interface with organelles such as lysosomes, mitochondria, and the endoplasmic reticulum, utilizing autophagic and other protein quality-control mechanisms for clearance. As these clearance pathways progressively decline with age, SGs can transition from promoting cellular adaptation to contributing to cellular dysfunction. In this mini-review, we examine how aging influences SG biology, detail the role of SGs in neurodegenerative diseases, and discuss emerging mechanistic insights and therapeutic strategies aimed at modulating SG dynamics in the context of brain aging.
Geroscience. 2026 Jan 12.

SOD1 deficiency drives ferroptosis-linked oxidative and reproductive aging, mitigated by ginseng root extract.

Juewon Kim, Shuichi Shibuya, Yusuke Ozawa, Yorino Sato, Kazuhiro Kawamura, Takahiko Shimizu.

  Aging is accompanied by cumulative oxidative stress that promotes tissue degeneration and reproductive decline. Here, we show that deficiency of superoxide dismutase 1 (SOD1) accelerates oxidative injury and reproductive aging through a ferroptosis-linked redox imbalance, and that ginseng root extract (GR) confers protection across species. Aged hairless Sod1⁻/⁻ mice exhibited markedly elevated skin and plasma oxidative stress markers-including 8-isoprostane, malondialdehyde (MDA), and pentosidine-together with dermal cyst formation and atrophic pathology. Complementary studies in C. elegans revealed that SOD1-deficient strains displayed increased reactive oxygen species, depleted glutathione, and elevated iron and lipid peroxidation-canonical features of ferroptosis-associated oxidative stress. These redox alterations coincided with shortened reproductive span and reduced progeny output, both rescued by ferroptosis inhibition or GR supplementation. In female Sod1⁻/⁻ mice, GR restored folliculogenesis, normalized estrous cyclicity, and improved ovarian morphology. Collectively, these findings identify SOD1 loss as a driver of ferroptosis-associated oxidative and reproductive aging and highlight GR as a promising redox-targeted intervention.

Keywords:  Ferroptosis; Ginseng root extract; Oxidative stress; Reproductive aging; SOD1 deficiency

DOI:  https://doi.org/10.1007/s11357-025-02093-8
Curr Opin Obstet Gynecol. 2026 Jan 13.

Menopause, cognition, and Alzheimer's disease risk.

Niyatee Samudra, Mytilee Vemuri, Julie Weitlauf.

   PURPOSE OF REVIEW: Cognitive symptoms are common throughout the menopause transition. This review outlines a comprehensive clinical approach, grounded in recent findings, to guide clinicians in addressing menopause-related cognitive concerns and neurodegenerative disease risk for midlife women.
RECENT FINDINGS: Research highlights the benefits of lifestyle and psychosocial interventions for cognitive symptoms during the menopause transition. Addressing underlying medical and mental health conditions, as well as difficulties with sleep, chronic stress, and vasomotor symptoms, can ameliorate symptoms and reduce risk for future dementia. Cognitive changes during the menopause transition do not typically indicate dementia. A subset of women, including apolipoprotein ε4 (APOE ε4) carriers and those who experience early menopause, face heightened risk. Alzheimer's disease biomarkers are clinically available and may change in some women during the menopause transition, particularly in APOE ε4 carriers, but our understanding of these changes, as well as their relationship to menopause hormone therapy, is evolving. There is presently insufficient evidence for the role of menopause hormone therapy for the treatment of menopause-related cognitive symptoms or neurodegenerative disease prevention.
SUMMARY: While typically transient, cognitive symptoms in menopause can benefit from addressing comorbid medical and psychosocial conditions. Research into dementia risk related to changes in the menopause transition is ongoing.

Keywords:  Alzheimer’s disease; cognition; dementia; menopause

DOI:  https://doi.org/10.1097/GCO.0000000000001087
Physiol Behav. 2026 Jan 09. pii: S0031-9384(26)00011-9. [Epub ahead of print] 115227

GDF11/TGFBR1 Activation Is Essential for the Antidepressant-like Effect of H₂S: Role of Suppressing the hippocampal cascade of necroptosis-neuroinflammation-Kynurenine Pathway Disorder.

Xiang Chen, Bo Wang, Yu-Hui Tang, Yi-Li Yi, Wei Zou, Xiao-Qing Tang, San-Qiao Yang.

   BACKGROUND: Depression remains a major global health challenge, and current treatments are suboptimal. Hydrogen sulfide (H₂S), an endogenous gasotransmitter, has antidepressant potential; however, its mechanisms remain incompletely understood. Understanding the mechanisms underlying the antidepressant-like role of H₂S is essential for developing H₂S as a therapeutic candidate for treating depression.
METHODS: Depressive-like behaviors were assessed via the open field test (OFT), novelty-suppressed feeding test (NSFT), sucrose preference test (SPT), tail suspension test (TST), and forced swim test (FST). Western blotting was used to analyze the protein expression levels of RIPK3, p-RIPK3, p-RIPK1, p-MLKL, and the ratio of phospho-Smad2/3 (p-Smad2/3) to total Smad2/3 in hippocampal tissues. Cytokines (TNF-α, IL-1β, IL-4, IL-6, and IL-10) were quantified via ELISA. Kynurenine-pathway (KP) enzymes and metabolites were assayed in hippocampal tissue.
RESULTS: Chronic unpredictable mild stress (CUMS) reduced hippocampal growth differentiation factor 11 (GDF11) expression. H₂S significantly increased GDF11 expression and the p-Smad2/3/Smad2/3 ratio, a downstream effector of TGFBR1, indicating activation of the GDF11/TGFBR1 pathway by H₂S in the hippocampus of CUMS-exposed rats. Furthermore, hippocampal GDF11 knockdown and pharmacological blockade of TGFBR1 with SB525334, which disrupts H₂S-induced activation of the GDF11/TGFBR1 pathway, reversed the molecular effects of H₂S in CUMS-exposed rats, including suppression of necroptosis, attenuation of neuroinflammation, and normalization of kynurenine-pathway enzymes and metabolites, as well as abolished the antidepressant-like effects of H₂S.
CONCLUSION: The hippocampal GDF11/TGFBR1 pathway mediates the antidepressant-like effects of H₂S by restraining the cascade of hippocampal necroptosis-neuroinflammation-KP disorder, suggesting that the GDF11/TGFBR1 pathway is a promising therapeutic target for depression.

Keywords:  Growth differentiation factor 11; Hydrogen sulfide; Kynurenine pathway; Necroptosis; Neuroinflammation; Transforming growth factor beta receptor 1

DOI:  https://doi.org/10.1016/j.physbeh.2026.115227
EMBO Rep. 2026 Jan 13.

Mitochondrial fission during mitophagy requires both inner and outer mitofissins.

Kentaro Furukawa, Tatsuro Maruyama, Yuji Sakai, Shun-Ichi Yamashita, Keiichi Inoue, Tomoyuki Fukuda, Nobuo N Noda, Tomotake Kanki.

  Mitophagy maintains mitochondrial homeostasis through the selective degradation of damaged or excess mitochondria. Recently, we identified mitofissin/Atg44, a mitochondrial intermembrane space-resident fission factor, which directly acts on lipid membranes and drives mitochondrial fission required for mitophagy in yeast. However, it remains unclear whether mitofissin is sufficient for mitophagy-associated mitochondrial fission and whether other factors act from outside mitochondria. Here, we identify a mitochondrial outer membrane-resident mitofissin-like microprotein required for mitophagy, and we name it mitofissin 2/Mfi2 based on the following results. Overexpression of an N-terminal Atg44-like region of Mfi2 induces mitochondrial fragmentation and partially restores mitophagy in atg44Δ cells. Mfi2 binds to lipid membranes and mediates membrane fission in a cardiolipin-dependent manner in vitro, demonstrating its intrinsic mitofissin activity. Coarse-grained molecular dynamics simulations further support the stable interaction of Mfi2 with cardiolipin-containing bilayers. Genetic analyses reveal that Mfi2 and the dynamin-related protein Dnm1 independently facilitate mitochondrial fission during mitophagy. Thus, Atg44 and Mfi2, two mitofissins with distinct localizations, are required for mitophagy-associated mitochondrial fission.

Keywords:  Atg44; Mfi2; Mitochondrial Fission; Mitofissin; Mitophagy

DOI:  https://doi.org/10.1038/s44319-025-00689-x
Sci China Life Sci. 2026 Jan 05.

Whole-grain black rice diet rewires the single-cell transcriptomic landscape of age-related ovarian decline in mice.

Yi-Xuan Tu, Dan-Yang Wang, Jun Ma, Ke-Chun Yu, Sheng-Hui Li, Bo-Han Li, Xin-Yin Deng, Shan Li, Hong-Kai Wang, Tailang Yin, Ling Wang, Zhen-Xia Chen.

  Ovarian aging poses significant challenges to female fertility and overall health. While whole-grain black rice diet (BRD) has emerged as a promising anti-aging intervention, its translational potential for ovarian health remains underexplored. This study systematically evaluated BRD's effects on ovarian functional decline through single-cell profiling and phenotypic validation. We demonstrated that BRD intervention effectively delays ovarian aging by preserving the ovarian reserve and maintaining hormonal balance, with granulosa cells (GCs) exhibiting the most pronounced responsiveness. Notably, BRD counteracts age-associated reductions in the GCs population and restores ovarian functional capacity. These findings highlight BRD's ability to rejuvenate the ovarian cellular landscape and stabilize aging-related tran-scriptional profiles. Our study provides actionable insights for developing BRD-based nutritional strategies to combat female reproductive aging, paving the way for clinically translatable dietary interventions and functional food innovations targeting the extension of women's healthspan.

Keywords:  female reproductive health; granulosa cells; ovary aging; single-cell RNA sequencing; whole-grain black rice

DOI:  https://doi.org/10.1007/s11427-025-3046-4
Food Sci Nutr. 2026 Jan;14(1): e71416

Nobiletin Ameliorates Skeletal Muscle Performance in D-Galactose-Induced Aging Mice by Boosting Aerobic Metabolism.

Huihui Wang, Yangguang Zhang, Yijia Zhang, Xintong Wang, Yixuan Li, Fazheng Ren, Yanan Sun.

  The decrease in muscle performance during aging will not only lead to challenges in movement but also increase the risk of fractures, diabetes, and other diseases, which seriously impacts the overall quality of life in the elderly. In the present study, we used D-galactose (D-gal)-induced 8-week C57BL/6J mice to establish a sarcopenia model and to explore the effects of Nobiletin (Nob), a naturally occurring small molecule derived from orange peel, on skeletal muscle function. Our findings demonstrated that Nob significantly improved exercise endurance, grip strength, glucose tolerance, cold tolerance, and energy expenditure in D-gal-induced aging mice. Additionally, Nob ameliorated mitochondrial morphology and enhanced aerobic metabolism of myofibers in D-gal-induced aging mice, thereby providing increased energy for the body. Notably, Nob activated the SIRT1/PGC1α/Nrf2 pathway to enhance superoxide dismutase (SOD) activity and scavenge reactive oxygen species (ROS) in the skeletal muscle of D-gal-induced aging mice. In conclusion, Nob improved the metabolic capacity and function of skeletal muscle by augmenting its antioxidant capacity and optimizing mitochondrial function.

Keywords:  aerobic metabolism; mitochondria; nobiletin; sarcopenia; skeletal muscle function

DOI:  https://doi.org/10.1002/fsn3.71416
Free Radic Biol Med. 2026 Jan 12. pii: S0891-5849(26)00027-4. [Epub ahead of print]

Mitochondrial DNA 6mA Methylation by METTL4 Drives Neuroinflammation via cGAS-STING Activation in Vascular Cognitive Impairment.

Zhe Gong, Ziyi Chen, Shuixian Sang, Lingfei Yang, Hongzhuo Qin, Qingsheng Li, Yanjie Jia.

   BACKGROUND: Vascular cognitive impairment (VCI) is strongly associated with mitochondrial dysfunction, yet the underlying molecular mechanisms connecting mitochondrial impairment to neuroinflammation remain elusive. While mitochondrial epigenetic modifications are emerging as key regulators of cellular metabolism, the role of mitochondrial DNA (mtDNA) N6-methyladenine (6mA) modification and its writer enzyme METTL4 in VCI pathogenesis has not been established.
METHODS: Using complementary in vitro (oxygen-glucose deprivation, OGD) and in vivo (chronic cerebral hypoperfusion, CCH) models of VCI, we systematically investigated METTL4-mediated mtDNA epigenetic regulation. Approaches included RNA sequencing (RNA-seq), mitochondrial functional assays, reactive oxygen species (ROS) measurement, and comprehensive analysis of cGAS-STING-mediated neuroinflammatory responses.
RESULTS: We identified mitochondrial-specific enrichment of METTL4 in hippocampal neurons, with significantly elevated mtDNA 6mA levels following CCH. Mechanistically, OGD-induced METTL4 preferentially methylated the light-strand promoter region of mtDNA, leading to: (1) impaired electron transport chain (ETC) activity, (2) excessive ROS production, and (3) oxidized mtDNA leakage. These mitochondrial abnormalities robustly activated the cGAS-STING neuroinflammatory pathway. Genetic inhibition of METTL4 normalized 6mA levels, restored mitochondrial gene expression profiles, and significantly improved cognitive function in VCI models.
CONCLUSION: Our study delineates a complete METTL4-mtDNA 6mA-mitochondrial dysfunction-neuroinflammation axis in VCI pathogenesis. These findings not only provide novel insights into the epigenetic control of neuroinflammation but also position METTL4 as a promising therapeutic target for mitigating cerebrovascular-related cognitive decline.

Keywords:  METTL4; cGAS-STING pathway; hippocampal neuron; mitochondrial dysfunction; mtDNA 6mA; vascular cognitive impairment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.019