bims-mistre 2026-01-25 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–01–25
ten papers selected by
Ellen Siobhan Mitchell, MitoQ

MitoQ upregulates CYP19A1 to protect dermal papilla cells from DHT-induced mitochondrial dysfunction and apoptosis in androgenetic alopecia.
Follicle-stimulating hormone linked to cognitive decline and amyloid burden in postmenopausal women.
Associations Between Growth Differentiating Factor-15 and Frailty in Older Adults From the MAPT Study.
Modulation of SIRT1/PPARγ pathways and tight junction proteins by nicotinamide riboside under chronic variable stress.
Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment.
Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.
Pathogenesis and potential therapies for perimenopausal depression: Insights from the estrogen-gut microbiota axis.
The Effect of Creatine Monohydrate on Mental Disorders: A Systematic Review of Randomized Controlled Trials: Effet du monohydrate de créatine sur les troubles mentaux : examen systématique des essais contrôlés à répartition aléatoire.
Beyond exercise and appetite: The expanding biology and therapeutic potential of N-lactoyl-phenylalanine.
β-Alanine Is an Unexploited Neurotransmitter in the Pathogenesis and Treatment of Alzheimer's Disease.

Biochem Pharmacol. 2026 Jan 20. pii: S0006-2952(26)00060-2. [Epub ahead of print] 117729

MitoQ upregulates CYP19A1 to protect dermal papilla cells from DHT-induced mitochondrial dysfunction and apoptosis in androgenetic alopecia.

Yujie Li, Tingru Dong, Jiamin Wu, Fenglan Yang, Shiyu Jin, Renxue Xiong, Meiya Li, Xiuzu Song, Cuiping Guan.

  Androgenetic alopecia (AGA) is a progressive hair loss disorder characterized by follicular miniaturization primarily driven by dihydrotestosterone (DHT). Mitochondrial dysfunction in dermal papilla cells (DPCs) has emerged as a key pathological feature, yet the upstream regulatory mechanisms remain unclear. Our previous work revealed that the mitochondria-targeted antioxidant MitoQ upregulates CYP19A1 (aromatase) and alleviates AGA-like pathology. Here, we investigated whether CYP19A1 modulates mitochondrial function and mediates the protective effects of MitoQ. Using a DHT-induced AGA mouse model and DPCs with CYP19A1 knockdown or overexpression, we examined hormone profiles, mitochondrial activity, and hair growth-related factors. DHT markedly reduced CYP19A1 expression and increased inhibitory factors such as DKK1, TGF-β, and IL-6, whereas CYP19A1 overexpression or MitoQ pretreatment reversed these effects. Both CYP19A1 and MitoQ decreased mitochondrial reactive oxygen species (mtROS), improved respiratory capacity, and preserved mitochondrial morphology. Importantly, our findings reveal a previously unrecognized aromatase-mitochondria cross-talk in hair-follicle cells, whereby CYP19A1-derived estrogens sustain mitochondrial homeostasis under androgenic stress. MitoQ amplifies this cross-talk through CYP19A1 activation, restoring redox balance and mitochondrial integrity. Collectively, these results identify CYP19A1 as a pivotal regulator of mitochondrial resilience and suggest that the CYP19A1-mitochondrial axis represents a promising pharmacological target for treating AGA.

Keywords:  Androgenetic alopecia; CYP19A1; Dermal papilla cells; MitoQ; Mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.bcp.2026.117729
Front Aging Neurosci. 2025 ;17 1697255

Follicle-stimulating hormone linked to cognitive decline and amyloid burden in postmenopausal women.

Sheng-Min Wang, Chaiho Jeong, Yoo Hyun Um, Dong Woo Kang, Sunghwan Kim, Soyoung Lee, Chang Uk Lee, Howard J Aizenstein, Ki-Hyun Baek, Hyun Kook Lim.

   Introduction: Women have a higher risk of developing Alzheimer's disease (AD) than men, with hormonal changes during menopause being a potential factor. However, the exact relationship between these hormonal changes, cognitive function, and AD pathology is not fully understood. This study investigates the differential associations between serum follicle-stimulating hormone (FSH) and estradiol levels with cognitive function and cerebral amyloid-βeta (Aβ) deposition, quantified using amyloid positron emission tomography, in postmenopausal women across the spectrum from cognitively normal aging to AD dementia.
Methods: A total of 884 postmenopausal women, aged 60 years or older, were enrolled in the study. Participants were classified into three groups based on their cognitive function: cognitively normal (CN), mild cognitive impairment (MCI), and AD dementia.
Results: Higher FSH levels were associated with poorer cognitive performance and greater cerebral Aβ deposition in postmenopausal women. FSH levels were highest in women with AD dementia, followed by those with MCI, and lowest in CN participants. No significant relationship was observed between estradiol levels and cognitive outcomes or Aβ burden. Further analysis showed a positive correlation between FSH levels and global as well as regional cerebral Aβ deposition. Mediation analysis indicated that FSH's impact on cognitive function was mediated by cerebral Aβ burden. Estradiol levels, however, had no significant association with either cognitive performance or Aβ pathology.
Discussion: Elevated FSH, not low E2, is linked to cognitive decline and Aβ pathology in postmenopausal women. FSH may be a key risk factor for cerebral Aβ deposition and cognitive decline in older women. Further research is needed to elucidate the mechanisms involved and explore hormonal interventions for AD.

Keywords:  Alzheimer’s disease; amyloid retention; cognitive impairment; estrogen; follicle-stimulating hormone

DOI:  https://doi.org/10.3389/fnagi.2025.1697255
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70182

Associations Between Growth Differentiating Factor-15 and Frailty in Older Adults From the MAPT Study.

MAPT/DSA Group

   BACKGROUND: Frailty is a prevalent syndrome in older adults and is associated with increased vulnerability to adverse health outcomes. Growth differentiation factor 15 (GDF-15), a cytokine involved in mitochondrial dysfunction and inflammation, has been proposed as a potential biomarker for age-related conditions. Evidence on the association between GDF-15 and frailty in older adults is limited. This study explores the relationship between plasma GDF-15 levels and frailty onset in community-dwelling older adults.
METHODS: A secondary analysis was performed on 1096 participants (mean age = 75.2 ± 4.5 years; 64.5% women) from the Multidomain Alzheimer Prevention Trial (MAPT). Plasma GDF-15 levels were measured at year 1. Frailty was assessed using the Fried phenotype. Logistic regression was used to examine cross-sectional associations between GDF-15 and frailty, while mixed effects logistic regression or Cox proportional hazards models assessed longitudinal associations over a 4-year follow-up.
RESULTS: Higher plasma GDF-15 levels (both as continuous and categorical) were cross-sectionally associated with frailty (high vs. low GDF-15: OR = 3.56, 95% CI = 1.58-8.03). Longitudinally, very high GDF-15 levels predicted an increased risk of incident frailty (HR = 1.69, 95% CI = 1.03-2.78).
CONCLUSIONS: Elevated plasma GDF-15 levels were associated with frailty in older adults, suggesting its potential as a biomarker for increased vulnerability and an indicator of increased risk over time. Our results support a pleiotropic role of GDF-15, with low physiological levels not contributing to frailty development.

Keywords:  ageing; biomarkers; frailty; growth differentiation factor 15

DOI:  https://doi.org/10.1002/jcsm.70182
J Physiol Biochem. 2026 Jan 22. 82(1): 3

Modulation of SIRT1/PPARγ pathways and tight junction proteins by nicotinamide riboside under chronic variable stress.

Abdullah Celik, Nurhan Sahin, Cemal Orhan, Besir Er, Fusun Erten, Busra Ozmen, Mehmet Tuzcu, Ibrahim Hanifi Ozercan, Kazim Sahin.

  Chronic stress disrupts homeostasis, leading to major health problems such as liver damage, intestinal barrier dysfunction, and impaired glucose metabolism. Although current treatments, including anxiolytics, sedatives, antidepressants, and beta blockers, are effective, their adverse effects emphasize the need for safer alternatives. Nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD+), plays a central role in energy metabolism and oxidative stress regulation; elevated NAD + levels have been associated with reduced risk of chronic diseases such as obesity and type 2 diabetes. However, the effects of NR on liver metabolism, intestinal barrier integrity, and related protein pathways remain unclear. This study investigated the effects of NR supplementation in rats exposed to chronic variable stress (CVS). Fifty-six male Sprague Dawley rats were divided into normal and CVS groups and treated in a 2 × 4 factorial design with 0, 150, 300, or 600 mg/kg NR. Under CVS conditions, serum glucose, corticosterone, ACTH, and insulin levels increased, whereas NAD+, NADPH, nicotinamide (NAM), and nicotinic acid (NA) decreased significantly (p < 0.001). NR supplementation effectively corrected these biochemical imbalances and upregulated hepatic markers, including PPARγ, SIRT1, GLUT2, IRS1, and FASN (p < 0.001). Furthermore, the increased expression of key transport proteins such as PepT1, LAT2, EAAT3, FABP2, and FATP4 contributed to maintaining intestinal barrier integrity and improving gut health. NR also promoted the recovery of tight and adherens junction proteins. Notably, high-dose NR (600 mg/kg) markedly alleviated liver fibrosis, improved glucose metabolism, and strengthened intestinal barrier function, demonstrating its therapeutic potential as an alternative strategy against stress-induced metabolic disorders. KEY POINTS: • NR mitigated chronic stress-induced liver, intestinal, and glucose dysregulation. • NR improved glycemia and NAD⁺-related biomarkers under stress. • NR reduced hepatic fibrosis markers. • NR strengthened TJ/AJ proteins, supporting intestinal barrier integrity. • Findings support NR's therapeutic potential in stress-related metabolism.

Keywords:  Gut; Liver; Nicotinamide riboside; Stress

DOI:  https://doi.org/10.1007/s13105-026-01153-7
Elife. 2026 Jan 20. pii: RP107161. [Epub ahead of print]14

Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment.

Nicholas Tolman, Taibo Li, Revathi Balasubramanian, Guorong Li, Rebecca Pfeiffer, Violet Bupp-Chickering, Ruth A Kelly, Marina Simón, John Peregrin, Christa Montgomery, Bryan Jones, W Daniel Stamer, Jiang Qian, Simon W M John.

  Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for (1) extracellular matrix structure and metabolism (TM1 subtype), (2) secreted ligand signaling to support Schlemm's canal cells (TM2), and (3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function, and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1bV265D/+ mutant mice (2491 TM cells). In Lmx1bV265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of Lmx1bV265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), which enhances mitochondrial function and metabolic resilience in other contexts, significantly protected Lmx1b mutant mice from IOP elevation.

Keywords:  ATAC sequencing; genetics; genomics; glaucoma; intraocular pressure; mouse; multiome; single-cell RNA-sequencing; trabecular meshwork

DOI:  https://doi.org/10.7554/eLife.107161
Aging Cell. 2026 Feb;25(2): e70386

Dietary Protein Restriction Ameliorates Cardiac Inflammaging via AMPK-ULK1-Mediated Mitochondrial Quality Control.

Wagner S Dantas, Elizabeth R M Zunica, Elizabeth C Heintz, Charles L Hoppel, Cristal M Hill, Christopher D Morrison, Christopher L Axelrod, Gangarao Davuluri, John P Kirwan.

  Calorie restriction (CR) is a robust intervention for improving metabolic health and delaying obesity and age-related diseases, yet its translational utility is limited by adherence challenges and diminished effectiveness later in life. Dietary protein restriction (DPR), which reduces dietary protein without decreasing total caloric intake, has emerged as a promising alternative, yet its cardioprotective potential in the context of obesity and aging remains poorly understood. Here, we demonstrate that DPR mitigates obesity-induced cardiac remodeling and inflammaging by activating the AMPK-ULK1 signaling axis and enhancing mitochondrial quality control. In middle-aged male mice with high-fat diet-induced obesity, 4 months of DPR attenuated cardiac hypertrophy and normalized heart failure markers, independently of FGF21 signaling. Transcriptomic and protein analyses revealed that DPR suppressed the activation of the cGAS-STING pathway, reduced mitochondrial DNA release into the cytosol, and blunted expression of pro-inflammatory mediators, including IRF3 and IFN-γ. DPR also restored mitochondrial dynamics, enhanced mitophagy, and maintained ATP content despite reduced respiratory capacity. Mechanistically, DPR increased AMPK-dependent ULK1 phosphorylation while suppressing mTOR signaling, thereby promoting mitochondrial turnover. These effects were confirmed in cardiomyocytes, where AMPK knockdown abrogated ULK1 activation and mitophagy under conditions of low amino acid availability. Together, these findings uncover a novel mechanism by which DPR attenuates cardiac inflammation and supports mitochondrial homeostasis, highlighting its therapeutic potential for enhancing cardiovascular health during obesity-mediated inflammaging.

Keywords:  bioenergetics; fission; fusion; heart; mitochondria; obesity; quality control

DOI:  https://doi.org/10.1111/acel.70386
Front Neuroendocrinol. 2026 Jan 19. pii: S0091-3022(26)00003-8. [Epub ahead of print] 101233

Pathogenesis and potential therapies for perimenopausal depression: Insights from the estrogen-gut microbiota axis.

Xuli Wang, Yudong Lin, Mingmei Zhou.

  Perimenopause represents a critical phase during which women are particularly susceptible to depression. Although fluctuations in estrogen levels resulting from ovarian aging and imbalances in the gut microbiota have been identified as contributing factors to the onset of depression, the interplay among these elements is frequently overlooked. Fluctuations in estrogen levels can further influence neurogenesis or apoptosis through effects on neurotransmitter balance, neuroinflammation, neuroendocrine regulation, and mitochondrial function. Meanwhile, dramatic shifts in estrogen levels can diminish microbial diversity and stability, thereby disrupting the homeostasis of metabolites and neurotransmitters via the gut-brain axis (GBA). Such disturbances may induce neuroinflammation, potentially leading to or exacerbating depressive symptoms. Additionally, the estrobolome (gut bacterial genes encoding estrogen-metabolizing enzymes) plays a regulatory role in the reabsorption, excretion, and systemic levels of estrogen through the modulation of β-glucuronidase activity, thereby affecting estrogen homeostasis. This review first examines the influence of fluctuations in estrogen levels on the composition and function of the gut microbiota, as well as the role of the gut microbiota in estrogen metabolism. It then discusses how estrogen deficiency and dysbiosis of the gut microbiota contribute to the pathogenesis of perimenopausal depression, discussing the potential for a vicious cycle mediated by the estrogen-gut microbiota axis that increases susceptibility to this condition. Finally, this review presents bioactive compounds derived from dietary sources or medicinal plants that exhibit estrogenic and prebiotic properties, which may offer diverse strategies for the prevention and management of perimenopausal depression through modulation of the estrogen-gut microbiota axis.

Keywords:  Estrobolome; Estrogen-gut microbiota axis; Neuroinflammation; Perimenopausal depression; Phytoestrogens; Probiotics/psychobiotics

DOI:  https://doi.org/10.1016/j.yfrne.2026.101233
Can J Psychiatry. 2026 Jan 20. 7067437251408171

The Effect of Creatine Monohydrate on Mental Disorders: A Systematic Review of Randomized Controlled Trials: Effet du monohydrate de créatine sur les troubles mentaux : examen systématique des essais contrôlés à répartition aléatoire.

Bassam Jeryous Fares, Carl Zhou, Nicholas Fabiano, Stanley Wong, Brendon Stubbs, Risa Shorr, David Puder, Darren G Candow, Sergej M Ostojic, Marco Solmi.

  ObjectiveThe objective of this systematic review is to synthesize and evaluate the evidence involving creatine monohydrate supplementation (CrM) across mental disorders.MethodsMEDLINE, Embase, Cochrane, and PsycINFO were searched up to 09/30/2025 for randomized controlled trials (RCTs) investigating the effect of CrM on psychiatric symptoms and safety in participants with a mental disorder. Risk of bias was assessed.ResultsSix articles from five RCTs were included (CrM: n = 126, placebo: n = 112; mean age=36 ± 14 years; male sex = 26%). Four RCTs reported on major depressive disorder (MDD), one bipolar depression. No other mental disorders were investigated. Two RCTs were low risk of bias and three had some concerns. CrM dosing ranged from 2 to 10 g/day for 4-8 weeks as adjunct treatment. In the treatment of MDD, CrM was tested as combination with escitalopram (k = 1, outperforming selective serotonin reuptake inhibitor (SSRI) + placebo; Cohen's d = 1.13 at 8 weeks), pharmacotherapy augmentation in adults (k = 1) and female adolescents (k = 1, no difference vs placebo), psychotherapy augmentation (k = 1, cognitive behavioural therapy (CBT) + CrM outperforming CBT + placebo) in MDD, and as pharmacotherapy augmentation in bipolar depression (k = 1, no difference vs placebo augmentation). Two trials in MDD found a correlation between CrM brain N-acetylaspartate and phosphocreatine, which was associated with larger improvement. CrM was generally well-tolerated. Two CrM out of 17 participants experienced hypomania/mania.ConclusionCrM shows promise as a combination treatment with SSRIs or for augmenting psychotherapy in MDD in adults. Double-blind, large-scale RCTs investigating the efficacy of CrM, with and without first-line therapies, are needed across mental disorders.

Keywords:  augmentation; bioenergetic; bioénergétique; bipolaire; bipolar; creatine; créatine; depression; dépression; intensification; mental health; santé mentale

DOI:  https://doi.org/10.1177/07067437251408171
J Pharmacol Exp Ther. 2025 Dec 18. pii: S0022-3565(25)40311-5. [Epub ahead of print]393(2): 103798

Beyond exercise and appetite: The expanding biology and therapeutic potential of N-lactoyl-phenylalanine.

Olaiya Peter Oni, Barry Scott, Lily C Schwartz, Tyson J MacCormack, Mohammed Hankir, Jillian L Rourke.

  N-lactoyl-phenylalanine (Lac-Phe) has emerged as a signaling metabolite connecting cellular metabolism to systemic physiology. Synthesized through carnosine dipeptidase 2-mediated conjugation of lactate and phenylalanine, Lac-Phe increases acutely in response to exercise and feeding, the primary drivers of its elevation under physiologic conditions. In preclinical models, Lac-Phe acts as a potent regulator of energy balance. Its administration suppresses appetite and reduces body weight in obesity, whereas pharmacologic interventions such as metformin elevate circulating Lac-Phe to produce similar anorexigenic effects. Converging evidence implicates central mechanisms, including inhibition of orexigenic agouti-related peptide neurons, positioning Lac-Phe as a mediator linking peripheral metabolic signals to appetite control. The first human Lac-Phe clinical trial in individuals with obesity began dosing in 2025, evaluating appetite suppression and glucose-lowering effects. Beyond metabolism, Lac-Phe promotes anti-inflammatory macrophage polarization, conferring protection in murine models of colitis and spinal cord injury. Circulating Lac-Phe also rises in conditions such as mitochondrial dysfunction, sepsis, and phenylketonuria, suggesting broader associations with perturbed energy metabolism and systemic stress responses. This review integrates current knowledge spanning molecular mechanisms, physiological regulation, and clinical translation. We examine Lac-Phe biosynthesis, tissue distribution, and regulatory patterns across physiological and disease states, and highlight emerging mechanisms of action in metabolic and inflammatory signaling. Finally, we discuss key knowledge gaps, highlighting the need to define targets, transporters, and tissue sources to shape the next phase of discovery. Collectively, these advances position Lac-Phe at the forefront of exerkine biology and as a promising molecular link between metabolism, immunity, and therapeutic innovation. SIGNIFICANCE STATEMENT: Evidence across molecular, physiological, and translational domains positions Lac-Phe as a promising therapeutic target. This review frames our understanding of Lac-Phe biology-from its biosynthesis to its roles in energy balance and outlines the key questions that will define ongoing discovery.

Keywords:  Appetite; Carnosine dipeptidase 2; Exerkine; N-lactoyl-amino acids; N-lactoyl-phenylalanine

DOI:  https://doi.org/10.1016/j.jpet.2025.103798
NeuroSci. 2026 Jan 15. pii: 13. [Epub ahead of print]7(1):

β-Alanine Is an Unexploited Neurotransmitter in the Pathogenesis and Treatment of Alzheimer's Disease.

Cindy M Wozniczka, Donald F Weaver.

  Alzheimer's disease (AD) remains an unmet medical challenge, as there are no effective therapies that alter the disease's progression. While approaches have targeted molecules like acetylcholine (ACh) and glutamate, these strategies have provided only limited benefits and do not address the complex molecular mechanisms underlying AD development. This review suggests that β-alanine (3-aminopropanoic acid) is an underexplored neurotransmitter that could serve as a potential AD drug target. Existing evidence indicates that β-alanine modulates GABAergic and glutamatergic neurotransmission, thereby affecting neuronal hyperexcitability. Additionally, studies suggest that β-alanine has antioxidant effects, reducing oxidative stress caused by reactive oxygen species (ROS). We propose that β-alanine might bind to Aβ/tau proteins, possibly targeting the six-amino acid sequences EVHHQK/DDKKAK, which are involved in protein aggregation. β-Alanine may also influence the release of pro-inflammatory cytokines from microglia, potentially reducing neuroinflammation. We also hypothesize that β-alanine may help regulate metal dyshomeostasis, which leads to ROS production. Taurine, structurally like β-alanine, appears to influence comparable mechanisms. Although structural similarity doesn't ensure therapeutic effectiveness, this evidence supports considering β-alanine as a treatment for AD. Furthermore, β-alanine and its analogues face challenges, including crossing the blood-brain barrier (BBB) and optimizing structure-activity relationships (SAR). This review includes articles through September 2025, sourced from four databases.

Keywords:  Alzheimer’s disease; carnosine; dementia; neurodegeneration; neurotransmitter; taurine; β-alanine

DOI:  https://doi.org/10.3390/neurosci7010013