bims-mistre 2026-08-09 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–08–09
eighteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Tau-induced mitochondrial reverse electron transport drives neurodegeneration.
Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.
SIRT1 in brain aging: molecular mechanisms and therapeutic potential of pharmacological and natural modulators.
Why studying females reveals more about aging: The reproductive resilience hypothesis for the evolution of sex-specific aging.
Aging is associated with altered estrogen receptor expression and alters redox protein balance in human female skeletal muscle.
Preclinical evidence of chrysin in metabolic disorder via mitochondrial signaling: a mechanistic review.
The potential therapeutic effect of quercetin on mitochondrial dysfunction in hepatorenal toxicity induced by aluminum chloride in an experimental rat model.
Astaxanthin attenuates skeletal muscle atrophy and mitochondrial dysfunction in streptozotocin-induced diabetic rats.
Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.
Hyper-aging in systemic sclerosis: linking genome instability, mitochondrial dysfunction, and inflammaging to fibrosis.
Scutellarin ameliorates PCOS mouse model by restoring mitochondrial function and inhibiting granulosa cell apoptosis.
Distinct associations of peripheral mtDNA copy number and bioenergetic function with cognition in women with HIV and psychiatric comorbidities.
Mechanistic pathways linking gut microbial metabolites, microbial structural products, and host-microbe co-metabolites to mitochondrial function.
The Role of Slow Gait Speed in Cognitive Decline among Aging Women: A Systematic Review.
Anthocyanin-rich bilberry extract and resveratrol as protectors against mitochondrial dysfunction induced by mixed micelles in Caco-2 intestinal epithelial cells.
Mitochondria-targeted therapeutic strategies in assisted reproduction: challenges and potential solutions.
Rapamycin-sensitive mTORC1 signaling in the medial prefrontal cortex contributes to the antidepressant-like behavioral effects of shikimic acid in mice.
N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity.

Neuron. 2026 Aug 06. pii: S0896-6273(26)00541-6. [Epub ahead of print]

Tau-induced mitochondrial reverse electron transport drives neurodegeneration.

Wen Li, Suman Rimal, Sunil Bhurtel, Lucas Yeung, Benjamin G Lu, Lea T Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu.

  Hyperphosphorylation and aggregation of tau are pathological hallmarks of tauopathies. Mitochondrial dysfunction is also a common feature of tauopathies. The mechanistic link between tau abnormalities and mitochondrial dysfunction and its relationship to the physiological function of tau, however, is unclear. Here, we demonstrate that tau regulates mitochondrial reverse electron transport (RET), which produces excess reactive oxygen species (ROS), reduces the NAD+/NADH ratio, and is activated by aging or stress. In flies, mice, and human induced pluripotent stem cell (hiPSC)-derived neurons, tau depletion eliminates stress-induced RET and confers resilience. Mechanistically, tau enters mitochondria and directly interacts with the complex I subunit NDUFS3 to promote RET in a phosphorylation-dependent manner. Elevated RET further drives tau hyperphosphorylation, establishing a self-perpetuating pathological loop. Inhibition of RET ameliorates tau toxicity across species. RET regulation thus represents a previously unrecognized normal function of tau that becomes pathological in disease, providing a therapeutic target for various conditions characterized by tau abnormalities and mitochondrial dysfunction.

Keywords:  Alzheimer’s disease; NAD(+)/NADH ratio; NDUFS3; ROS; complex I; mitochondria; phosphorylation; reverse electron transport; tau; tauopathy

DOI:  https://doi.org/10.1016/j.neuron.2026.07.012
J Mol Neurosci. 2026 Aug 05. pii: 124. [Epub ahead of print]76(3):

Mitochondrial Permeability Transition Regulators As Emerging Therapeutic Targets in Aging and Neurodegeneration: Recent Insights.

Lishu Guo.

  Aging is characterized by increased reactive oxygen species (ROS) and leads to mitochondrial dysfunction. This age-related decline in mitochondrial function is a major factor in the development of neurodegenerative diseases. Mitochondrial permeability transition pore (PTP) is a multi-protein complex that forms a non-specific channel across the inner mitochondrial membrane, and its opening is tightly linked to mitochondrial function and cell death. Dysregulation of PTP opening is now recognized as a central pathogenic mechanism in both normal aging and age-associated neurodegenerative diseases. This review integrates current understanding of mitochondrial permeability transition with emerging evidence implicating three novel regulatory components: F-ATP synthase inhibitory factor 1 (IF1), subunit j of F-ATP synthase, and mitochondrial carrier homolog 2 (MTCH2), expanding the therapeutic landscape for treating aging and neurodegeneration through targeting the PTP.

Keywords:  Aging; Mitochondria; Mitochondrial permeability transition; Neurodegeneration; The permeability transition pore

DOI:  https://doi.org/10.1007/s12031-026-02583-0
Biogerontology. 2026 Aug 07. pii: 137. [Epub ahead of print]27(4):

SIRT1 in brain aging: molecular mechanisms and therapeutic potential of pharmacological and natural modulators.

Esraa M Mosalam, Mahmoud S Abdallah, Ahmed R Gardouh, Eman Hamza, Mostafa M Bahaa, Mahmoud Nazih, Reham A Al-Dhelaan, Noha Kamal.

  Aging is a multifactorial process affects different tissues and organs and is modulated by genetic and environmental factors. In aging, the frequency of DNA repair errors and genomic instability are augmented. Depletion of endogenous antioxidant capacity during aging promotes the development of oxidative stress which triggers oxidative stress-induced DNA injury. Brain aging is manifested by cognitive impairment and memory disorders. Development of neuronal senescence is the major pathway in the progression of brain aging. Silent information regulator sirtuin 1 (SIRT1) is a class III histone deacetylase plays a critical role in genomic stability during aging. SIRT1 is highly expressed in specific brain regions involved in energy expenditure and metabolic activity that is necessary for brain development and control of brain senescence. Therefore, SIRT1 may have neuroprotective effects against brain aging and related neurodegenerative diseases. This narrative review aims to critically evaluate the role of SIRT1 in brain aging and to summarize current evidence on compounds that directly or indirectly modulate SIRT1 activity, with a focus on their mechanistic pathways and potential therapeutic implications. Findings of the present review highlighted that SIRT1 activators such as resveratrol, metformin and statins have neuroprotective effects against brain aging by regulating inflammatory and oxidative stress disorders through modulation of downstream signaling pathways.

Keywords:  Aging; Brain aging; Geroprotector effects; SIRT1 modulators

DOI:  https://doi.org/10.1007/s10522-026-10480-7
Cell. 2026 Aug 06. pii: S0092-8674(26)00811-1. [Epub ahead of print]189(16): 4832-4856

Why studying females reveals more about aging: The reproductive resilience hypothesis for the evolution of sex-specific aging.

Parminder Singh, Vineeta Tanwar, Yifan Xiang, Lizbeth Enriquez Najera, Steven N Austad, Pankaj Kapahi.

Classical evolutionary theories of aging, including antagonistic pleiotropy (AP) and the disposable soma theory (DST), explain why aging exists but are often applied without considering how sex-specific reproductive strategies shape the forces of natural selection on survival. They do not explain why females consistently outlive males across taxa, despite their greater reproductive investment, or why in some contexts, such as eusocial queens, extraordinary fecundity is coupled with exceptional longevity. To explain these patterns, we propose the reproductive resilience hypothesis (RRH), which posits that when reproductive success depends on prolonged survival and caregiving, natural selection favors coupling reproduction with enhanced somatic maintenance rather than trading it off. We suggest that reproductive events, including age at sexual maturity, pregnancy, lactation, and menopause, are pivotal life-history transitions and must be explicitly integrated into studies of sex differences that drive aging and susceptibility to age-related diseases. We further propose that loss of reproductive resilience is a sex-specific hallmark of aging that coordinates the emergence of multiple downstream hallmarks, helping explain the acceleration of systemic aging and age-related disease following reproductive decline. We propose that, for these reasons, studying females should be prioritized, as it has unique implications for discovering pathways to slow aging and prevent age-related diseases, ultimately benefiting both women and men.

DOI: https://doi.org/10.1016/j.cell.2026.07.013
Geroscience. 2026 Aug 07.

Aging is associated with altered estrogen receptor expression and alters redox protein balance in human female skeletal muscle.

Andrea Tamariz-Ellemann, Line Boel Nørregaard, Mikkel Oxfeldt, Line Barner Dalgaard, Susana Novella, Mette Hansen, Ylva Hellsten, Lasse Gliemann.

  It has been hypothesized that age‑related declines in skeletal muscle and vascular function in females may be partly estrogen‑dependent. This study investigated skeletal muscle protein expression of estrogen receptor α (ERα), estrogen receptor β (ERβ), and G protein-coupled estrogen receptor 1 (GPER1), and their association with proteins involved in redox regulation and vascular function, in relation to age, menopausal status, and lifelong physical activity. Skeletal muscle biopsies were obtained from 107 healthy females aged 19-70 years, including 26 postmenopausal females who were lifelong exercise trained. Protein expression of ERα, ERβ, GPER1, and downstream redox‑ and vascular‑related proteins was quantified. Age‑ and menopause‑related differences, associations between protein targets, and effects of lifelong exercise were examined. ERα protein expression was lower in older females with a 48% lower expression in the ≥ 55 years age group compared with the < 30-year group. GPER1 protein expression was 22% lower across all older age groups compared with the < 30-year group. ERβ expression was reduced in mid‑life (45-59 years) but not in the oldest age group. Both ERα and ERβ were positively correlated with endothelial nitric oxide synthase (eNOS) expression, whereas GPER1 showed no association with eNOS. ERβ expression was associated with pro‑oxidative NOX2 expression. Aging in females is associated with a lower ERα and GPER1 protein expression in skeletal muscle. Furthermore, lower ER expression by aging is associated with a lower eNOS expression, indicating associations with proteins involved in nitric oxide-related redox regulation in skeletal muscle in aged females.

Keywords:  Estrogen receptors; Females vascular aging; Menopause; Oxidative stress; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-026-02432-3
Mol Biol Rep. 2026 Aug 07. pii: 1362. [Epub ahead of print]53(1):

Preclinical evidence of chrysin in metabolic disorder via mitochondrial signaling: a mechanistic review.

Monika Bansal, Soumarshi Das, Manish Kumar, Teenu Sharma, Sushma Devi.

  Metabolic disorders involve impaired glucose and lipid homeostasis, insulin resistance, chronic low-grade inflammation, and mitochondrial dysfunction, all of which contribute to the development of type 2 diabetes mellitus and related cardiometabolic complications. Recent evidence emphasises mitochondrial signaling as a key regulator of cellular energy balance and metabolic flexibility, positioning it as a promising therapeutic target. Chrysin, a naturally occurring flavone found abundantly in honey, propolis, and various medicinal plants, has attracted interest for its metabolic regulatory properties in preclinical studies. This mechanistic review critically examines experimental evidence on how chrysin influences metabolic disorders through mitochondrial signaling pathways. Preclinical studies demonstrate that chrysin improves mitochondrial bioenergetics by enhancing oxidative phosphorylation efficiency, ATP generation, and mitochondrial biogenesis, while simultaneously reducing excessive reactive oxygen species production. Chrysin has been shown to activate key energy-sensing pathways, including AMP-activated protein kinase and downstream regulators, thereby promoting glucose uptake, suppressing hepatic gluconeogenesis, and improving insulin sensitivity in peripheral tissues. Additionally, chrysin-mediated modulation of mitochondrial dynamics and antioxidant defence systems contributes to the attenuation of inflammation and lipid accumulation. In adipose and hepatic tissues, these effects translate into improved lipid metabolism, reduced free fatty acid release, and normalisation of metabolic enzyme expression. Collectively, the available preclinical evidence supports chrysin as a multi-target metabolic modulator acting through mitochondrial signaling networks.

Keywords:  AMP-activated protein kinase; Chrysin; Insulin resistance; Metabolic disorder; Mitochondrial signaling; Oxidative stress

DOI:  https://doi.org/10.1007/s11033-026-12557-5
Sci Rep. 2026 Aug 03. pii: 23767. [Epub ahead of print]16(1):

The potential therapeutic effect of quercetin on mitochondrial dysfunction in hepatorenal toxicity induced by aluminum chloride in an experimental rat model.

Tasneem N Hafez, Magda A Megahed, Bothaina F Mahmoud, Mohammed Salama, Nesma A Ghazal.

  Aluminum is a xenobiotic element known to induce hepatorenal toxicity through mechanisms involving mitochondrial dysfunction, oxidative stress, and inflammation. Quercetin, a dietary flavonoid with potent antioxidant and anti-inflammatory properties, has shown promise as a therapeutic agent. This study aimed to evaluate the potential therapeutic effects of quercetin against aluminum chloride (AlCl₃)-induced hepatorenal toxicity and mitochondrial dysfunction in rats. Hepatorenal toxicity was induced by oral administration of hydrated aluminum chloride (75 mg/kg body weight) daily for six weeks. Quercetin was administered intraperitoneally at a dose of 30 mg/kg body weight daily for four weeks. Biochemical assays, mitochondrial gene expression analysis, and histopathological examinations were conducted to assess the therapeutic effects. Quercetin significantly ameliorated lipid, protein, and DNA oxidation parameters (MDA, AOPPs and 8-OHdG respectively), reduced inflammation marker (TNF-α), and restored mitochondrial biogenesis markers, including PGC-1α, mtTFA and mitochondrial DNA copy number (mtDNA-CN). In addition, Quercetin significantly decreased TNF-α and increased PGC-1α contents at protein levels. Histopathological findings corroborated these results, demonstrating that quercetin improved liver and kidney architecture. These findings suggest that quercetin may serve as a potential therapeutic agent for aluminum-induced hepatorenal toxicity.

Keywords:  Aluminum chloride; Hepatorenal toxicity; Mitochondrial biogenesis; Quercetin; mtDNA-CN

DOI:  https://doi.org/10.1038/s41598-026-62378-6
Biochem Biophys Res Commun. 2026 Jul 30. pii: S0006-291X(26)01138-1. [Epub ahead of print]832 154374

Astaxanthin attenuates skeletal muscle atrophy and mitochondrial dysfunction in streptozotocin-induced diabetic rats.

Masayuki Tanaka, Miho Kanazashi, Ryosuke Nakanishi, Hiroyo Kondo, Hidemi Fujino.

  Diabetes mellitus (DM) induces skeletal muscle atrophy and mitochondrial dysfunction. Although antioxidant supplementation has exhibited beneficial effects on diabetic skeletal muscle, the effects of astaxanthin (AST), a potent antioxidant that protects mitochondrial function, remain unclear. We investigated whether AST supplementation attenuates DM-induced skeletal muscle alterations in streptozotocin (STZ)-induced diabetic rats. Male Wistar rats were assigned to control, DM, and DM + AST groups. DM was induced via STZ injection, and AST (100 mg/kg/day) was administered orally for 6 weeks. The plantaris muscle was analyzed for morphology, mitochondrial function, oxidative stress, inflammatory status, and signaling pathways related to protein metabolism and atrophy. Diabetic rats exhibited reductions in muscle mass and fiber cross-sectional area, decreases in mitochondrial enzyme activity and mitochondrial protein content, and increased oxidative stress. The expression of pro-inflammatory cytokines was elevated, along with markers associated with ubiquitin-proteasome system-, autophagy-, and apoptosis-related signaling. AST supplementation improved muscle mass and fiber cross-sectional area, partially restored mitochondrial enzyme activity and related protein expression, reduced oxidative stress, and attenuated inflammatory and atrophy-related signaling, without improving hyperglycemia. These findings indicate that AST attenuates DM-induced skeletal muscle atrophy and mitochondrial dysfunction in fast-twitch plantaris muscle. The protective effects of AST appear to be associated with reduced oxidative stress, attenuated inflammation, and attenuation of atrophy-related signaling rather than the restoration of anabolic signaling.

Keywords:  Astaxanthin; Diabetes mellitus; Mitochondrial dysfunction; Muscle atrophy; Oxidative stress; Streptozotocin

DOI:  https://doi.org/10.1016/j.bbrc.2026.154374
Mol Neurobiol. 2026 Aug 01. pii: 800. [Epub ahead of print]63(1):

Targeting Mitochondrial Dysfunction in Microglia: A New Frontier for Treating Neurodegenerative Diseases.

Mengqi Chu, Miaomiao Tan, Xulin Gan, Shumao Cui, Liyun Shi.

  Neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose an urgent global health challenge. Growing evidence establishes microglia-driven neuroinflammation as a key driver of disease onset and progression, with mitochondrial dysfunction emerging as an early trigger of microglial activation. This review comprehensively summarizes current progress on how mitochondrial alterations regulate microglial activation across AD, PD, and ALS. We identify conserved mechanisms including metabolic reprogramming, impaired mitophagy, and inflammatory signaling, though Aβ, α-synuclein, and TDP-43 engage these pathways through disease-specific molecular routes. Therapeutic strategies targeting microglial mitochondria, including cGAS-STING and NLRP3 inhibitors, TREM2 agonists, and mitochondrial transplantation, remain largely preclinical. Emerging targets such as OLFML3 and GPNMB require functional validation in microglia. Collectively, this review underscores that preserving microglial mitochondrial health represents a promising therapeutic frontier and identifies key priorities for translating these strategies toward clinical application.

Keywords:  Microglia; Mitochondria; Neurodegenerative diseases

DOI:  https://doi.org/10.1007/s12035-026-06091-5
Curr Opin Rheumatol. 2026 Aug 06.

Hyper-aging in systemic sclerosis: linking genome instability, mitochondrial dysfunction, and inflammaging to fibrosis.

Mohammad Waseem, Azait Imtiaz, Amit Datta, Rafael Contreras-Galindo.

   PURPOSE OF REVIEW: Systemic sclerosis (SSc) is a progressive autoimmune disease characterized by fibrosis, vasculopathy, and immune dysregulation. Emerging evidence indicates that SSc shares multiple hallmarks of accelerated biological aging, including genomic instability, telomere attrition, mitochondrial dysfunction, cellular senescence, and chronic innate immune activation. This review summarizes recent advances published during the last 18 months supporting the concept of SSc as a disorder of maladaptive or 'hyper-aging'.
RECENT FINDINGS: Recent epigenetic clock studies, including DunedinPACE and other DNA methylation-based aging models, demonstrate accelerated biological aging in SSc, particularly in patients with interstitial lung disease and severe organ involvement. Gene expression meta-analysis has confirmed that aging and senescence signatures are markedly enriched in SSc-ILD lung tissue. Multiple aging-associated mechanisms contribute to disease progression, including telomere shortening, mitochondrial dysfunction, micronuclei formation, and chromosomal instability. Cytosolic DNA derived from damaged nuclei or mitochondria activates the cGAS-STING pathway, sustaining type I interferon signaling, inflammaging, and fibrotic remodeling. Recent transcriptomic and spatial studies further support a close relationship between metabolic collapse, mitochondrial stress, immune dysregulation, and tissue fibrosis in SSc.
SUMMARY: Current evidence supports the concept that SSc represents a state of accelerated and dysregulated biological aging involving persistent innate immune activation, mitochondrial stress, and defective genome surveillance. Therapeutic strategies targeting aging-associated pathways, particularly mitochondrial dysfunction, cGAS-STING signaling, and cellular senescence, may provide new opportunities to modulate fibrosis, inflammation, and immune imbalance in SSc.

Keywords:  cyclic GMP-AMP synthase-stimulator of interferon genes; hyper-aging; inflammaging; mitochondrial dysfunction; systemic sclerosis

DOI:  https://doi.org/10.1097/BOR.0000000000001181
J Endocrinol. 2026 Aug 03. pii: JOE-25-0429. [Epub ahead of print]

Scutellarin ameliorates PCOS mouse model by restoring mitochondrial function and inhibiting granulosa cell apoptosis.

Zhi Li, Xiaoping Yang, Weifen Deng, Yudong Liu, Peixuan Lan, Yibo Song, Yanqiu Xie, Yuhua Shi.

   BACKGROUND: Polycystic ovary syndrome (PCOS), a common endocrine-metabolic disorder, lacks effective therapeutic options. Granulosa cell (GC) apoptosis and mitochondrial dysfunction are critical drivers of ovarian dysfunction in PCOS, yet targeted therapies are scarce. Scutellarin, a bioactive flavonoid, is a promising but unexplored candidate for treating PCOS.
METHODS: We investigated scutellarin's effects in a dehydroepiandrosterone (DHEA)-induced PCOS mouse model and in DHEA-treated human granulosa-like KGN cells. We assessed metabolic and reproductive parameters, ovarian histology, and fertility, and examined molecular mechanisms using transcriptomics, qRT-PCR, and Western blotting. Apoptosis and mitochondrial function were evaluated via TUNEL staining, flow cytometry, and real-time mitochondrial assays.
RESULTS: Scutellarin treatment was associated with improved metabolic phenotypes in PCOS mice, including glucose intolerance and insulin resistance, a normalized estrous cycle, lower serum testosterone and LH levels, better ovarian morphology, and enhanced fertility. Mechanistically, scutellarin correlated with reduced ovarian GC apoptosis and modulation of BCL2, BAX, and cleaved Caspase-3. Transcriptomic analysis identified the PI3K/Akt signaling pathway as a key mediator, and scutellarin dampened its abnormal activation in DHEA-induced PCOS in vivo and in vitro. Furthermore, scutellarin was associated with improved mitochondrial function in DHEA-treated KGN cells, evidenced by reduced ROS production and restored membrane potential.
CONCLUSION: Scutellarin is associated with the amelioration of metabolic and reproductive abnormalities in a PCOS mouse model, correlating with reduced GC apoptosis and improved mitochondrial function. By modulating these cellular defects, scutellarin offers potential dual benefits on ovarian and systemic dysfunctions, highlighting its value for clinical investigation and providing novel mechanistic insights.

Keywords:  Granulosa cell apoptosis; Mitochondrial dysfunction; Ovarian homeostasis; Polycystic ovary syndrome; Scutellarin

DOI:  https://doi.org/10.1530/JOE-25-0429
AIDS. 2026 Aug 06.

Distinct associations of peripheral mtDNA copy number and bioenergetic function with cognition in women with HIV and psychiatric comorbidities.

Hannah Stadtler, Leah H Rubin, Gretchen N Neigh.

   BACKGROUND: Women with HIV (WWH) are disproportionately affected by cognitive impairment across multiple domains, with learning and memory consistently among the most vulnerable. Mechanistic investigations into the increased burden of cognitive impairment in people with HIV have highlighted mitochondrial dysfunction as a potential contributor. This study examined associations between two peripheral markers of mitochondrial health, mitochondrial DNA copy number (mtDNAcn) and mitochondrial bioenergetic function, and cognitive function in WWH. We hypothesized that mtDNAcn and mitochondrial function metrics would demonstrate distinct associations with cognitive outcomes, particularly learning and memory.
METHODS: Fifty-eight WWH completed 12 neuropsychological tests assessing - verbal learning, verbal memory (recall and recognition), attention, working memory, executive function, fluency, processing speed, and motor function. Peripheral blood mononuclear cells (PBMCs) were isolated, and mitochondrial health was assessed using qPCR (mtDNAcn) and the Seahorse Cell Mito Stress Test (mitochondrial function). Pearson correlations examined associations between mitochondrial health and cognitive domain scores.
RESULTS: Participants were on average 54.9 years old (SD = 8.2), 94.8% were Black, 58.6% had a lifetime diagnosis of major depressive disorder, and 63.7% met criteria for cognitive impairment in ≥2 domains. Higher mitochondrial proton leak was significantly associated with worse verbal memory including recall (r = -0.396, P = 0.002) and recognition (r = -0284, P = 0.031), as well as poorer working memory (r = -0.261, P = 0.048). No significant associations were observed between mtDNAcn and cognition.
CONCLUSIONS: These findings identify peripheral mitochondrial proton leak as a potential biological correlate of verbal and working memory difficulties in WWH and highlight the importance of assessing multiple dimensions of mitochondrial health when investigating cognitive impairment.

Keywords:  HIV; cognition; memory; mitochondria; women

DOI:  https://doi.org/10.1097/QAD.0000000000004597
Gut Microbes. 2026 Dec 31. 18(1): 2694140

Mechanistic pathways linking gut microbial metabolites, microbial structural products, and host-microbe co-metabolites to mitochondrial function.

Richard E Frye, Daniel A Rossignol.

  Gut-derived microbial metabolites modulate host mitochondrial function. To our knowledge, no prior systematic review has synthesized evidence linking these metabolites to direct mitochondrial endpoints across all major metabolite classes. PubMed, Scopus, and Web of Science were systematically searched through March 2026 for studies examining direct mitochondrial endpoints in relation to ten classes of gut-derived metabolites. Gut-derived microbial metabolites exert diverse effects on mitochondrial function, ranging from bioenergetic enhancement to direct toxicity. After contextual evidence was excluded from the certainty assessment, four metabolite-mitochondrial outcome groupings had moderate certainty: butyrate, propionate, indoxyl sulfate, and lipopolysaccharide. Evidence for p-cresyl sulfate, H₂S, and urolithin A was rated low; evidence for the remaining metabolite classes was low or very low. Butyrate generally enhances mitochondrial biogenesis, ATP generation, and electron transport chain activity across multiple experimental models. Indoxyl sulfate generally impaired mitochondrial function, whereas p-cresyl sulfate produced concentration- and model-dependent effects. PGC-1α emerges as a central regulatory node, integrating microbial metabolic signals to control mitochondrial biogenesis and oxidative metabolism. Many microbial metabolites demonstrate concentration-dependent biphasic effects. These findings support a mechanistic microbiome-mitochondrial framework in which diverse gut-derived molecules converge on a limited set of mitochondrial control nodes: electron transport chain activity, reactive oxygen species handling, biogenesis, and mitophagy. The evidence base is predominantly preclinical; these insights should be considered hypothesis-generating.

Keywords:  Gut microbiome; butyrate; electron transport chain; microbial metabolites; microbiome–mitochondria axis; mitochondrial function; short-chain fatty acids; systematic review

DOI:  https://doi.org/10.1080/19490976.2026.2694140
HSOA J Gerontol Geriatr Med. 2026 ;pii: 280. [Epub ahead of print]12(1):

The Role of Slow Gait Speed in Cognitive Decline among Aging Women: A Systematic Review.

Joel Acevedo-Nieto, Karen Martínez, Claudia Amaya.

  The prevalence of Alzheimer's disease and related dementias are increasing at an alarming rate, with projections estimating that by 2060, approximately 13.8 million adults aged 65 years and older in the U.S. will be affected by one or both. Among the many symptoms associated with cognitive decline, gait impairment is one that significantly affects functional independence and mobility.
Methods: A systematic review was conducted to analyze 49 peer-reviewed studies using the Covidence systematic review software and adhering to PRISMA guidelines. The selected articles examined variables related to gait speed, and cognition. Participants were assessed through validated neurocognitive and mobility measures, including the MoCA and Dynamic Gait Index.
Results: A significant negative correlation was identified between usual walking speed and age. This trend was particularly pronounced in women, in whom a significant negative association between MoCA scores and age (P = -0.019) was observed, suggesting an increased susceptibility to cognitive deterioration with advancing age.
Conclusion: These findings underline the sex-specific nature of the relationship between gait speed and cognitive function, highlighting increased vulnerability in aging women. The decline in mobility and cognition observed in this population underscores the urgency of developing targeted interventions that integrate physical and cognitive rehabilitation strategies.

Keywords:  Aging; Alzheimer’s Disease; Cognitive Decline

DOI:  https://doi.org/10.24966/ggm-8662/100280
Appl Physiol Nutr Metab. 2026 Aug 06.

Anthocyanin-rich bilberry extract and resveratrol as protectors against mitochondrial dysfunction induced by mixed micelles in Caco-2 intestinal epithelial cells.

Maryam Ershad, Mark K Shigenaga, Brian Bandy.

Healthy and efficient mitochondria have a critical role in maintaining intestinal cell function and preventing pathological conditions. The influence of dietary fat, and possible protection by dietary polyphenols, on mitochondrial function in intestinal epithelial cells, however, is relatively unexplored. In this study we aimed to test the influence of dietary fat on mitochondrial content and function in intestinal epithelial cells, possible protection by berry anthocyanins and resveratrol, and the mechanisms involved. Caco-2 intestinal epithelial cells were exposed to 0.4 or 0.1 mM mixed micelles (MM) composed of lipids and bile acid in the absence or presence of 20 µM resveratrol or anthocyanins in an anthocyanin-rich bilberry extract (ARBE), added 5h or 2h, respectively prior to MM. After 24 h, indices of mitochondrial content and function were measured. MM exposure decreased measures of mitochondrial function (membrane potential and respiratory functions), as well as citrate synthase activity and expression of mRNA for mtDNA-encoded respiratory complex proteins (MTND1, MTCYB, MTCO1, MTATP) (P<0.05). Treatment with resveratrol increased mitochondrial content and transcription of genes involved in mitochondrial biogenesis (PGC-1α, NRF-1, TFAM) (P<0.05) but did not significantly protect against MM-induced declines in mitochondrial functions. Conversely, ARBE protected against decreases in parameters of mitochondrial function (P<0.05) but had little effect on indices of mitochondrial content and biogenesis. Neither resveratrol nor ARBE protected against the MM-induced decrease in expression of mtDNA-encoded mRNAs. The results support that MM, representing emulsified dietary fat, produce mitochondrial dysfunction in intestinal epithelial cells, and that berry anthocyanins, unlike resveratrol, can protect intestinal cell mitochondria by a direct mechanism not involving mitochondrial biogenesis.

DOI: https://doi.org/10.1139/apnm-2025-0446
Hum Reprod. 2026 Aug 03. pii: deag118. [Epub ahead of print]

Mitochondria-targeted therapeutic strategies in assisted reproduction: challenges and potential solutions.

Raziye Melike Yildirim, Gizem Nur Sahin, Richard T Scott, Emre Seli.

  Mitochondria are central to oocyte competence and early embryonic development, with roles that extend beyond energy production to include regulation of redox homeostasis, apoptosis and cellular aging. Mitochondrial dysfunction is increasingly recognized as a key contributor to diminished ovarian reserve, impaired embryo development, and accelerated reproductive aging. Mitochondria-targeted therapeutic strategies, including pharmacological approaches such as Coenzyme Q10, mitoquinone, resveratrol, rapamycin, and NAD+ precursors, as well as mitochondrial replacement techniques such as maternal spindle and pronuclear transfer, have shown promise in preclinical models; however, clinical outcomes remain heterogeneous and often inconclusive. This translational gap likely reflects critical limitations, including variability in therapeutic targets, suboptimal timing of intervention relative to oocyte development, and insufficiently powered or standardized clinical studies. Greater emphasis on well-defined, physiologically justified therapeutic targets, along with the use of physiologically relevant experimental systems, may improve therapeutic precision and efficacy. Rigorous evaluation of safety, particularly for interventions with pleiotropic effects or heritable consequences, remains essential. A more targeted, developmentally informed and systematically validated approach is needed to advance mitochondria-based therapies toward meaningful improvements in reproductive outcomes.

Keywords:  embryo aneuploidy; mitochondrial dysfunction; mitochondrial replacement therapy; oocyte quality; ovarian reserve

DOI:  https://doi.org/10.1093/humrep/deag118
Life Sci. 2026 Aug 05. pii: S0024-3205(26)00428-5. [Epub ahead of print]403 124619

Rapamycin-sensitive mTORC1 signaling in the medial prefrontal cortex contributes to the antidepressant-like behavioral effects of shikimic acid in mice.

Satoshi Deyama, Kana Ito-Shintai, Rinako Sugie, Masaki Tabata, Haruki Sakaguchi, Katsuyuki Kaneda.

   AIMS: Major depressive disorder (MDD) represents a major contributor to disability, yet currently prescribed monoamine-based antidepressants are limited by modest therapeutic efficacy and delayed clinical onset. Recent studies have demonstrated that ketamine, an N-methyl-d-aspartate receptor antagonist, rapidly engages mechanistic target of rapamycin complex 1 (mTORC1) signaling in the medial prefrontal cortex (mPFC), critically linked to its fast-acting antidepressant actions. Shikimic acid (SA), a natural compound widely found in various plants, has been reported to exhibit mTORC1-related signaling activity. In this study, we investigated whether SA induces antidepressant-like behavioral responses through mTORC1-related signaling in the mPFC.
MATERIALS AND METHODS: Antidepressant-like effects of SA were assessed in male and female outbred ICR and inbred C57BL/6 J mice using the forced swim test (FST), with locomotor activity evaluated in the open field test. The role of mTORC1 signaling was evaluated by systemic and intra-mPFC administration of the mTORC1 inhibitor rapamycin. The antidepressant-like effects of SA were further examined in ovariectomized (OVX) mice, a model of menopause-associated depression.
KEY FINDINGS: SA significantly reduced immobility in the FST in naïve male but not female ICR mice, and this effect was abolished by systemic and intra-mPFC rapamycin. Comparable effects were observed in naïve male, but not female, C57BL/6 J mice. SA also reversed OVX-induced increase in immobility, and this effect was completely prevented by intra-mPFC rapamycin.
SIGNIFICANCE: These findings suggest that SA exerts antidepressant-like effects via rapamycin-sensitive mTORC1-dependent mechanisms within the mPFC. Our results support SA as a candidate compound targeting mPFC mTORC1-related signaling for novel rapid-acting antidepressants.

Keywords:  Antidepressant; Depression; Mechanistic target of rapamycin complex 1; Medial prefrontal cortex; Shikimic acid

DOI:  https://doi.org/10.1016/j.lfs.2026.124619
J Oleo Sci. 2026 ;75(8): 921-932

N-Acetylcysteine, Dichloroacetate, and Metformin Restore Mitochondrial Homeostasis by Counteracting Oxidative Stress and Fusion-Fission Imbalance in Palmitic Acid-Induced Lipotoxicity.

Zhixing Cai, Yue Chen, Lili Chen, Danyang Zhu.

   BACKGROUND: Palmitic acid (PA)-driven lipotoxicity in skeletal muscle is associated with excessive reactive oxygen species (ROS) and disturbed mitochondrial dynamics. This study aimed to characterize PA-induced alterations in oxidative status and fusion-fission balance in C2C12 skeletal muscle cells and to test whether N-acetylcysteine (NAC), dichloroacetate (DCA), or metformin mitigate these changes.
METHODS: Differentiated C2C12 myotubes were exposed to PA under conditions detailed in the Methods. Intracellular ROS was quantified, antioxidant defenses were assessed by activities of catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), and mitochondrial dynamics were evaluated by expression of the fusion protein mitofusin 1 (MFN1) and the fission protein dynamin-related protein 1 (DRP1), together with morphological assessment of mitochondrial fragmentation.
RESULTS: PA exposure increased ROS and was accompanied by decreases in CAT, GPx, and SOD activities. PA shifted mitochondrial dynamics toward fission, with reduced MFN1, elevated DRP1, and increased mitochondrial fragmentation. Co-treatment with NAC, DCA, or metformin attenuated PA-induced ROS accumulation, improved antioxidant enzyme activities relative to PA alone, and partially normalized MFN1 and DRP1 expression, with reduced fragmentation.
CONCLUSIONS: In an in vitro C2C12 model, PA-induced lipotoxicity is associated with oxidative stress and a fusion-fission imbalance favoring mitochondrial fragmentation. NAC, DCA, and metformin mitigate these alterations and help preserve mitochondrial homeostasis. These findings support targeting oxidative stress and mitochondrial dynamics as a potential approach to counteract mitochondrial dysfunction under lipotoxic conditions.

Keywords:  insulin resistance; mitochondrial dysfunction; oxidative stress; palmitic acid

DOI:  https://doi.org/10.5650/jos.ess25268