bims-mistre 2025-08-10 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–08–10
28 papers selected by
Ellen Siobhan Mitchell, MitoQ

Redox-regulated signalling of adaptations to contractile activity in skeletal muscle: Implications for age-related muscle weakness.
Impacts of aging on brain metabolism.
Hormesis and brain metabolism in aging and neurodegeneration.
Genetic mapping of lifespan and mitochondrial stress response in C. elegans.
Phytochemicals and brain health: The effects of curcumin, isoflavonoids, and ouabain.
NADH reductive stress drives metabolic reprogramming.
Mitochondrial dysfunction in peripheral mononuclear blood cells (PBMC) of individuals with mild cognitive impairment.
Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.
Oxidative Stress in DNA Damage and Neurodegenerative Diseases: Unveiling The Mechanisms and Therapeutic Opportunities.
Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.
AMPK/mTOR balance during exercise: implications for insulin resistance in aging muscle.
Puerarin as a multi-targeted modulator of lipid metabolism: molecular mechanisms, therapeutic potential and prospects for nutritional translation.
The role of mitochondrial dysfunction in diabetes-associated cognitive dysfunction: A bibliometric analysis.
Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.
Phytocompounds as modulators of HSF1 in neurodegenerative disease: Special emphasis on Alzheimer's disease.
Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.
Effects and Safety of FGF21 Analogs on Glycemic Parameters, Lipid Profiles, and Adiponectin in Overweight and Obese Adults: A Meta-Analysis of Randomized Controlled Trials.
Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis in mice.
Chronic stress-secreted glucocorticoid induces NAFLD-like changes in male rats: Oxidative stress/NLRP3 inflammasome signalling.
Cysteine Oxidation of a Redox Hub within Complex I can Facilitate Electron Transport Chain Supercomplex Formation.
Hormesis-induced neuroplasticity: Targeting neuroinflammation signaling cascades for therapeutic insights in aging and neurodegenerative diseases.
Three-Dimensional Network of Creatine Metabolism: from Intracellular Energy Shuttle to Systemic Metabolic Regulatory Switch.
Protective Effect of N-Acetylcysteine (NAC) on oxLDL-Induced Endothelial Dysfunction.
Mechanistic insights into ubiquinone Q10 in Parkinson's disease: mitochondrial protection, ferroptosis inhibition, and antioxidant recycling.
Mechanisms of mitochondrial reactive oxygen species action in bone mesenchymal cells.
Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates.
Lithium deficiency and the onset of Alzheimer's disease.
NMN improves cardiac function in SIRT3 knockout mice via the SIRT1/PGC-1α pathway.

Exp Physiol. 2025 Aug 05.

Redox-regulated signalling of adaptations to contractile activity in skeletal muscle: Implications for age-related muscle weakness.

Malcolm J Jackson.

  Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H2O2). Early research framed ROS as deleterious byproducts of exercise, but subsequent studies have established their roles as signalling molecules involved in mitochondrial biogenesis, stress responses and metabolic regulation. Central to this process appear to be peroxiredoxins (Prdxs), particularly Prdx2, which current evidence suggests mediate redox relays by sensing physiological H2O2 levels and initiating transcriptional programs. Our recent findings demonstrate that low levels of H2O2, or electrically induced contractions, rapidly oxidise Prdx1, Prdx2 and Prdx3 in mouse muscle fibres. Transcriptomic analysis of human skeletal muscle myotubes confirmed that Prdx2 is essential for upregulating mitochondrial genes in response to H2O2 or contraction. With ageing, skeletal muscle exhibits impaired redox signalling with elevated ROS levels. Using an ageing mouse model, we observed diminished Prdx2 oxidation during contraction, suggesting redox signalling dysfunction. This impaired response likely contributes to sarcopenia by blunting the adaptive capacity of aged muscle. Our findings emphasise the importance of redox homeostasis (not merely ROS suppression) in maintaining muscle health. Understanding the nuanced role of ROS and Prdxs in exercise adaptation and ageing could inform therapeutic strategies aimed at restoring redox-sensitive signalling to preserve muscle function across the lifespan.

Keywords:  NMJ; hydrogen peroxide; mitochondria; motor neuron

DOI:  https://doi.org/10.1113/EP092458
Prog Brain Res. 2025 ;pii: S0079-6123(25)00067-6. [Epub ahead of print]295 9-38

Impacts of aging on brain metabolism.

Bianca Andrade Rodrigues, Thays Calista Santiago Pretes, Josiane do Nascimento Silva.

  Changes in energy homeostasis in aging have significant implications for brain health. Decreased glucose utilization efficiency, mitochondrial dysfunction, loss of metabolic flexibility, and increased oxidative stress can compromise cognitive functions and increase vulnerability to neurodegenerative diseases. Understanding these changes provides valuable insights for prevention and treatment strategies, such as dietary interventions, physical exercise, and pharmacological therapies, aimed at restoring or preserving energy homeostasis in the brain and thus improving cognitive health throughout life. This chapter explores the metabolic changes in the brain associated with aging, examining the underlying biochemical and molecular mechanisms, as well as therapeutic strategies that may alleviate the detrimental effects of brain aging.

Keywords:  Brain aging; Brain metabolism; Energy homeostasis; Glucose; Ketone bodies; Metabolic flexibility; Mitochondrial dysfunction; Oxidative stress

DOI:  https://doi.org/10.1016/bs.pbr.2025.05.009
Prog Brain Res. 2025 ;pii: S0079-6123(25)00063-9. [Epub ahead of print]295 285-331

Hormesis and brain metabolism in aging and neurodegeneration.

Robbert Mota Pereira, Kairo Alan Albernaz-Mariano, Paloma Marinho Jucá, Vitor Augusto Laurino Juliano, Lucas Luzia Sampaio, Carolina Demarchi Munhoz.

  This chapter explores sex-specific differences in brain development and hormones' critical role throughout life. Understanding these variabilities is vital for mental health, particularly concerning stress responses, aging, and the risk of neurodegenerative and cardiometabolic diseases. We examine the biological mechanisms involved, highlighting how hormones affect brain formation, neuronal plasticity, and stress responses, focusing on male and female variations. Research from animal studies and human data shows that males and females have distinct susceptibilities to diseases influenced by sex-specific hormonal effects on genes, cellular functions, and energy metabolism. Additionally, we examine the role of glucocorticoids in these diseases, considering their sex-specific effects on normal and dysfunctional physiological processes. A closer look at hormonal transition periods-such as early childhood, puberty, and menopause-emphasizes the need for sex-specific strategies in research and treatment. Overall, this chapter underscores the importance of understanding the interplay between biological sex, hormonal changes, and environmental stressors throughout life, as these factors significantly impact the onset and progression of various health conditions. Tailored approaches in health research and treatment are advocated to better address these differences.

Keywords:  Aging; Cardiometabolic diseases; Health; Hormones; Neurodegenerative diseases; Sex; Stress

DOI:  https://doi.org/10.1016/bs.pbr.2025.05.005
Res Sq. 2025 Jul 31. pii: rs.3.rs-7093535. [Epub ahead of print]

Genetic mapping of lifespan and mitochondrial stress response in C. elegans.

Johan Auwerx, Xiaoxu Li, Weisha Li, Arwen Gao, YunYun Zhu, Elena Katsyuba, Katherine Overmyer, Terytty Yang Li, Ziwen Wang, Luc Legon, Lucie Plantade, Laurent Mouchiroud, Matteo Cornaglia, Hao Li, Riekelt Houtkooper, Joshua Coon.

The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, highlighting its translational relevance. Overall, our dataset (https://lisp-lms.shinyapps.io/RIAILs_Dox/) serves as a unique resource to dissect lifespan and mitochondrial stress response modulators in a large genetic reference population.

DOI: https://doi.org/10.21203/rs.3.rs-7093535/v1
Prog Brain Res. 2025 ;pii: S0079-6123(25)00062-7. [Epub ahead of print]295 135-188

Phytochemicals and brain health: The effects of curcumin, isoflavonoids, and ouabain.

Arthur B Cantanzaro, Ana Maria Orellana.

  Recent data underscores a critical public health issue: more than 40 % of the global population suffers from neurological conditions, for which no cures currently exist. To combat this pressing challenge, researchers are turning to phytochemicals-bioactive compounds derived from plants that hold promising health benefits, particularly for cognitive function. This chapter intends to shed light on groundbreaking discoveries regarding curcumin, isoflavonoids, and cardiotonic steroids, natural compounds that act on the brain. These substances have shown significant potential for enhancing brain health as we age, especially in addressing neurodegenerative processes such as Alzheimer's and Parkinson's diseases. We will also examine the intricate molecular mechanisms these compounds activate to offer neuroprotection, supported by both in vitro and in vivo studies. Furthermore, we will analyze clinical trials that inspire optimism for the development of innovative therapeutic drugs in the near future. Supporting research in this area could be vital to transforming the landscape of neurological health.

Keywords:  Aging; Alzheimer´s disease; Brain health; Cardiotonic steroids; Curcumin; Isoflavonoids; Ouabain; Parkinson´s disease; Phytochemicals

DOI:  https://doi.org/10.1016/bs.pbr.2025.05.004
Trends Cell Biol. 2025 Aug 05. pii: S0962-8924(25)00157-6. [Epub ahead of print]

NADH reductive stress drives metabolic reprogramming.

Ronghui Yang, Zihao Guo, Binghui Li.

  Cellular metabolism is intricately regulated by redox signaling, with the NADH/NAD+ couple serving as a central hub. Emerging evidence reveals that NADH reductive stress, marked by NADH accumulation, is not merely a passive byproduct of metabolic dysfunction but an active regulatory signal driving metabolic reprogramming. In this Review, we synthesize recent advances in understanding NADH reductive stress, including its origins, regulatory mechanism, and manipulation. We examine its broad impact on cellular metabolism, its interplay with oxidative and energy stress, and its pathogenic roles in a range of diseases. By integrating these findings, we propose NADH reductive stress as a master regulator for metabolic reprogramming and highlight new avenues for mechanistic exploration and therapeutic intervention.

Keywords:  NADH reductive stress; NADH-reductive-stress-associated diseases; energy stress; metabolic reprogramming; oxidative stress

DOI:  https://doi.org/10.1016/j.tcb.2025.07.005
Geroscience. 2025 Aug 06.

Mitochondrial dysfunction in peripheral mononuclear blood cells (PBMC) of individuals with mild cognitive impairment.

Fabian Dieter, Karlotta Jacobs, Alice Quentin, David Prvulovic, Andreas Reif, Johannes Pantel, Ulrich Pilatus, Elke Hattingen, Silke Matura, Gunter Peter Eckert.

  Mitochondrial dysfunction is a hallmark of aging and many age-related neurodegenerative diseases. Mild cognitive impairment (MCI) refers to a clinical condition characterized by noticeable cognitive decline that exceeds normal age-related changes but does not significantly interfere with daily functioning. MCI is often considered an early stage of neurodegenerative conditions, including Alzheimer's disease. We therefore investigated the relationship between mitochondrial function in peripheral blood cells and cognitive performance in individuals with amnestic (aMCI) and nonamnestic mild cognitive impairment (naMCI). Control groups consisted of young (YC) and older adults (OC) who were physically and mentally healthy. Cross-sectional observational study involving 90 participants, including young adults, cognitively healthy older adults, and individuals with MCI. Mitochondrial function was determined in cryopreserved PBMCs. Cognitive status was assessed using the German version of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test battery. ATP levels in cryopreserved PBMC isolated from individuals with aMCI were significantly lower than those of OC and YC. Endogenous respiration varied significantly between groups, with the MCI group exhibiting the lowest respiration. Linear regression analyses with ATP as a predictor for cognitive performance showed a significant positive relationship between ATP levels and both immediate recall and fluency. The regression coefficients indicated a moderate positive correlation between ATP levels and performance in both tests. This suggests that higher ATP levels are associated with improved cognitive performance. Our data suggest that mitochondrial dysfunction in PBMC is associated with MCI and correlates with cognitive impairment. Subjects who performed poorly on neuropsychological tests also exhibited lower ATP levels. Given that PBMC are easily accessible, they offer valuable insights into the bioenergetic status of individuals at increased risk for dementia. The study (PEM-MCI) has been retrospectively registered at the German Register of Clinical Trials (DRKS) DRKS00036017 (registered on 30.01.2025).

Keywords:  Aging; Mild cognitive impairment; Mitochondrial function; PBMC

DOI:  https://doi.org/10.1007/s11357-025-01813-4
bioRxiv. 2025 Jul 29. pii: 2025.07.28.667051. [Epub ahead of print]

Saturated lipid stress attenuates mitochondrial genome synthesis in human cells.

Casadora Boone, Sophie Judge, Ahmad Shami, Bezawit Danna, Andrea B Ball, Tejashree Pradip Waingankar, Hera Saqub, Ajit S Divakaruni, Samantha C Lewis.

Fatty acids are trafficked between organelles to support membrane biogenesis and act as signaling molecules to rewire cellular metabolism in response to starvation, overnutrition, and environmental cues. Mitochondria are key cellular energy converters that harbor their own multi-copy genome critical to metabolic control. In homeostasis, mitochondrial DNA (mtDNA) synthesis is coupled to mitochondrial membrane expansion and division at sites of contact with the endoplasmic reticulum (ER). Here, we provide evidence from cultured hepatocytes that mtDNA synthesis and lipid droplet biogenesis occur at spatially and functionally distinct ER-mitochondria membrane contact sites. We find that, during saturated lipid stress, cells pause mtDNA synthesis and mitochondrial network expansion secondary to rerouted fatty acid trafficking through the ER and lipid droplet biogenesis, coincident with a defect in soluble protein import to the ER lumen. The relative composition of fatty acid pools available to cells is critical, as monounsaturated fatty acid supplementation rescued both ER proteostasis and mtDNA synthesis, even in the presence of excess saturated fat. We propose that shutoff of mtDNA synthesis conserves mtDNA-to-mitochondrial network scaling until cells can regain ER homeostasis.
Summary: Overnutrition of cultured human cells causes endoplasmic reticulum dysfunction, which downregulates mitobiogenesis in turn by constraining mtDNA synthesis.

DOI: https://doi.org/10.1101/2025.07.28.667051
Cell Biochem Biophys. 2025 Aug 02.

Oxidative Stress in DNA Damage and Neurodegenerative Diseases: Unveiling The Mechanisms and Therapeutic Opportunities.

Md Anisur Rahman, Mst Tania Khatun, Afsana Khanom Mim, Md Parvez Khandocar, Ahidur Rahman, Md Hasibul Hasan, Afia Ibnath Shimki, Md Sabbir Hossain, Mst Sadia Afroz Shoily, Arafat Faraque, Md Faisal Amin, Rafia Ferdous, Md Shoriful Islam.

  Oxidative stress is marked by disproportionate levels of reactive oxygen species (ROS) and antioxidant defenses and is a key factor in initiating DNA damage and neurodegenerative diseases. Increased reactive oxygen species (ROS) levels can lead to oxidative DNA lesions, disrupting cellular function and contributing to genomic instability. Oxidative stress is linked to neuronal degeneration, particularly in conditions such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), where DNA damage accelerates the progression of these disorders. Hence, the importance of therapeutic measures to reduce oxidative damage and enhance DNA repair is emphasized. This review reveals the intricate mechanisms by which oxidative stress triggers DNA damage and its subsequent impact on neuronal health. By conducting a comprehensive literature search across various databases, we explore the molecular pathways involved, including mitochondrial dysfunction, inflammation, and altered signaling pathways, which exacerbate neuronal death and dysfunction. Furthermore, we investigate potential therapeutic strategies targeting oxidative stress and DNA repair mechanisms, focusing on antioxidant approaches, gene editing technologies, and pharmacological interventions to mitigate oxidative damage. Understanding the relationship between oxidative stress, DNA damage, and neurodegeneration is essential for developing effective therapies to slow down or stop the worsening of these disabling illnesses.

Keywords:  Alzheimer’s disease; DNA damage; Neurodegenerative diseases; Oxidative stress; Parkinson’s disease

DOI:  https://doi.org/10.1007/s12013-025-01845-9
Cancer Res. 2025 Aug 07.

Alzheimer's Disease-Associated Amyloid Beta Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Anti-Tumor Immunity.

Mohamed Faisal Kassir, Han Gyul Lee, Natalia V Oleinik, Wyatt Wofford, Chase Walton, Firdevs Cansu Atilgan, Alhaji H Janneh, Paramita Chakraborty, Kubra Calisir, Elif Percin, Silvia G Vaena, Kalyani Sonawane, Ashish Deshmukh, Narayan R Bhat, Kumar Sambamurti, Onder Albayram, Ozgur Sahin, Shikhar Mehrotra, Besim Ogretmen.

Alzheimer's disease (AD) patients have a decreased incidence of cancer., with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD compared to AD patients. Here, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress-mediated hyperactive mitophagy in aging T-cells, improving their anti-tumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice. Additionally, adoptive cell transfer (ACT)-based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage. Mechanistically, APP interaction with TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T-cells, preventing ceramide-dependent mitophagy. Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving anti-tumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T-cells, enhancing their anti-tumor activity to control tumor growth. Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched AD patients. Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance anti-tumor functions.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-4740
Mol Cell Biochem. 2025 Aug 04.

AMPK/mTOR balance during exercise: implications for insulin resistance in aging muscle.

Xie Mingzheng, Weng You.

  Age-related reductions in skeletal muscle insulin responsiveness promote metabolic dysregulation and contribute to an elevated probability of type 2 diabetes onset. The malfunction of nutrient-responsive signaling routes, specifically AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), constitutes a central component of this biological process. The integrated activity of these kinases in controlling energy dynamics, protein formation, and glucose processing is fundamental to ensure metabolic homeostasis in skeletal muscle tissue. Through its modulation of AMPK and mTOR pathways, exercise helps reinstate signaling equilibrium and supports better insulin efficacy in aging skeletal muscle. This review explores the molecular mechanisms by which different forms of exercise-endurance, resistance, and combined training-modulate the AMPK/mTOR axis in aging muscle. This analysis focuses on exercise-induced AMPK signaling as a catalyst for mitochondrial development, enhanced glucose processing, and intensified fatty acid breakdown, while also temporally coordinating mTOR activity to support muscle maintenance without exacerbating insulin resistance. By integrating insights from aging biology, exercise physiology, and molecular metabolism, this review highlights the therapeutic potential of targeting AMPK/mTOR signaling through physical activity to combat insulin resistance in the elderly.

Keywords:  AMPK; Exercise intervention; Insulin resistance; Skeletal muscle aging; mTOR

DOI:  https://doi.org/10.1007/s11010-025-05362-4
Front Nutr. 2025 ;12 1598897

Puerarin as a multi-targeted modulator of lipid metabolism: molecular mechanisms, therapeutic potential and prospects for nutritional translation.

Shu Ou, Qingzhi Liang, Yulin Leng, Ting Luo, Xin Xu, Hongyan Xie, Hong Gao, Jun Li, Chunguang Xie.

  Lipid metabolism is a dynamic and intricate process involving the uptake, synthesis, storage and catabolism of lipid compounds in the body. Its homeostasis is crucial for maintaining the health of the organism. The regulatory network of lipid metabolism homeostasis consists of several key molecules, including SREBPs, PPARs, ChREBP, FXR, LXR, AMPK, and ncRNAs. Puerarin (Pue), an isoflavone derivative, has been demonstrated to enhance lipid metabolism by modulating the aforementioned signaling cascades. Pue has found extensive application in the pharmaceutical, food, and nutraceutical industries. Considering the multi-target and multi-pathway pharmacological properties of Pue, the present study focuses on the molecular mechanism of Pue in the regulation of lipid metabolism, the spectrum of metabolic diseases, as well as the limitations of the current study and the prospect of nutritional translation. It is hoped that this study will provide a reference for the regulation of lipid homeostasis and remodeling of lipid metabolism, with the aim of optimizing clinical use and product development.

Keywords:  Puerarin; lipid metabolism; molecular mechanism; natural product; nutrient transformation

DOI:  https://doi.org/10.3389/fnut.2025.1598897
J Alzheimers Dis. 2025 Aug 06. 13872877251364845

The role of mitochondrial dysfunction in diabetes-associated cognitive dysfunction: A bibliometric analysis.

Chen Wang, Siyi He, Lingling Wang, Yushuang Yin, Wenqi Zhang, Guanwen Lin, Duozhi Wu, Qin Zhou, Zhihua Wang.

  BackgroundDiabetes, a prevalent chronic disorder, is frequently complicated by diabetes-associated cognitive dysfunction (DACD). The impact of diabetes on specific cerebral regions accelerates the progression from mild cognitive impairment to Alzheimer's disease. Research has indicated that mitochondrial dysfunction is a pivotal factor in DACD, yet its underlying mechanisms remain elusive.ObjectiveOur research aims to elucidate the research trends in this field over the past fifteen years by employing bibliometric analysis.MethodsA systematic search and aggregation of literatures related to mitochondrial dysfunction in DACD published within the Web of Science Core Collection from 2010 to 2024 were performed. Subsequently, a bibliometric analysis was conducted employing four bibliometric software: HistCite, R-bibliometrix, VOSviewer, and CiteSpace.ResultsA total of 309 papers were identified for analysis. The most prolific country, institution, and authors were China, University of Coimbra, Moreira PI, and Li YS, respectively. The USA, Texas Tech University, and Reddy PH were the key country, institution, and author, respectively. Among references to articles in this field, Diabetes has the most cumulative citations. According to the analysis of co-citations, oxidative stress was the largest cluster. The primary keywords were "Alzheimer's disease" and "oxidative stress". In recent years, the keyword "mitophagy" has received a lot of attention.ConclusionsOxidative stress represents a principal research topic within this field. Mitophagy offers a potential therapeutic avenue for DACD and may emerge as a novel focus of future investigations.

Keywords:  Alzheimer's disease; bibliometric analysis; diabetes-associated cognitive dysfunction; mitochondrial dysfunction; mitophagy; oxidative stress

DOI:  https://doi.org/10.1177/13872877251364845
bioRxiv. 2025 Jul 31. pii: 2025.07.28.667250. [Epub ahead of print]

Sigma-1 Receptor Promotes Glycolysis in Neuronal Systems by Suppressing GRIM19.

Simon Couly, Yuko Yasui, Ioannis Grammatikakis, Yuriko Kimura, Josh Hinkle, Juan Gomez, Hsiang-En Wu, Ghosh Paritosh, Ashish Lal, Michael Michaelides, Brandon Harvey, Tsung-Ping Su.

Sigma-1 receptor (S1R) is a Ca 2+ sensitive, ligand-operated receptor chaperone protein present on the endoplasmic reticulum (ER) membrane and more specifically at the mitochondria-associated ER membrane (MAM). Upon activation by ER calcium depletion or ligand binding, S1R can increase calcium efflux from the ER into the mitochondria by chaperoning IP3 receptor type3 (Ip3R3). Mitochondrial metabolism has an intricate relationship with glycolysis. Despite S1R affecting mitochondria, the relevance of S1R to glycolysis and its impact on the overall cellular energy metabolism is not known. This study utilizes wild-type (Wt) and S1R knockout (S1R KO) Neuro2a (N2a) cells and Wt and S1R KO mice for primary culture of cortical neurons studies and longitudinal in-vivo imaging. In this manuscript we describe the fundamental functions of S1R on glycolysis, mitochondrial activity and NAD + /NADH metabolism, keystone coenzymes essential for glycolysis and for mitochondrial activity. Both N2a cells and cortical neurons lacking S1R had reduced glycolytic activity, and increased mitochondria complex I protein GRIM19 but no change in mitochondrial oxygen consumption. Furthermore, we observed an increased NAD + /NADH ratio in S1R KO condition. Positron emission tomography revealed decreased [ 18 F]fluorodeoxyglucose brain uptake in S1R KO mice. We observed that knocking down GRIM19 in S1R KO condition rescued the glycolysis deficit. Altogether, these data show for the first time that S1R modulates glycolysis and NAD metabolism in various neuronal systems. This new insight on the S1R function may lead to new therapeutic applications of S1R ligands where compromised glycolysis and cellular NAD+/NADH ratios occur such as aging and neurodegeneration.

DOI: https://doi.org/10.1101/2025.07.28.667250
Eur J Pharmacol. 2025 Aug 05. pii: S0014-2999(25)00788-5. [Epub ahead of print]1005 178034

Phytocompounds as modulators of HSF1 in neurodegenerative disease: Special emphasis on Alzheimer's disease.

Vinod Kumar Nelson, M Yasmin Begum, Ayed A Dera, Syed Parween Ali, Punna Rao Suryadevara.

  Alzheimer's disease (AD) is the most common age-related neurodegenerative disease that affects millions of people every year globally. In addition to a drastic rise in AD cases, there is a significant increase in the death rate as well. According to the latest statistics, the death rate increased to 1.62 million in 2019 and is expected to rise further. The primary pathological hallmark of the disease is the accumulation of misfolded aggregates, such as amyloid beta (Aβ) plaques and tau neurofibrillary tangles, which induce toxic effects and initiate neuronal dysfunction, ultimately leading to disease symptoms, including cognitive impairment. Hence, targeting and eliminating these protein aggregates could significantly inhibit the disease pathogenesis. Previous studies have also suggested that the activation of heat shock factor 1 (HSF1) and the up-regulation of its encoded heat shock proteins (HSPs) can clear toxic aggregates by triggering proteostasis mechanisms, such as autophagy and the ubiquitin-proteasome system (UPS). However, in neurodegenerative diseases (NDs) like AD, the proteotoxic stress response (PSR) is defective and can't effectively remove harmful aggregates. In such conditions, the forced activation of HSF1 and its targeted molecular chaperone proteins, such as HSPs, by using various plant-derived compounds, such as celastrol, curcumin, and resveratrol, has shown promising neuroprotective effects by eliminating protein aggregates across multiple AD models. Hence, this review focused on various plant-derived compounds and their mode of activating HSF1 and its encoded HSPs. This review also described other compounds from multiple natural sources that affect HSF1 and HSPs in different disease models. In this way, the current review will be a complete reference for natural compounds that activate HSF1 and help researchers identify potential drug candidates for NDs like Alzheimer's disease.

Keywords:  Alzheimer's disease; Clear protein aggregates; Modulators of HSF1; Natural compounds; Neuroprotection; Pathogenesis; Phytocompounds; Protein aggregates; UPS

DOI:  https://doi.org/10.1016/j.ejphar.2025.178034
bioRxiv. 2025 Jul 31. pii: 2025.07.30.667736. [Epub ahead of print]

Metabolic dysfunction promoted by mitochondrial DNA mutation burden drives retinal degeneration.

Johnathon Sturgis, Ke Jiang, Stephanie A Hagstrom, Maya Moorthy, Vera L Bonilha.

Retinal degenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma, have been linked to mitochondrial dysfunction. However, the impact of mitochondrial DNA (mtDNA) mutation accumulation in the context of these retinopathies has yet to be thoroughly explored. Our previous studies focused on the retinal phenotype observed in the PolgD257A mutator mice (D257A), revealing the effects of aging and mtDNA mutation accumulation in the retina. We have reported that this model exhibited significant morphological and functional deficits in the retina by 6 months of age, with notable alterations in the retinal pigment epithelium (RPE) occurring as early as 3 months, including changes in the cristae density and reduction in length of mitochondria. This study investigated how mtDNA mutations affect the metabolic interaction between the retina and RPE in young (3 months) and old (12 months) wild-type (WT) and D257A mice. We assessed cellular energy production using freshly dissected retina samples from both groups through Seahorse analysis, immunofluorescence, and Western blot experiments. The analysis of aged D257A retina punches revealed significantly reduced basal and maximal mitochondrial respiration, along with increased mitochondrial reserve capacity compared to WT. However, glycolytic flux, measured as a function of extracellular acidification rate (ECAR), did not differ between WT and D257A mice. Both D257A retina and RPE exhibited decreased expression of essential electron transport proteins involved in oxidative phosphorylation. Additionally, we observed a reduction in the expression of glucose transporter 1 (GLUT-1) and lactate transporter (MCT1) at the apical surface of the RPE. Enzymes associated with glycolysis, including hexokinase II and lactate dehydrogenase A, were significantly lower in the aged D257A retina, while hexokinase I and pyruvate kinase 2 were upregulated in the RPE. These findings indicate that the accumulation of mtDNA mutations leads to impaired metabolism in both the retina and RPE. Furthermore, it suggests that glucose from the choroidal blood supply is being utilized by the RPE rather than being transported to the neural retina. Mitochondrial dysfunction in RPE promotes a glycolytic state in these cells, leading to reduced availability of metabolites and, consequently, diminished overall retinal function. These results are essential for advancing our understanding of the mechanisms underlying retinal degeneration and provide a new perspective on the role of mtDNA mutations in these diseases.

DOI: https://doi.org/10.1101/2025.07.30.667736
Int J Endocrinol. 2025 ;2025 9943228

Effects and Safety of FGF21 Analogs on Glycemic Parameters, Lipid Profiles, and Adiponectin in Overweight and Obese Adults: A Meta-Analysis of Randomized Controlled Trials.

Zizheng Nie, Jiaoyang Xu, Yingying Liu, Qinglong Cao, Xinyi Qiu, Yiping Su, Shufen Han.

  Objective: Fibroblast growth factor 21 (FGF21) analogs have been used to improve glucose homeostasis and lipid metabolism; however, their effects remain contentious. The present meta-analysis aimed to review the effects and safety of FGF21 analogs on glycemic parameters, lipid profiles, and adiponectin (ADP) levels in overweight or obese adults. Methods: A systematic literature search for randomized controlled trials (RCTs) was conducted up to June 2025. A random-effects model or a common-effect model was used to calculate the mean difference (MD) or standardized MD (SMD), along with the corresponding 95% confidence intervals (CIs). Results: This meta-analysis including 11 RCTs showed that FGF21 analogs reduced triglycerides (MD = -59.33 mg/dL, 95% CI = -84.61 to -34.04), total cholesterol (MD = -17.14 mg/dL, 95% CI = -25.11 to -9.18), and low-density lipoprotein cholesterol (MD = -10.50 mg/dL, 95% CI = -14.42 to -6.59). Furthermore, FGF21 analogs increased high-density lipoprotein cholesterol (MD = 10.64 mg/dL, 95% CI = 6.23-15.05) and circulating ADP (MD = 3.18 μg/mL, 95% CI = 1.94-4.42). However, FGF21 analogs had no effect on fasting glucose (SMD = -0.22, 95% CI = -0.52 to 0.07) or insulin concentrations (SMD = -0.49, 95% CI = -1.04 to 0.06). Subgroup analyses revealed that the lipid-lowering effects varied among different FGF21 analogs. FGF21 treatment did not show any statistically significant difference in the incidence of serious side effects. Conclusions: We identified significant favorable effects of FGF21 analogs in improving lipid profiles and elevating circulating ADP levels in overweight and obese adults. Future studies are needed to evaluate the clinical benefits in this area of research.

Keywords:  FGF21; glycemic parameters; lipid profiles; meta-analysis; obesity

DOI:  https://doi.org/10.1155/ije/9943228
bioRxiv. 2025 Jul 30. pii: 2025.07.28.667247. [Epub ahead of print]

Sex-specific effects of chronic unpredictable stress on mitochondrial function in the HPA axis in mice.

Alexia M Crockett, Noelle I Frambes, Alaina Mullaly, Amelia M Churillo, Rinaldo R Dos Passos, Cameron Folk, Lisa Freeburg, Eliana Cavalli, Josephine Gardiner, Evelynn N Harrington, Timothy L Philbeck, Stephanie Wilczynski, Fernanda Priviero, Francis G Spinale, R Clinton Webb, Susan K Wood, Michael J Ryan, Fiona Hollis.

Stress, whether real or perceived, activates physiological and behavioral responses via the hypothalamic- pituitary-adrenal (HPA) axis and sympathetic nervous system activation. Under chronic stress, however, these adaptive responses become dysfunctional leading to pathological changes in behavior and health. Mitochondria are dynamic organelles essential for cellular energy production and for initiating glucocorticoid synthesis and release from adrenal glands during stress. Thus, mitochondria may represent a first line of response to environmental challenges. However, the effects of chronic stress on mitochondrial function within the HPA axis, particularly regarding sex differences, are unexplored. We exposed adult male and female C57BL6/J mice to four weeks of chronic unpredictable stress and examined behavioral and mitochondrial responses in the hypothalamus and adrenal glands - two key HPA axis regions. As previous reports indicated sex differences in stress responsivity, we hypothesized that chronic stress would differentially impact mitochondrial respiration within HPA axis regions in a sex-specific manner. Chronic stress increased avoidance behavior in males and passive coping behavior in females, indicating sex-specific behavioral responses. In females, stress significantly decreased mitochondrial respiration in both the hypothalamus and adrenal glands, while males were not significantly affected. In males, stress increased adrenal expression of mitochondrial complex II protein, which may have served a compensatory role to preserve mitochondrial function. Mitochondrial respiration significantly correlated with behavioral measures in stressed animals, highlighting a relationship between metabolism and stress-induced impairments. These findings reveal sex-specific metabolic adaptations to chronic stress and suggest that females may be more vulnerable to stress-induced mitochondrial dysfunction within the HPA axis.
Clinical Perspectives: Chronic stress is widely prevalent, associated with neuropsychiatric disease that affect women at a rate twice as high as men, and mediated by mitochondria, yet sex differences in the effects of chronic stress on mitochondrial function have not been characterized.Despite similar behavioral outcomes, chronic unpredictable stress exposure significantly decreases mitochondrial respiration only in the hypothalamus and adrenal glands from females, in association with stress-induced behavioral alterations.Females may have increased vulnerability to metabolic effects of chronic stress and therapies targeting mitochondrial function may be more efficacious in preventing behavioral impacts of stress in females.

DOI: https://doi.org/10.1101/2025.07.28.667247
J Mol Endocrinol. 2025 Aug 08. pii: JME-25-0056. [Epub ahead of print]

Chronic stress-secreted glucocorticoid induces NAFLD-like changes in male rats: Oxidative stress/NLRP3 inflammasome signalling.

Qi Shao, Chuxin Zhang, Jie Mu, Jing Ji, Changxiang Li, Chongyang Ma, Fafeng Cheng.

  To investigate the mechanism by which chronic stress (CS) induces non-alcoholic fatty liver disease (NAFLD)-like changes, and the role of oxidative stress and the NLRP3 inflammasome in this mechanism. Transcriptomic data extracted from the Sequence Read Archive (SRA) at the NCBI was employed to identify the molecular targets of the CS-induced NAFLD. Fifty 8-week-old healthy male Wistar rats were divided into five groups (n=10 each) as follows: control, CS, CS+Mifepristone (CS+Mif), CS+Metyrapone (CS+Met), and Corticosterone (Cort). The CS, CS+Mif, and CS+Met groups underwent restraint stress training. Rats in the CS+Mif, CS+Met, and Cort groups were administered with mifepristone, metyrapone, and corticosterone for 8 weeks. Data showed that CS induced NAFLD-like liver damage via increasing GC. Moreover, CS increased malonaldehyde (MDA) levels and decreased superoxide dismutase (SOD) activity in the liver and serum samples, suggesting the occurrence of oxidative stress. Furthermore, CS activated various inflammatory pathways via the NLRP3 inflammasome (NLRP3, ASC, caspase-1), which enhanced the cytokine levels (IL-1β, IL-6, TNF-α) in liver tissue. Notably, treatment with metyrapone or mifepristone alleviated liver lesions induced by CS, which implies that the GC signalling pathway may be an important mediator of stress-induced liver inflammation. In this study, we investigated the molecular mechanism underlying the CS-related NAFLD. GC mediates the development of oxidative stress and inflammation in the liver, and inhibition of the GC signalling may be a new therapeutic strategy.

Keywords:  ASC; Caspase-1; Chronic stress; MDA; NAFLD; SOD; Total cholesterol; Triglycerides

DOI:  https://doi.org/10.1530/JME-25-0056
J Biol Chem. 2025 Jul 31. pii: S0021-9258(25)02406-8. [Epub ahead of print] 110555

Cysteine Oxidation of a Redox Hub within Complex I can Facilitate Electron Transport Chain Supercomplex Formation.

Runtai Chen, Seyed Amirhossein Tabatabaei Dakhili, Rokas Geruskis, Yuan Yuan Zhao, Steven Lockhart, Lusine Tonoyan, Arno Siraki, Guocheng Huang, Adam Kinnaird, Darren H Freed, Shelley Minteer, Evangelos D Michelakis, John R Ussher, Gopinath Sutendra.

  The mitochondrial Electron Transport Chain (ETC) is a four complex unit that could be considered the most essential infrastructure within the mitochondria, as it primarily functions to generate the mitochondrial membrane potential (ΔΨm, the cells equivalent to battery capacity), which can then be utilized for ATP synthesis or heat production. Another important aspect of ETC function is the generation of mitochondrial reactive oxygen species (mtROS), which are essential physiologic signaling mediators that can be toxic to the cell if their levels become too high. Currently, it remains unresolved how a highly utilized and functioning ETC can sense excessive mtROS generation and adapt, to enhance ΔΨm. Here we identified a redox hub consisting of cysteine (Cys) residues 64, 75, 78 and 92 within Ndufs1 of complex I of the ETC. Oxidation of these Cys residues promotes the incorporation of complex I into the respirasome supercomplex. Mechanistically, oxidation of the redox hub increased the distance between Fe-S clusters N5 and N6a in complex I, compromising complex I activity. This impairment was rescued by integration with complex III2 and IV into the respirasome supercomplex. Compared to parental cells or Ndufs1-KO cells, C92D (an oxidation mimetic) Ndufs1-knockin A549 cells had higher levels of ETC supercomplexes, ΔΨm and oxygen consumption rates, while isolated mitochondrial membranes generated more electrical current when integrated onto a biobattery platform. Knockdown of complex III2 significantly reduced complex I activity (within the respirasome) from C92D Ndufs1-knockin cells, but not parental A549 cells. Finally, disruption of ETC supercomplexes with the small molecule drug MitoTam increased the therapeutic efficacy of mtROS inducing chemotherapeutics in both C92D Ndufs1-knockin or metastatic lung cancer cells. These findings provide new insights into how the ETC can initiate supercomplex transformation.

Keywords:  Cancer Resistance; Cysteine Oxidation; Electron Transport Chain; Mitochondria; Reactive Oxygen Species; Supercomplex

DOI:  https://doi.org/10.1016/j.jbc.2025.110555
Prog Brain Res. 2025 ;pii: S0079-6123(25)00066-4. [Epub ahead of print]295 259-284

Hormesis-induced neuroplasticity: Targeting neuroinflammation signaling cascades for therapeutic insights in aging and neurodegenerative diseases.

Thays Calista Santiago Pretes, Cristoforo Scavone.

  The signaling pathways associated with α-Klotho, glutamate, mediators of the inflammatory response in the central nervous system (CNS) and that related to different isoforms of the Na, K-ATPase (NKA) protein as a pump and receptor for endogenous steroids (ouabain-like hormones) are associated with neuroplasticity and neuroprotection. This neuroadaptive response induced by pharmacologic (Cardiotonic Steroids, Klotho, Resveratrol, Curcumin, and other Phytochemicals), and non-pharmacologic strategies (intermittent fasting and physical exercise) involves glial and neuronal cell crosstalk through activation of different intracellular pathways involving mediators, such as glutamate, cytokines, transcription factors, and gene expression which will exert a marked influence on the adaptive processes (neuroplasticity) that prevent premature aging, in addition to playing an essential role in cognition and neurodegenerative processes. The present text addresses the effect of these agents on the Central Nervous System (CNS), exploring neuroplasticity changes associated with the neuroinflammation induced by these mediators in the presence of a modified expression or signaling of the α-Klotho and the different α-isoforms of NKA. The studies involve in vitro approaches using models of neuronal and glial cells and in vivo studies with a behavioral and biochemical approach. Studies were also done in the presence (or absence) of changes in the expression of these proteins (by using vectors, interference RNA, and transgenic animals with specific protein-modified expression, such as TNF-α and Klotho). It has been also several human studies evaluating these hermetic strategies associated with physical exercise and intermittent diet. The present chapter discusses the benefit of these strategies in the induction of neuroadaptive response.

Keywords:  Aging; Hormesis; Neurodegenerative disorders; Neuroinflammation; Neuroplasticity

DOI:  https://doi.org/10.1016/bs.pbr.2025.05.008
Mol Metab. 2025 Aug 06. pii: S2212-8778(25)00135-8. [Epub ahead of print] 102228

Three-Dimensional Network of Creatine Metabolism: from Intracellular Energy Shuttle to Systemic Metabolic Regulatory Switch.

Yuhui Su.

   BACKGROUND: Creatine serves as an intracellular shuttle for high-energy phosphate bonds, enabling rapid ATP transfer from energy-producing to energy-consuming cellular compartments. In skeletal muscle, creatine coordinates energy distribution among mitochondrial oxidative phosphorylation, glycolysis, and the phosphagen system. Consequently, creatine supplementation acutely enhances muscular performance and is widely utilized as an ergogenic aid in power-based sports. Recent studies demonstrate that enhanced creatine metabolism in adipose tissue promotes brown adipocyte renewal and boosts energy expenditure in cold environments or sedentary conditions, thereby improving overall systemic metabolism. Beyond its traditional role as an exercise supplement, the creatine metabolic network has emerged as a promising therapeutic target for metabolic disorders.
SCOPE OF REVIEW: This review begins by revisiting the history and latest advancements in creatine research, and ultimately proposes three dimensions for the current explanation of creatine metabolism: (1) subcellular energy transport; (2) muscle-fat metabolic axis; (3) systemic energy sensing and metabolic reprogramming.
MAJOR CONCLUSIONS: The creatine cycle enables directed energy flow through mitochondrial supercomplexes (VDAC/ANT-CK) and resets systemic metabolism via subcellular energy tunnels and inter-organ interactions. Creatine kinase (CK) condensates, through liquid-liquid phase separation, can rapidly meet energy demands during exercise. Therefore, targeting the dynamics of the CK phase may be promising for enhancing athletic performance and improving metabolic diseases.

Keywords:  Creatine; Energy metabolism; Exercise; Metabolic diseases; Phase separation; Thermogenesis

DOI:  https://doi.org/10.1016/j.molmet.2025.102228
J Microbiol Biotechnol. 2025 Aug 05. 35 e2504039

Protective Effect of N-Acetylcysteine (NAC) on oxLDL-Induced Endothelial Dysfunction.

Chathuri K Marasinghe, Indyaswan Tegar Suryaningtyas, Won-Kyo Jung, Jae-Young Je.

  N-acetylcysteine (NAC), a well-known antioxidant and glutathione precursor, has been extensively studied for its free radical-scavenging properties, anti-inflammatory effects, and ability to enhance cellular redox balance. NAC has also been shown to mitigate oxidative damage in various disease models, yet its role in endothelial dysfunction remains underexplored. In this study, we evaluated the ability of NAC to counteract oxLDL-induced endothelial dysfunction in human umbilical vein endothelial cells (HUVECs). NAC treatment significantly reduced ROS levels, lipid peroxidation, and apoptotic markers while restoring mitochondrial membrane potential (MMP) and NO bioavailability. Additionally, NAC regulated the expression of eNOS, LOX-1, ICAM-1, and VCAM-1, demonstrating its role in reducing endothelial inflammation and improving vascular homeostasis. Furthermore, NAC prevented excessive cholesterol accumulation, suggesting its potential to regulate lipid metabolism in endothelial cells. These findings highlight the therapeutic potential of NAC in protecting against oxLDL-induced endothelial dysfunction and preventing vascular complications associated with cardiovascular diseases.

Keywords:  Endothelial dysfunction; N-acetylcysteine; cardiovascular diseases; oxLDL; oxidative stress

DOI:  https://doi.org/10.4014/jmb.2504.04039
Arch Physiol Biochem. 2025 Aug 05. 1-17

Mechanistic insights into ubiquinone Q10 in Parkinson's disease: mitochondrial protection, ferroptosis inhibition, and antioxidant recycling.

Mohamed J Saadh, Tamara Nazar Saeed, Ali Fawzi Al-Hussainy, Ashishkumar Kyada, Suhas Ballal, Mayank Kundlas, A Sabarivani, Jasur Rizaev, Sada Ghalib Taher, Mariem Alwan, Mahmood Jawad, Hiba Mushtaq.

   BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder characterised by the loss of dopaminergic neurons in the substantia nigra. Although the exact cause of Parkinson's disease is still unknown, neuroinflammation and mitochondrial dysfunction have been identified as essential factors in the disease's pathophysiology.
METHODS: Coenzyme Q10 has gathered considerable attention as a potential therapeutic agent due to its dual function in antioxidant defense and mitochondrial bioenergetics. It is an essential electron carrier in the mitochondrial electron transport chain and plays a crucial role in reducing oxidative stress, a primary cause of neuronal degeneration in Parkinson's disease.
RESULTS: Coenzyme Q10 supplements can enhance mitochondrial activity, reduce oxidative stress, and protect dopaminergic neurons from degeneration. To improve Coenzyme Q10 formulations and ascertain its effectiveness in slowing the progression of Parkinson's disease, more study is required.
CONCLUSION: This review examines the neuroprotective mechanisms of Coenzyme Q10 and its potential as a therapeutic option for Parkinson's disease.

Keywords:  CoQ10; Parkinson’s disease; coenzyme Q10; mitochondrial dysfunction; neuroprotective therapies

DOI:  https://doi.org/10.1080/13813455.2025.2541698
J Biol Chem. 2025 Jul 31. pii: S0021-9258(25)02402-0. [Epub ahead of print] 110551

Mechanisms of mitochondrial reactive oxygen species action in bone mesenchymal cells.

Md Mohsin Ali, Intawat Nookaew, Ana Resende-Coelho, Adriana Marques-Carvalho, Aaron Warren, Qiang Fu, Ha-Neui Kim, Charles A O'Brien, Maria Almeida.

  Mitochondrial reactive oxygen species (mtROS), insufficient NAD+, and cellular senescence all contribute to the decrease in bone formation with aging. ROS can cause senescence and decrease NAD+, but it remains unknown whether these mechanisms mediate the effects of ROS in vivo. Here, we generated mice with deletion of the mitochondrial antioxidant enzyme Sod2 in Osx1-Cre (Sp7-tTA,tetO-EGFP/cre) targeted cells designated Sod2ΔOsx1 mice. We showed that Sod2 deletion caused low bone mass. Osteoblastic cells from these mice had impaired mitochondrial respiration and attenuated NAD+ levels. Administration of an NAD+ precursor improved mitochondrial function in vitro but failed to rescue the low bone mass of Sod2ΔOsx1 mice. Single-cell RNA-sequencing of bone mesenchymal cells indicated that ROS had no significant effects on markers of senescence but disrupted parathyroid hormone signaling, iron metabolism, and proteostasis. Our data support the rationale that treatment combinations aimed at decreasing mtROS and senescent cells and increasing NAD+ should confer additive effects in delaying age-associated osteoporosis.

Keywords:  NAD+; Skeletal aging; cellular senescence; mitochondrial dysfunction; nicotinamide riboside; proteostasis; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.jbc.2025.110551
bioRxiv. 2025 Aug 01. pii: 2025.07.30.667787. [Epub ahead of print]

Mitochondrial Response to Psychological Stress and Its Medial Prefrontal Biomarker Correlates.

Ankeeta Ankeeta, Ashutosh Tripathi, Yizhou Ma, Bindu Pillai, Joshua J Chiappelli, Jennifer N Jernberg, Keiko Kunitoki, Bhim M Adhikari, Si Gao, Xiaoming Du, Loise Kabui, Francisco Pallares Solano, Oluwabunmi Akindona, Zhenyao Ye, Shuo Chen, Mohammad Milad, Peter Kochunov, Anilkumar R Pillai, Elliot L Hong.

BACKGROUND: Stress response obligates increased mitochondrial activities to meet stress induced high energy requirement. This stress mitochondrial response process involves glucocorticoid but also multiple alternative pathways that are top down regulated by the medial prefrontal cortex (mPFC). These pathways are important for many neuropsychiatric conditions that are sensitive to stress. However, the field lacks a reliable, clinically accessible stress mitochondrial response paradigm to study the process in humans.
METHOD: We used an established psychological stress challenge combined with assaying salivary cell-free mitochondrial DNA (cf mtDNA), thought to reflect heightened mitochondrial changes or disruptions, in 35 healthy individuals (21 males). We also explored if these stress induced cf mtDNA marker elevations were associated brain metabolites as measured by magnetic resonance spectroscopy (MRS), as well as high resolution brain imaging based cortical thickness focusing on the mPFC.
RESULTS: We found that salivary cf mtDNA was significant elevated immediately after the stress challenge (p=2.0x10-7) and gradually declined after. Exploratory causal analysis showed that this cf mtDNA response was not primarily driven by cortisol response. Instead, individuals with higher baseline dACC lactate+ levels, thought to in part reflect mitochondrial dysfunctions, was significantly associated with the cf mtDNA response (r=0.80, p<0.001). Higher mtDNA response was also significantly associated with thinner dorsomedial prefrontal cortex (r=-0.52, p=0.01). Age had a U-shape effect such that cf mtDNA response trended lower in earlier adulthood but higher in older people, explaining 33.8% of the ct mtDNA response variance (p=0.003).
CONCLUSION: This stress challenge-salivary cf mtDNA assay paradigm may offer a new, noninvasive approach to evaluate the stress-mitochondrial pathway functioning in aging, psychopharmacology, and neuropsychiatric conditions where psychological stress plays a role.

DOI: https://doi.org/10.1101/2025.07.30.667787
Nature. 2025 Aug 06.

Lithium deficiency and the onset of Alzheimer's disease.

Liviu Aron, Zhen Kai Ngian, Chenxi Qiu, Jaejoon Choi, Marianna Liang, Derek M Drake, Sara E Hamplova, Ella K Lacey, Perle Roche, Monlan Yuan, Saba S Hazaveh, Eunjung A Lee, David A Bennett, Bruce A Yankner.

The earliest molecular changes in Alzheimer's disease (AD) are poorly understood1-5. Here we show that endogenous lithium (Li) is dynamically regulated in the brain and contributes to cognitive preservation during ageing. Of the metals we analysed, Li was the only one that was significantly reduced in the brain in individuals with mild cognitive impairment (MCI), a precursor to AD. Li bioavailability was further reduced in AD by amyloid sequestration. We explored the role of endogenous Li in the brain by depleting it from the diet of wild-type and AD mouse models. Reducing endogenous cortical Li by approximately 50% markedly increased the deposition of amyloid-β and the accumulation of phospho-tau, and led to pro-inflammatory microglial activation, the loss of synapses, axons and myelin, and accelerated cognitive decline. These effects were mediated, at least in part, through activation of the kinase GSK3β. Single-nucleus RNA-seq showed that Li deficiency gives rise to transcriptome changes in multiple brain cell types that overlap with transcriptome changes in AD. Replacement therapy with lithium orotate, which is a Li salt with reduced amyloid binding, prevents pathological changes and memory loss in AD mouse models and ageing wild-type mice. These findings reveal physiological effects of endogenous Li in the brain and indicate that disruption of Li homeostasis may be an early event in the pathogenesis of AD. Li replacement with amyloid-evading salts is a potential approach to the prevention and treatment of AD.

DOI: https://doi.org/10.1038/s41586-025-09335-x
Sci Rep. 2025 Aug 07. 15(1): 28975

NMN improves cardiac function in SIRT3 knockout mice via the SIRT1/PGC-1α pathway.

Xiyao Zhao, Mengrui He, Lina He, Ruijie Han, Yanan Liu.

  SIRT3 knockout mice develop cardiac insufficiency due to decreased mitochondrial function. However, upregulation of the NAD+/NADH ratio can compensate for SIRT3 deficiency through the SIRT1/PGC-1α pathway, thereby improving mitochondrial function. We therefore hypothesized that upregulation of SIRT1 expression could improve cardiac function in SIRT3 knockout mice through its interactive compensatory effect. We first determined that SIRT3 knockout mice would develop cardiac insufficiency at 8 weeks of age by ultrasound cardiac function testing, and then we selected 6-week-old SIRT3 knockout mice with similar body weights of both sexes and performed intraperitoneal injections of NMN over a 14-day period to increase the content of NAD + in the myocardial tissue of the mice. The results showed that NMN injection effectively increased the NAD + content as well as the NAD+/NADH ratio within the myocardial tissue of SIRT3 knockout mice and stimulated the expression of SIRT1 protein. In addition, protein expression of PGC-1α and its downstream molecules as well as molecules related to subunits of the respiratory chain complex was increased in mouse myocardial mitochondria. Meanwhile, NMN injection improved the cardiomyocyte and mitochondrial structure of mice, ultimately ameliorating cardiac insufficiency in SIRT3 knockout mice. In conclusion, our results suggest that NMN can compensate for SIRT3 deficiency via the SIRT1/PGC-1α pathway and improve mitochondrial biosynthesis and oxidative respiration, thereby improving cardiac function in Sirt3-/- mice. This may provide new ideas for the clinical treatment of cardiac insufficiency.

Keywords:  Mitochondria; NMN; PGC-1α; sirt3 knockdown

DOI:  https://doi.org/10.1038/s41598-025-14349-6