bims-mistre Biomed News
on Mito stress
Issue of 2025–08–17
seventeen papers selected by
Ellen Siobhan Mitchell, MitoQ
  1. Mitochondrial Dysfunction in Aging and Age-related Disorders.
  2. Biopsychosocial correlates of resting and stress-reactive salivary GDF15: preliminary findings.
  3. ROS-dependent localization of glycolytic enzymes to mitochondria.
  4. Mitochondrial sirtuins, key regulators of aging.
  5. Brain myelin as a deficient energy source in aging and disease.
  6. Predictors of powerhouse: a perspective of mitochondrial biomarkers in type 2 diabetes.
  7. The Roles of Lactate and Lactylation in Diseases Related to Mitochondrial Dysfunction.
  8. Mitochondrial Metabolism in T-Cell Exhaustion.
  9. Integrative effects of Telomere Length, Epigenetic Age, and Mitochondrial DNA abundance in Alzheimer's Disease.
  10. Mitochondrial dysfunction in oocytes: implications for fertility and ageing.
  11. cGAS-STING axis: A central regulator of neural homeostasis and neuroinflammatory pathogenesis.
  12. Impaired Mitochondrial DNA Copy Number in Visceral Adipose Tissue of Insulin-Resistant Individuals: Implications for Metabolic Dysregulation.
  13. Mitochondrial energy production genes affecting reactive oxygen species and ATP synthesis, inflammatory pathways, and neuron viability are differentially expressed in brains of Alzheimer's disease patients.
  14. Molecular Links Between Metabolism and Mental Health: Integrative Pathways from GDF15-Mediated Stress Signaling to Brain Energy Homeostasis.
  15. Energy deprivation in youth and old age.
  16. Mechanistic insights into heart failure induction in ovariectomized rats: The role of mitochondrial dysfunction.
  17. Estrogens protect bone mass by inhibiting NAD + metabolism in osteoclasts.
  1. Aging Dis. 2025 Jul 31. 16(5): 2495-2497
    Mitochondrial Dysfunction in Aging and Age-related Disorders.
    Aida Adlimoghaddam.
      Mitochondrial dysfunction is increasingly recognized as a unifying mechanism underlying aging and a wide range of age-related diseases. This special issue brings together recent advances that elucidate how impaired mitochondrial function contributes to neurodegenerative, cardiovascular, and metabolic disorders. The featured articles highlight molecular pathways of mitochondrial decline, its systemic consequences, and potential interventions aimed at restoring mitochondrial health. Collectively, these studies reinforce the concept that targeting mitochondrial integrity holds significant promise for promoting healthy aging and preventing chronic disease.
    DOI:  https://doi.org/10.14336/AD.2025.10731
  2. Brain Behav Immun. 2025 Aug 07. pii: S0889-1591(25)00302-2. [Epub ahead of print] 106068
    Biopsychosocial correlates of resting and stress-reactive salivary GDF15: preliminary findings.
    Cynthia C Liu, Caroline Trumpff, Qiuhan Huang, Robert-Paul Juster, Martin Picard.
      Growth differentiation factor 15 (GDF15) is a biomarker of energetic stress related to aging, disease, and mitochondrial defects. We recently showed that GDF15 is quantifiable in saliva and acutely inducible by psychosocial stress. To date, the associations between GDF15 and biopsychosocial factors and individual characteristics remain unknown. Here, in a sample of healthy working adults (n = 198, 70 % females), we first confirmed that salivary GDF15 reacts to acute psychosocial stress, peaking 10 min following a socio-evaluative stress paradigm (+28.3 %, g = 0.50, p < 0.0001). We then explored associations between i) resting/baseline GDF15 and ii) GDF15 stress reactivity and a variety of trait- and state-level biopsychosocial factors including sex and gender characteristics; measures of mental health, stress, and burnout; physical health and health behaviors; and anthropometric and blood-based metabolic biomarkers. Baseline salivary GDF15 was higher in men than in women and was positively correlated with testosterone, while negatively correlated with estrogen and traditionally feminine gender roles. Of the psychosocial factors examined, we found that work-related stress variables were most consistently related to GDF15, with work-related cynicism, burnout, and emotional exhaustion predicting higher GDF15 reactivity, while job-related autonomy and utilization of competence predicted smaller GDF15 responses. Consistent with GDF15's induction in metabolic and renal diseases, baseline GDF15 was also positively correlated with indirect markers of metabolic disease including waist-to-hip ratio, creatinine, and albumin. Finally, participants with greater GDF15 reactivity also exhibited greater cortisol reactivity, consistent with the role of GDF15 in stress regulation and energy mobilization. Together, this exploratory analysis of salivary GDF15 suggest new biological and psychosocial correlates, calling for large-scale studies connecting human experiences with biological markers of energetic stress.
    Keywords:  GDF15; Metabokine; Mitochondria; Psychobiology; Psychophysiology; Sex/gender; Stress response; Trier social stress test – TSST
    DOI:  https://doi.org/10.1016/j.bbi.2025.106068
  3. Redox Biol. 2025 Aug 12. pii: S2213-2317(25)00325-8. [Epub ahead of print]86 103812
    ROS-dependent localization of glycolytic enzymes to mitochondria.
    Pau B Esparza-Moltó, Arvind V Goswami, Süleyman Bozkurt, Christian Münch, Laura E Newman, Alexandra G Moyzis, Gladys R Rojas, Deann Guan, Jeffrey R Jones, Fred H Gage, Gerald S Shadel.
      Mitochondrial reactive oxygen species (mtROS) regulate cellular signaling pathways, but also cause oxidative stress when de-regulated during aging and pathological conditions such as neurodegenerative diseases. The dynamic redistribution of proteins between cellular compartments is a common mechanism to control their stability and biological activities. By targeting the BirA∗ biotin ligase to the outer mitochondrial membrane in HEK293 cells, we identified proteins whose labeling increased or decreased in response to treatment with menadione, consistent with a dynamic change in their mitochondrial localization in response to increased mtROS production. These proteins represent potential candidates for future studies of mitochondrial oxidative stress signaling. A subset of glycolytic enzymes was found in this screen and confirmed, by mitochondrial fractionation and imaging, to increase localization to mitochondria in response to menadione, despite no change in their overall abundance. Submitochondrial fractionation studies are consistent with import of a pool of these enzymes to the mitochondrial intermembrane space. Localization of glycolytic enzymes to mitochondria was also increased in cells grown under hypoxia or that express a mitochondria-targeted d-amino-acid oxidase (conditions that induce increased mtROS production), and inhibited basally under normal growth conditions by the mitochondrial antioxidant MnTBAP. Finally, primary Alzheimer's disease fibroblasts also had glycolytic enzymes associated with mitochondria that was reduced by antioxidants, consistent with increased mtROS altering their relative distribution between the cytoplasm and mitochondria. We speculate that the increased mitochondrial localization of glycolytic enzymes is an adaptive response to mtROS that alters glucose flux toward the antioxidant pentose phosphate pathway, creates distinct regulatory pools of mitochondrial metabolites or new metabolic circuits, and/or provides cytoprotection or other adaptive responses via moonlighting functions unrelated to their enzymatic activity.
    Keywords:  Alzheimer's disease; Glycolytic enzymes; Mitochondria; Proximity labeling; Reactive oxygen species; Stress signaling
    DOI:  https://doi.org/10.1016/j.redox.2025.103812
  4. Life Med. 2025 Aug;4(4): lnaf019
    Mitochondrial sirtuins, key regulators of aging.
    Zhejun Ji, Guang-Hui Liu, Jing Qu.
      Mitochondrial dysfunction is a hallmark of aging, characterized by a decline in mitochondrial biogenesis and quality control, compromised membrane integrity, elevated ROS production, damaged mitochondrial DNA (mtDNA), impaired mitochondrial-nuclear crosstalk, and deregulated metabolic balance. Among the key longevity regulators, sirtuin family members SIRT3, SIRT4, and SIRT5 are predominantly localized to mitochondria and play crucial roles in maintaining mitochondrial function and homeostasis. This review explores how mitochondrial sirtuins mitigate aging-related mitochondrial dysfunctions and their broader implications in aging-related diseases. By elucidating the intricate interplay between mitochondrial dysfunction and mitochondrial sirtuins, we aim to provide insights into therapeutic strategies for promoting healthy aging and combating age-related pathologies.
    Keywords:  aging; mitochondrial dysfunction; mitochondrial sirtuins
    DOI:  https://doi.org/10.1093/lifemedi/lnaf019
  5. Trends Endocrinol Metab. 2025 Aug 12. pii: S1043-2760(25)00152-3. [Epub ahead of print]
    Brain myelin as a deficient energy source in aging and disease.
    Carlos Matute, Alexei Verkhratsky.
      Central nervous system (CNS) myelin may act as a dynamic energy store that supports brain metabolism; its consumption and replenishment is a newly recognized form of metabolic plasticity aimed at maintaining brain function upon limited glucose supply. In this forum article we propose that myelin dysfunctions may affect human health in aging and neurodegenerative diseases.
    Keywords:  aging; energy metabolism; myelin; neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.tem.2025.07.006
  6. Front Endocrinol (Lausanne). 2025 ;16 1595557
    Predictors of powerhouse: a perspective of mitochondrial biomarkers in type 2 diabetes.
    Mónica Muñoz-Úbeda, Surjya Narayan Dash.
      Mitochondria play a critical role in maintaining the metabolic balance of the cell. The onset and progression of diabetes have been linked to mitochondrial dysfunction, leading to oxidative stress and dysregulation of metabolic intermediates, ultimately leading to a loss of energy production. Mitochondria play a crucial role in glucose stimulated-insulin secretion in pancreatic β-cells and oxidative phosphorylation in beta cells and skeletal muscles. In type-2 diabetes, impaired oxidative phosphorylation and insulin release is linked to insulin resistance (IR). Given the possible involvement of mitochondrial activity in the pathophysiology of diabetes, it would be highly desirable to investigate possible biomarkers or indicators that may provide details on the onset, severity or progression of the disease. The use of biomarkers is essential both for the diagnosis of mitochondrial diseases and for monitoring their metabolic status. The discovery and characterization of numerous biomarkers that correlate with mitochondrial diseases has led to the development of a number of new biomarkers. Biomarkers associated with human mitochondrial dysfunction are critical for the development of targeted therapies and early diagnosis of diabetes. Based on an investigation of the literature, this perspective outlines the state of knowledge on mitochondrial biomarkers and examines the data supporting their application in the early diagnosis, prognosis, and monitoring of diabetes.
    Keywords:  insulin resistance; metabolic syndrome; mitochondrial biomarkers; mitochondrial dysfunction; type-2 diabetes
    DOI:  https://doi.org/10.3389/fendo.2025.1595557
  7. Int J Mol Sci. 2025 Jul 24. pii: 7149. [Epub ahead of print]26(15):
    The Roles of Lactate and Lactylation in Diseases Related to Mitochondrial Dysfunction.
    Fei Ma, Wei Yu.
      Glycolysis and oxidative phosphorylation are the main pathways of cellular energy production. Glucose is metabolized via glycolysis to generate pyruvate, which, under anaerobic conditions, is converted into lactate, while, under aerobic conditions, pyruvate enters mitochondria for oxidative phosphorylation to produce more energy. Accordingly, mitochondrial dysfunction disrupts the energy balance. Lactate, historically perceived as a harmful metabolic byproduct. However, emerging research indicates that lactate has diverse biological functions, encompassing energy regulation, epigenetic remodeling, and signaling activities. Notably, the 2019 study revealed the role of lactate in regulating gene expression through histone and non-histone lactylation, thereby influencing critical biological processes. Metabolic reprogramming is a key adaptive mechanism of cells responding to stresses. The Warburg effect in tumor cells exemplifies this, with glucose preferentially converted to lactate for rapid energy, accompanied by metabolic imbalances, characterized by exacerbated aerobic glycolysis, lactate accumulation, suppressed mitochondrial oxidative phosphorylation, and compromised mitochondrial function, ultimately resulting in a vicious cycle of metabolic dysregulation. As molecular bridges connecting metabolism and epigenetics, lactate and lactylation offer novel therapeutic targets for diseases like cancer and neurodegenerative diseases. This review summarizes the interplay between metabolic reprogramming and mitochondrial dysfunction, while discussing lactate and lactylation's mechanistic in the pathogenesis of related diseases.
    Keywords:  epigenetics; lactate; lactylation; metabolic reprogramming; mitochondrial dysfunction
    DOI:  https://doi.org/10.3390/ijms26157149
  8. Int J Mol Sci. 2025 Jul 31. pii: 7400. [Epub ahead of print]26(15):
    Mitochondrial Metabolism in T-Cell Exhaustion.
    Fei Li, Yu Feng, Zesheng Yin, Yahong Wang.
      T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion.
    Keywords:  T-cell exhaustion; metabolic reprogramming; metabolism; mitochondria; mitochondrial dynamics
    DOI:  https://doi.org/10.3390/ijms26157400
  9. medRxiv. 2025 Jul 17. pii: 2025.07.16.25331683. [Epub ahead of print]
    Integrative effects of Telomere Length, Epigenetic Age, and Mitochondrial DNA abundance in Alzheimer's Disease.
    Alzheimer’s Disease Neuroimaging Initiative
       Background and Objectives: Biological age, reflecting the cumulative molecular and cellular damage such as telomere attrition, epigenetic alterations and mitochondrial dysfunction, may better capture age-related decline and Alzheimer's disease (AD) risk than chronological age. Most studies have focused on one measure of biological age and not investigated joint or interactive contributions to AD pathogenesis.
    Methods: We estimated blood-derived telomere length (TL) via qPCR, epigenetic age (DNAm age) using the CausAge clock, and mitochondrial DNA copy number (mtDNAcn) from whole genome sequencing in 640 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI; Age: 74.91±7.56, Female: 44.8%, Cognitively Unimpaired: 34.3%, Mild Cognitive Impairment: 52%, AD: 12.9%). Linear mixed-effects models examined the associations and interactions of these markers with cognitive decline for memory, executive function, language ability, visuospatial ability, and global cognition, while linear regression tested associations with cross-sectional AD biomarkers (CSF Aβ 42 , total-tau, pTau 181 , and meta-ROI for cortical thickness and gray matter volume). Models adjusted for baseline age, sex, clinical dementia rating scale, APOE , blood cell composition, and outcome-specific covariates (education and intracranial volume).
    Results: Individually, TL and DNAm age, were not associated with cognition, CSF biomarkers, or neuroimaging outcomes, while higher mtDNAcn was associated with lower CSF tau and ptau 181 . Interaction models revealed that mtDNAcn modified the effects of both TL and DNAm age: at higher mtDNAcn, shorter TL predicted poorer global cognition (β = 0.033 ± 0.014, p = 0.020) and older DNAm age predicted poorer language performance (β = -0.059 ± 0.028, p = 0.038). A significant three-way interaction showed that the combination of higher mtDNAcn, longer TL, and older DNAm age was associated with lower grey-matter volume.
    Discussion: These findings suggest that increased mtDNAcn may act as a compensatory response to accelerated epigenetic aging and telomere attrition. Our results underscore the importance of evaluating the interplay among multiple biological aging markers when investigating AD pathogenesis.
    DOI:  https://doi.org/10.1101/2025.07.16.25331683
  10. J Ovarian Res. 2025 Aug 14. 18(1): 186
    Mitochondrial dysfunction in oocytes: implications for fertility and ageing.
    Tong Wang, Peixin Xu, Jianlong Yuan, Hong Chen, Xin Guo, Jing Gao, Yurong Wang, Dongmei Yao, Xin Li, Bingchun Liu, Yang Liu.
      The impact of environmental pollution on fertility has become an essential issue in global public health. Maturation, fertilisation, and embryonic development of oocytes depend on the energy provided by mitochondria; however, with increased environmental pollution and ageing, mitochondrial dysfunction and its subsequent functional and metabolic abnormalities have become leading causes of female fertility decline. When mitochondrial dysfunction occurs in the oocyte, reduced metabolic efficiency leads to impaired nuclear and cytoplasmic maturation of the oocyte, affecting the quality of the oocyte, which further contributes to decreased female fertility and increased risk of infertility, miscarriage, and aneuploid foetuses due to ovarian dysfunction. Several factors affect mitochondrial function, including excess reactive oxygen species (ROS)-induced mutations in mitochondrial DNA (mtDNA), changes in mtDNA copy number, oxidative stress (OS), damage to key cellular components and organelles, and changes in metabolic intermediates and byproducts at the cellular level, further affecting oocyte developmental competence. Mitochondrial dysfunction leads to problems such as abnormal spindle formation and chromosome misalignment, reducing fertilisation potential and embryonic developmental capacity. Mitochondrial dysfunction plays a key role in oocyte ageing and the decline in germ cell function, and an in-depth study of its molecular mechanisms and intervention strategies is highly important for slowing oocyte ageing, increasing fertility, and improving the success rate of assisted reproduction techniques. Clinical trial numberNot applicable.
    DOI:  https://doi.org/10.1186/s13048-025-01764-6
  11. Neural Regen Res. 2025 Aug 13.
    cGAS-STING axis: A central regulator of neural homeostasis and neuroinflammatory pathogenesis.
    Jiajie Zhang, Jiarui Li, Yanan Li, Chunxiao Liu, Lei Shi, Yuxuan Qian, Qian Chen, Qi Zhang.
      An increasing amount of evidence shows that type I interferon response, which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and stimulator of interferon genes (STING) is closely associated with health and neuroinflammatory diseases. Abnormal activation or loss of control of the cGAS-STING axis affects the development of neuroinflammation. Thus, we examined its role in major neurological diseases, including traumatic brain injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, herpes simplex encephalitis, and ataxia-telangiectasia. Additionally, targeted intervention of the cGAS-STING axis to control neuroinflammation and treat related diseases has become the focus of current clinical research. This article describes the development of cGAS inhibitors and small molecules that target the cGAS-STING axis and explores the potential applications of STING inhibitors and agonists in clinical research. In summary, the cGAS-STING axis may impact neurological diseases more than a single protein or gene. Future studies should focus on elucidating the functional dynamics and regulatory networks of this axis and delineating its crosstalk with other signaling cascades. These investigations will provide mechanistic insights for developing targeted therapeutic strategies for associated disorders and potentially facilitate drug repurposing across diverse disease contexts.
    Keywords:  NLRP3; astrocytes; cGAS-STING axis; microglia; mitochondrial DNA; neurodegeneration; neuroimmunology; neuroinflammation; neurological disorders; small molecule inhibitors; type I interferon
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00367
  12. Int J Mol Sci. 2025 Jul 31. pii: 7398. [Epub ahead of print]26(15):
    Impaired Mitochondrial DNA Copy Number in Visceral Adipose Tissue of Insulin-Resistant Individuals: Implications for Metabolic Dysregulation.
    Monika Ołdakowska, Aneta Cierzniak, Tomasz Jurek, Małgorzata Małodobra-Mazur.
      Insulin resistance is a fundamental pathophysiological mechanism contributing to the development of type 2 diabetes and metabolic syndrome. Recently, attention has focused on mitochondria's role in glucose and lipid metabolism. Mitochondrial dysfunction is strongly associated with impaired energy metabolism and elevated oxidative stress. We investigated the mitochondrial DNA (mtDNA) copy number in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in insulin-sensitive (IS) and insulin-resistant (IR) individuals. Twenty-seven paired adipose tissue biopsies were obtained during elective abdominal surgery. DNA and RNA were extracted, and mtDNA copy number was quantified using Real-Time PCR. We found that mtDNA content in VAT was approximately two-fold lower than in SAT. Furthermore, in IR individuals, mtDNA copy number was significantly reduced in both SAT and VAT compared to IS subjects. A strong positive correlation was observed between mtDNA content in VAT and body mass index (BMI), and a negative correlation was found with the QUICKI index. Additionally, mtDNA copy number in VAT positively correlated with the expression of several genes involved in insulin signalling, lipid metabolism, and other metabolic pathways. These findings underscore the central role of mitochondrial function in VAT in the context of metabolic disorders and suggest that targeting mitochondrial regulation in this tissue may represent a promising therapeutic approach.
    Keywords:  insulin resistance; mitochondrial DNA (mtDNA); subcutaneous adipose tissue; visceral adipose tissue
    DOI:  https://doi.org/10.3390/ijms26157398
  13. J Alzheimers Dis. 2025 Aug 13. 13872877251362884
    Mitochondrial energy production genes affecting reactive oxygen species and ATP synthesis, inflammatory pathways, and neuron viability are differentially expressed in brains of Alzheimer's disease patients.
    Haley Pflanzer, Kimberly A Kerns, Joseph Knoble, Blake S Gershon, Jason Shugoll, Morgan Shelton, Randolph A Coleman, Frank J Castora.
      BackgroundWe have previously reported that a subset of nuclear-encoded mitochondrial genes involved in mitochondrial biogenesis was differentially expressed in Alzheimer's disease (AD) brains. These were associated with compromised biological pathways of mitochondria such as mitochondrial morphology, fragmentation, transmembrane potential and neuronal cell death.ObjectiveTo use an array of energy production genes to determine whether expression changes compromise mitochondrial function and other important biological processes or pathways impacting the development of AD.MethodsRT2-PCR arrays were used to assess expression of mitochondrial energy production genes in AD brains. A subset of genes of interest was identified using Ingenuity Pathway Analysis. Expression values from this filtered group of genes were included in a mathematical model being developed to identify potential therapeutic targets for AD.ResultsA majority of these genes was downregulated in AD brains. These AD-related gene expression changes were seen to affect a number of biological functions and pathologic conditions, including synthesis of ATP, generation of reactive oxygen species (ROS), and nerve cell viability. Most importantly, UQCRC1, an essential component of RCIII that is also involved in efficient assembly of the mitochondrial respirasome, was identified by our array analysis and, subsequently implicated by inclusion in our mathematical model to be a potential therapeutic target.ConclusionsThere are significant gene expression changes in a small number of nuclear-encoded mitochondrial genes involved in energy production in AD brains. These affect ROS and nucleotide synthesis and pro- and anti-inflammatory pathways and reflect the mitochondrial dysfunction associated with neuronal cell death and AD.
    Keywords:  Alzheimer's disease; energy production; neuronal cell viability; nucleotide synthesis; oxidative phosphorylation; respiratory complex I; respiratory complex III; respiratory complex IV; respiratory complex V
    DOI:  https://doi.org/10.1177/13872877251362884
  14. Int J Mol Sci. 2025 Aug 06. pii: 7611. [Epub ahead of print]26(15):
    Molecular Links Between Metabolism and Mental Health: Integrative Pathways from GDF15-Mediated Stress Signaling to Brain Energy Homeostasis.
    Minju Seo, Seung Yeon Pyeon, Man S Kim.
      The relationship between metabolic dysfunction and mental health disorders is complex and has received increasing attention. This review integrates current research to explore how stress-related growth differentiation factor 15 (GDF15) signaling, ceramides derived from gut microbiota, and mitochondrial dysfunction in the brain interact to influence both metabolic and psychiatric conditions. Evidence suggests that these pathways converge to regulate brain energy homeostasis through feedback mechanisms involving the autonomic nervous system and the hypothalamic-pituitary-adrenal axis. GDF15 emerges as a key stress-responsive biomarker that links peripheral metabolism with brainstem GDNF family receptor alpha-like (GFRAL)-mediated anxiety circuits. Meanwhile, ceramides impair hippocampal mitochondrial function via membrane incorporation and disruption of the respiratory chain. These disruptions may contribute to sustained pathological states such as depression, anxiety, and cognitive dysfunction. Although direct mechanistic data are limited, integrating these pathways provides a conceptual framework for understanding metabolic-psychiatric comorbidities. Furthermore, differences in age, sex, and genetics may influence these systems, highlighting the need for personalized interventions. Targeting mitochondrial function, GDF15-GFRAL signaling, and gut microbiota composition may offer new therapeutic strategies. This integrative perspective helps conceptualize how metabolic and psychiatric mechanisms interact for understanding the pathophysiology of metabolic and psychiatric comorbidities and highlights therapeutic targets for precision medicine.
    Keywords:  GDF15; anxiety; biomarkers; depression; gut–brain axis; mental health; metabolism; mitochondria; precision medicine; stress
    DOI:  https://doi.org/10.3390/ijms26157611
  15. J Cell Sci. 2025 Aug 15. pii: jcs264018. [Epub ahead of print]138(16):
    Energy deprivation in youth and old age.
    Michael Stern.
      In youth, energy deprivation primarily results from fasting. Because inconsistent nutrient availability is common for most organisms, natural selection has provided mechanisms that detect nutrient-deprived states, followed by adaptive responses that increase the likelihood of survival until nutrients are restored. Organisms respond to fasting first by oxidizing the cellular cytoplasm, then by activating redox-sensitive kinases - namely the c-Jun N-terminal kinases (henceforth collectively termed JNK) and AMP-activated protein kinase (AMPK) - and Foxo transcription factors (henceforth referred to collectively as Foxo). Together, JNK, AMPK and Foxo induce autophagy. This fasting response is beneficial because autophagy supplies substrates for metabolism that replace missing nutrients and enhances removal of damaged organelles such as mitochondria, which increases lifespan and enhances survival through the fast. Although this response is adaptive in the context of acute nutrient deprivation, it can have harmful consequences when activated chronically. Here, I propose that cells from old organisms are constitutively energy deprived because of lifetime accumulation of dysfunctional mitochondria. As a result, these cells reactivate the fasting response seen in youth. Hence, old organisms constitutively oxidize the cellular cytoplasm and activate JNK, AMPK, Foxo and, finally, autophagy. However, because energy deprivation in old age is driven by mitochondrial insufficiency rather than nutrient deprivation, this response fails to restore ATP production and becomes chronic and deleterious. I suggest that many age-related pathologies, such as oxidative stress, neurodegeneration and sarcopenia, result from aberrant activation of the fasting response.
    Keywords:  Aging; Autophagy; Nutrient deprivation; Oxidative Stress; Signal transduction
    DOI:  https://doi.org/10.1242/jcs.264018
  16. Medicine (Baltimore). 2025 Aug 08. 104(32): e43709
    Mechanistic insights into heart failure induction in ovariectomized rats: The role of mitochondrial dysfunction.
    Ki-Woon Kang, Seong-Kyu Lee.
       BACKGROUND: Premature menopause is recognized as a factor that increase the risk of heart failure (HF). However, the fundamental pathophysiology concerning cardiac dysfunction remains inadequately understood.
    METHODS: This study investigated whether cardiac function was altered in ovariectomy (OV) rats compared to controls. Female rats (n = 12) were randomly assigned into 2 groups: control (sham operation) and bilateral OV group.
    RESULTS: The echocardiographic analysis revealed that the E and E/A were significantly decreased, while the deceleration time was significantly increased in the OV group compared to the control group, indicating the presence of HF in the OV rats. ATP levels in the myocardium were significantly decreased, and oxidative DNA damage was elevated in the OV group compared to the control group. Furthermore, the mRNA levels of peroxisome-proliferator-activated receptor-gamma (PPARγ) co-activator-1 alpha (PGC-1α) and CR6 interacting factor 1 (Crif1) were reduced in the OV group.
    CONCLUSION: These findings suggest that OV may induce HF through mechanisms linked to mitochondrial dysfunction.
    Keywords:  cardiac dysfunction; mitochondria; ovariectomy
    DOI:  https://doi.org/10.1097/MD.0000000000043709
  17. bioRxiv. 2025 Jul 16. pii: 2025.07.11.664289. [Epub ahead of print]
    Estrogens protect bone mass by inhibiting NAD + metabolism in osteoclasts.
    Adriana Marques-Carvalho, Gareeballah Osman Adam, Ankita Chalke, Ana Resende-Coelho, Olivia Reyes-Castro, Aaron Warren, Luis F Grilo, Claudia Cs Chini, Benjamin Stronach, Farah Alturkmani, Elena Ambrogini, Eduardo N Chini, Ha-Neui Kim, Maria Almeida.
      Estrogens protect against bone loss by reducing osteoclast number and bone resorption, primarily via direct actions on osteoclast precursors. In these cells, estrogens attenuate RANKL-induced stimulation of mitochondrial complex I, which is crucial for ATP generation through NADH oxidation. NAD + promotes redox reactions and activates NAD + -dependent enzymes, including the mitochondrial deacetylase SIRT3. However, the contribution of NAD + to the skeletal effects of estrogens remains unknown. We show that NAD + levels and SIRT3 activity are upregulated by RANKL and inhibited by 17β-estradiol (E 2 ) in mouse and human osteoclast precursors. Increasing NAD + or the mitochondrial NAD + /NADH ratio reverses the inhibitory effects of E 2 on SIRT3 activity and osteoclastogenesis in vitro . Deletion of Nampt , a key NAD salvage enzyme, reduces NAD + and prevents bone loss in ovariectomized mice. Similarly, deletion of Sirt3 in osteoclast precursors mitigates estrogen deficiency-induced bone resorption. These findings indicate that suppression of NAD + levels and mitochondrial redox metabolism by estrogens contributes to their anti-resorptive effects via inhibition of SIRT3.
    DOI:  https://doi.org/10.1101/2025.07.11.664289
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