bims-mistre 2025-09-21 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–09–21
nineteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline.
Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.
STX4 is indispensable for mitochondrial homeostasis in skeletal muscle.
Exploring the protective effects of coenzyme Q10 on female fertility.
Mitochondrial oxidative stress, cellular damages and stem cell aging in premature aging models with complex II electron transport defect.
Coenzyme Q10 in Heart Failure: Mechanisms and Therapeutic Potential.
A Blood Based Mitochondrial Functional Index Biomarker for Alzheimer's Disease.
APOE genotype-dependent differences in human astrocytic energy metabolism.
Ergothioneine for Cognitive Health, Longevity and Healthy Aging: Where Are We Now?
Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease.
Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.
Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals.
Decoding ovarian aging in women: Cellular damage, signaling networks, and treatment frontiers.
Astaxanthin alleviates oxidative stress and skeletal muscle damage by promoting mitochondrial biogenesis.
Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.
Curcumin improves diabetic vascular aging rats and high glucose-induced cells aging by promoting mitophagy.
Biochemical changes associated with non-alcoholic fatty liver disease in response to berberine treatment: a systematic review and meta-analysis of clinical and preclinical research.
Temporal Effects of Lipid Oversupply on Energy Metabolism and Mitochondrial Homeostasis in Hepatocytes.
Creatine as a mitochondrial theranostic in predictive, preventive, and personalized medicine.

ACS Pharmacol Transl Sci. 2025 Sep 12. 8(9): 2868-2886

Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline.

Smita Jain, Reetuparna Acharya, Lavkush Verma, Aparna Chauhan.

  Age-related cognitive decline, a hallmark of neurodegenerative disorders such as Alzheimer's disease, has been increasingly associated with metabolic dysregulation. Targeting metabolic pathways to enhance brain function and slow neurodegeneration presents a novel therapeutic approach. This review discusses key metabolic interventions that may reverse or delay cognitive decline. Mitochondrial dysfunction, oxidative stress, and impaired energy metabolism are central to neurodegenerative progression. Therapies aimed at boosting mitochondrial biogenesis, such as nicotinamide adenine dinucleotide (NAD+) precursors, adenosine monophosphate-activated protein kinase (AMPK) activators, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) modulators, have shown promise in improving neuronal energy balance and reducing oxidative damage. Metabolic interventions like caloric restriction, intermittent fasting, and ketogenic diets have demonstrated neuroprotective effects by enhancing insulin sensitivity, promoting autophagy, and shifting the brain's energy reliance toward ketone bodies, which improves cognitive function. These strategies also mitigate neuroinflammation, a key driver of neuronal damage, by modulating immune responses and reducing the accumulation of toxic protein aggregates. Lipid metabolism also plays a crucial role in maintaining neuronal integrity. Enhancing lipid turnover, optimizing fatty acid profiles, and regulating cholesterol homeostasis may improve synaptic plasticity and reduce neuroinflammation, offering additional therapeutic avenues. By integrating current insights into metabolic regulation, this review underscores the potential of metabolic therapies to reverse or mitigate the cognitive decline associated with aging. Advancing our understanding of the intricate relationship between metabolism and neurodegeneration may pave the way for novel treatments targeting age-related cognitive impairment.

Keywords:  caloric restriction; insulin signaling; lipid metabolism; mitochondrial dysfunction; neurodegeneration

DOI:  https://doi.org/10.1021/acsptsci.5c00077
Aging Adv. 2025 Sep;2(3): 108-111

Mitoepigenetic Targeting of Age-Related Dysfunction: Mechanisms, Therapeutic Avenues, and Transgenerational Implications.

Kit Neikirk, Suraj Thapliyal, Sepiso K Masenga, Ashton Oliver, Margaret Mungai, Han Le, Heather K Beasley, Andrea G Marshall, Anthonya T Cooper, Taneisha Gillyard Cheairs, Benjamin I Rodriguez, Edgar Garza-Lopez, Prasanna Katti, Antentor Hinton.

  Mitochondrial epigenetics, a burgeoning field bridging mitochondrial biology and epigenetic regulation, has emerged as a critical determinant of aging and age-related diseases. While nuclear epigenetics is well-characterized, the mechanisms governing mitochondrial DNA (mtDNA) regulation, including nucleoid dynamics, non-coding RNAs (ncRNAs), and metabolite-driven modifications, remain underexplored. This review synthesizes evidence that mitochondrial epigenetics influences cardiovascular pathogenesis through altered DNA methylation and histone acetylation patterns, which dysregulate oxidative phosphorylation and nucleoid stability. In neurodegenerative diseases, endoplasmic reticulum-mitochondrial contact points, disrupted by aging, impair calcium homeostasis and promote neuronal apoptosis, while oxidative stress exacerbates mtDNA instability through inefficient repair mechanisms. Cancer cells exploit mitochondrial metabolic reprogramming, where shifts in acetyl-CoA and α-ketoglutarate levels modulate epigenetic enzymes, fostering drug resistance. Potential therapeutic targets include pharmacological modulation of Mitochondrial transcription factor A acetylation/phosphorylation to enhance mtDNA transcription and dietary interventions to boost NAD+ levels, thereby improving mitochondrial function. Transgenerational studies reveal matrilineal inheritance of mtDNA methylation patterns and stress-induced epigenetic memory, though technical limitations in detecting mtDNA methylation persist. Clinically, mitochondrial epigenetic biomarkers like mtDNA hydroxymethylation and lncRNA expression (e.g., Mitoregulin) show promise for early diagnosis and treatment monitoring. Despite advances, challenges include standardizing methods for mtDNA methylation analysis and translating preclinical findings into therapies. This perspective review underscores the need for integrative approaches combining single-cell sequencing and CRISPR-based technologies to dissect mitochondrial-nuclear crosstalk, ultimately paving the way for precision medicine strategies targeting mitoepigenetic pathways to mitigate age-related decline.

Keywords:  aging; epigenetics; methylation; mitochondria; mitochondrial nucleoid; mtDNA

DOI:  https://doi.org/10.4103/agingadv.agingadv-d-25-00006
bioRxiv. 2025 Sep 03. pii: 2025.09.02.673840. [Epub ahead of print]

STX4 is indispensable for mitochondrial homeostasis in skeletal muscle.

Joseph M Hoolachan, Rekha Balakrishnan, Erika M McCown, Karla E Merz, Chunxue Zhou, Elizabeth Bloom-Saldana, Patrick T Fueger, Angelica Hamilton, Tali Kiperman, Ke Ma, Eunjin Oh, Lei Jiang, Patrick Pirrotte, Orian Shirihai, Debbie C Thurmond.

Background: Mitochondrial homeostasis is vital for optimal skeletal muscle integrity. Mitochondrial quality control (MQC) mechanisms that are essential for maintaining proper functions of mitochondria include mitochondrial biogenesis, dynamics and mitophagy. Previously, Syntaxin 4 (STX4) traditionally considered a cell surface protein known for glucose uptake in skeletal muscle, was also identified at the outer mitochondrial membrane. STX4 enrichment was sufficient to reverse Type 2 diabetes-associated mitochondrial damage in skeletal muscle by inactivation of mitochondrial fission. However, whether STX4 could modulate skeletal muscle mitochondrial homeostasis through MQC mechanisms involving mitochondrial biogenesis or mitophagy remains to be determined.
Methods: To determine the requirements of STX4 in mitochondrial structure, function and MQC processes of biogenesis and mitophagy, we implemented our in-house generated inducible skeletal muscle-specific STX4-knockout (skmSTX4-iKO) mice ( Stx4 fl/fl ; Tg(HSA-rtTA/TRE-Cre )/B6) and STX4-depleted immortalized L6.GLUT4myc myotubes via siRNA knockdown (siSTX4).
Results: We found that non-obese skmSTX4-iKO male mice (>50% reduced STX4 abundance, Soleus and Gastrocnemius ***p<0.001, Tibialis anterior (TA) ****p<0.0001) developed insulin resistance (**p<0.01), together with reduced energy expenditure (AUC *p<0.05), respiratory exchange ratio (AUC **p<0.01), and grip strength (*p<0.05). STX4 ablation in muscle also impaired mitochondrial oxygen consumption rate (****p<0.0001). Mitochondrial morphological damage was heterogenous in STX4 depleted muscle, presenting with small fragmented mitochondria (****p<0.0001) and deceased electron transport chain (ETC) abundance (CI ***p<0.001, CII *p<0.05, CIV **p<0.01) in oxidative soleus muscle, while glycolytic TA fibers display enlarged swollen mitochondria (****p<0.0001) with no change in ETC abundance. Notably, >60% reduction of STX4 in siSTX4 L6.GLUT4myc myotubes (****p<0.0001) also decreased ETC abundance (CI ****p<0.0001, CII ****p<0.0001, CIV *p<0.05) without changes in mitochondrial glucose metabolism, as shown by [U- 13 C] glucose isotope tracing. For MQC, both skmSTX4-iKO male mice (*p<0.05) and siSTX4 L6.GLUT4myc myotubes (*p<0.05) showed decreased mitochondrial DNA levels alongside reduced mRNA expression of mitochondrial biogenesis genes Ppargc1a (PGC1-α, *p<0.05) and Tfam (*p<0.05) in skmSTX4-iKO soleus muscle and PGC1-α (mRNA *p<0.05, protein ***p<0.001), NRF1 (mRNA and protein *p<0.05) and Tfam (mRNA *p<0.05) in siSTX4 L6.GLUT4myc myotubes. Furthermore, live cell imaging using mt-Keima mitophagy biosensor in siSTX4 L6.GLUT4myc cells revealed significantly impaired mitochondrial turnover by mitophagy (*p<0.05) and mitochondria-lysosome colocalization (*p<0.05). STX4 depletion also reduced canonical mitophagy markers, PINK1 and PARKIN in both skmSTX4-iKO muscle (PARKIN *p<0.05, PINK1 **p<0.01) and siSTX4 L6.GLUT4myc myotubes (PARKIN ****p<0.0001, PINK1 *p<0.05).
Conclusions: Our study demonstrated STX4 as a key mitochondrial regulator required for mitochondrial homeostasis in skeletal muscle.

DOI: https://doi.org/10.1101/2025.09.02.673840
Front Cell Dev Biol. 2025 ;13 1633166

Exploring the protective effects of coenzyme Q10 on female fertility.

Yu Jiang, Yao Han, Pengyun Qiao, Fa Ren.

  The global decline in fertility rates has intensified the reliance on assisted reproductive technology (ART) for infertility treatment. Antioxidant supplementation, particularly with coenzyme Q10 (CoQ10), has gained prominence as a therapeutic strategy to enhance fertility outcomes and ART success. As a lipid-soluble benzoquinone, CoQ10 plays dual roles in the metabolism of mitochondrial energy and antioxidant protection. By regulating oxidative stress and reducing reactive oxygen species (ROS), CoQ10 improves oocyte quality, ovarian function, and mitochondrial efficiency, thereby optimizing ART outcomes. Clinical studies demonstrate that CoQ10 supplementation enhances ovarian function, increases the number of eggs, and improves the quality of embryo, particularly in women with weak ovarian reserve functions or older age. This review synthesizes current evidence on CoQ10's mechanisms in safeguarding female fertility, including its effects on oocyte maturation, embryonic development, and ovarian aging. Furthermore, it explores CoQ10's potential in addressing conditions such as premature ovarian failure and polycystic ovary syndrome. This review provides an overview of CoQ10's protective effect on female fertility and its potential clinical application in reproductive medicine, aiming to offer guidance for the future use of CoQ10 in ART clinical practice.

Keywords:  ART; CoQ10; ROS; female infertility; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2025.1633166
J Clin Biochem Nutr. 2025 Sep 01. 77(2): 101-112

Mitochondrial oxidative stress, cellular damages and stem cell aging in premature aging models with complex II electron transport defect.

Takamasa Ishii, Kayo Yasuda, Masaki Miyazawa, Hiromi Onouchi, Sumino Yanase, Naoaki Ishii.

  Mitochondria which are the major intracellular reactive oxygen species (ROS) sources produce especially superoxide anion (O2 •-) as a byproduct of energy production. It has been well known that O2 •- is converted from oxygen (O2) and is overproduced by excessive electron leakage from the mitochondrial electron transport chain (ETC), mainly complexes I and III. However we have previously reported that several point mutations (specifically G71E in C. elegans, I71E in Drosophila and V69E in mouse) in succinate dehydrogenase C subunit (SDHC) of complex II cause mitochondrial electron transport defect leading to O2 •- overproduction from mitochondria. These mutations can cause endogenous oxidative stress resulting in tumorigenesis and apoptosis as well as premature death. Recently, we have also demonstrated that premature aging of hematopoietic stem cell with a mutation in SDHC is developed after the growth phase and normal development. Here, we review cellular damages by complex II electron transport defect-induced endogenous oxidative stress in premature aging models.

Keywords:  aging; apoptosis; complex II; mitochondria; oxidative stress

DOI:  https://doi.org/10.3164/jcbn.25-62
Cardiol Rev. 2025 Sep 18.

Coenzyme Q10 in Heart Failure: Mechanisms and Therapeutic Potential.

Amogh Jyothi Arun, William H Frishman.

  Heart failure (HF) is a progressive and debilitating condition characterized by the heart's inability to meet the body's metabolic demands, often due to impaired cardiac contractility and energy depletion. Mitochondrial dysfunction and oxidative stress are central to the pathophysiology of HF, leading to disrupted bioenergetics and exacerbating cardiac damage. Coenzyme Q10 (CoQ10), a key component of the mitochondrial electron transport chain, has garnered attention for its potential therapeutic role in HF due to its dual functions in adenosine triphosphate production and antioxidant defense. Clinical trials, notably the CoQ10 as adjunctive treatment of chronic HF focusing on changes in Symptoms, BIomarker status, and long-term Outcome (Q-SYMBIO) trial, have demonstrated that long-term CoQ10 supplementation significantly reduces cardiovascular and all-cause mortality in patients with chronic HF. Additionally, CoQ10 improves functional capacity and ejection fraction, with minimal side effects. Despite its promise, further large-scale trials are needed to confirm these findings and determine optimal dosing. CoQ10's potential to modulate mitochondrial function and oxidative stress makes it a promising adjunctive therapy in the management of HF.

Keywords:  Q-SYMBIO trial; coenzyme Q10; heart failure; mitochondrial dysfunction; oxidative stress

DOI:  https://doi.org/10.1097/CRD.0000000000001056
medRxiv. 2025 Sep 08. pii: 2025.09.05.25335197. [Epub ahead of print]

A Blood Based Mitochondrial Functional Index Biomarker for Alzheimer's Disease.

Brittany M Hauger, Riley E Kemna, Paul J Kueck, Taylor A Strope, Casey S John, Keith P Smith, Hana D Mayfield, Ellen Herrold, Keri L Cox, Rebecca Bothwell, Leonidas Bantis, Russell H Swerdlow, Jill K Morris, Heather M Wilkins.

INTRODUCTION: Alzheimer's disease (AD) pathology is complex and involves mitochondrial dysfunction. There are emerging therapies targeting mitochondrial function in clinical trials for AD. This highlights the need for biomarkers that measure mitochondrial function.
METHODS: We determined the utility of a novel blood based mitochondrial biomarker, the mitochondrial functional index (MFI) in the context of AD.
RESULTS: In vitro and in vivo models of AD had a reduced MFI. MFI was lower in human AD subjects and APOE4 carriers. ROC analysis for individual biomarkers was completed and MFI had a higher area under the curve than other plasma biomarkers. The MFI biomarker correlated with the Mini Mental State Exam (MMSE) and the clinical dementia rating scale (CDR).
DISCUSSION: This study highlights the potential utility of MFI as a functional blood based mitochondrial biomarker to interrogate energy metabolism. Ongoing studies are examining the relationship of MFI with brain energy metabolism outcomes.

DOI: https://doi.org/10.1101/2025.09.05.25335197
Front Cell Neurosci. 2025 ;19 1603657

APOE genotype-dependent differences in human astrocytic energy metabolism.

Vanessa Budny, Chantal Bodenmann, Kathrin J Zürcher, Maik Krüger, Sherida M de Leeuw, Rebecca Z Weber, Ruslan Rust, Luca Ravotto, Iván Ruminot, L Felipe Barros, Bruno Weber, Christian Tackenberg.

   Introduction: The main genetic risk factor for Alzheimer's disease (AD) is the presence of the apolipoprotein E4 (APOE4) allele. While APOE4 increases the risk of developing AD, the APOE2 allele is protective and APOE3 is risk-neutral. In the brain, APOE is primarily expressed by astrocytes and plays a key role in various processes including cholesterol and lipid transport, neuronal growth, synaptic plasticity, immune response and energy metabolism. Disruptions in brain energy metabolism are considered a major contributor to AD pathophysiology, raising a key question about how different APOE isoforms affect the energy metabolism of human astrocytes.
Methods: In this study, we generated astrocytes (iAstrocytes) from APOE-isogenic human induced pluripotent stem cells (iPSCs), expressing either APOE2, APOE3, APOE4 or carrying an APOE knockout (APOE-KO), and investigated APOE genotype-dependent changes in energy metabolism.
Results: ATP Seahorse assay revealed a reduced mitochondrial and glycolytic ATP production in APOE4 iAstrocytes. In contrast, glycolysis stress tests demonstrated enhanced glycolysis and glycolytic capacity in APOE4 iAstrocytes while genetically encoded nanosensor-based FLIM analysis revealed that APOE does not affect lactate dynamics. In agreement with the increased glycolytic activity, APOE4 iAstrocytes also showed elevated mitochondrial respiration and activity, indicated by proteomic GO enrichment analysis and mitochondrial stress test. This was accompanied by elevated proton leak in APOE4 iAstrocytes while levels of mitochondrial uncoupling proteins (UCPs) were not affected. Mass spectrometry-based metabolomic analysis identified various energy and glucose metabolism-related pathways that were differentially regulated in APOE4 compared to the other genotypes, including mitochondrial electron transport chain (ETC) and glycolysis. In general, APOE2 and APOE-KO iAstrocytes showed a very similar phenotype in all functional assays and differences between APOE2/APOE-KO and APOE4 were stronger than between APOE3 and APOE4.
Discussion: Our study provides evidence for APOE genotype-dependent effects on astrocyte energy metabolism and highlights alterations in the bioenergetic processes of the brain as important pathomechanisms in AD.

Keywords:  Alzheimer’s disease (AD); apolipoprotein E (APOE); energy metabolism; glycolysis; human astrocytes; induced pluripotent stem cells (iPSCs); mitochondrial function; mitochondrial uncoupling

DOI:  https://doi.org/10.3389/fncel.2025.1603657
Proc Nutr Soc. 2025 Sep 19. 1-40

Ergothioneine for Cognitive Health, Longevity and Healthy Aging: Where Are We Now?

Linda May-Zhang, Irwin Cheah, Ian Zajac, Emily Brindal, Naomi Kakoschke.

  As the global population ages, the prevalence of cognitive decline is rising, creating urgent demand for proactive strategies that support brain health and healthy aging. Ergothioneine, a unique dietary amino-thione absorbed via the OCTN1 transporter, has recently gained attention for its potential as a neuroprotective, longevity-promoting compound. This review synthesizes growing evidence from observational, interventional, and mechanistic studies. Observational data consistently associate low blood ergothioneine levels with cognitive impairment, neurodegenerative diseases, cardiovascular disorders, frailty, and mortality. Interventional trials in older adults suggest that ergothioneine supplementation may improve cognition, memory, sleep quality, and stabilize neurodegeneration biomarkers, with no safety concerns at doses up to 25 mg/day. Mechanistic studies reveal that ergothioneine acts through multiple pathways: mitigating oxidative stress, reducing neuroinflammation, preserving mitochondrial function, and potentially modulating neurogenesis and NAD⁺ metabolism, although some mechanisms require further investigation. Beyond cognition, ergothioneine shows promise in supporting other physiological systems relevant to aging, including cardiovascular, metabolic, gut, eye, auditory, liver, kidney, immune, skin, and lung health. Together, current evidence positions ergothioneine as a promising nutritional intervention for promoting cognitive resilience and systemic health in aging, although larger, long-term interventional trials are needed to confirm causality and optimize use.

Keywords:  Cognition; Ergothioneine; Healthy Aging; Oxidative Stress

DOI:  https://doi.org/10.1017/S0029665125101754
EBioMedicine. 2025 Sep 15. pii: S2352-3964(25)00368-8. [Epub ahead of print]120 105924

Therapeutic assessment of a novel mitochondrial complex I inhibitor in in vitro and in vivo models of Alzheimer's disease.

Sergey Trushin, Thi Kim Oanh Nguyen, Andrea Stojakovic, Mark Ostroot, J Trey Deason, Su-Youne Chang, Liang Zhang, Slobodan I Macura, Toshihiko Nambara, Wenyan Lu, Takahisa Kanekiyo, Eugenia Trushina.

   BACKGROUND: Despite recent approval of monoclonal antibodies that reduce amyloid (Aβ) accumulation, the development of disease-modifying strategies targeting the underlying mechanisms of Alzheimer's disease (AD) is urgently needed.
METHODS: We demonstrate that mitochondrial complex I (mtCI) represents a druggable target, where its weak inhibition activates neuroprotective signalling, benefiting AD mouse models with Aβ and p-Tau pathologies. Rational design and structure‒activity relationship studies yielded mtCI inhibitors profiled in a drug discovery funnel designed to address safety, selectivity, and efficacy.
FINDINGS: The lead compound C458 is highly protective against Aβ toxicity, has favourable pharmacokinetics, and minimal off-target effects. C458 exhibited excellent brain penetrance, activating neuroprotective pathways with a single dose. Preclinical studies in APP/PS1 mice were conducted using functional tests, metabolic assessment, in vivo31P-NMR spectroscopy, blood cytokine panels, ex vivo electrophysiology, and Western blotting. Chronic oral administration improved long-term potentiation, reduced oxidative stress and inflammation, and enhanced mitochondrial biogenesis, antioxidant signalling, and cellular energetics. Efficacy against Aβ and p-Tau was confirmed in human organoids.
INTERPRETATION: These studies provide further evidence that the restoration of mitochondrial function in response to mild energetic stress represents a promising disease-modifying strategy for AD.
FUNDING: This research was supported by grants from NIH AG 5549-06, NS1 07265, AG 062135, UG3/UH3 NS 113776, and ADDF 291204 (all to ET); U19 AG069701 (to TK); the Alzheimer's Association Research Fellowship grant 23AARF-1027342 (to TKON).

Keywords:  APP/PS1 mice; Alzheimer's disease; Drug discovery; Mitochondrial complex I; Organoids; Rational design; Small molecules

DOI:  https://doi.org/10.1016/j.ebiom.2025.105924
bioRxiv. 2025 Sep 09. pii: 2025.09.08.674963. [Epub ahead of print]

Redox regulation of neuroinflammatory pathways contributes to damage in Alzheimer's disease brain.

Lauren N Carnevale, Piu Banerjee, Xu Zhang, Jazmin Navarro, Charlene K Raspur, Parth Patel, Tomohiro Nakamura, Emily Schahrer, Henry Scott, Nhi Lang, Jolene K Diedrich, Amanda J Roberts, John R Yates, Stuart A Lipton.

The mechanism(s) whereby redox stress mediates aberrant immune signaling in age-related neurological disorders remains largely unknown. Normally, the innate immune system mounts a robust response to infectious stimuli. However, unintentional activation by host-derived factors, such as aggregated proteins associated with neurodegenerative disorders or by cytoplasmic genomic or mitochondrial DNA, can elicit aberrant immune responses. One such immune response is represented by the cytosolic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Using redox chemical biology and mass spectrometry approaches, we identified S -nitrosylation of STING cysteine 148 as a novel posttranslational redox modification underlying aberrant type 1 interferon signaling in Alzheimer's disease (AD). Critically, we observed S -nitrosylated STING (SNO-STING) in postmortem human AD brains, in hiPSC-derived microglia (hiMG) exposed to amyloid-β (Aβ)/α-synuclein (αSyn) aggregates, and in 5xFAD transgenic mice. Mechanistically, our findings reveal that STING S -nitrosylation is critical in initiating signaling cascades by promoting the formation of disulfide-bonded STING oligomers. This leads to neuroinflammation early in the course of disease in vivo in 5xFAD mice with consequent synaptic loss. Collectively, our research supports the role of SNO-STING in neuroinflammation associated with AD, and points to a novel druggable cysteine residue in STING to prevent this S -nitrosylation reaction with its inherent inflammatory response.
One Sentence Summary: S -Nitrosylation of STING triggers activation of cGAS-STING signaling in Alzheimer's disease brain and subserves a novel link between excessive nitrosative stress and dysregulated innate immunity, thus contributing to disease progression.

DOI: https://doi.org/10.1101/2025.09.08.674963
Metabolism. 2025 Sep 13. pii: S0026-0495(25)00260-4. [Epub ahead of print]173 156391

Relationship of GDF15 with hepatic mitochondrial respiration is depending on the presence of fibrosis in obese individuals.

Anna Giannakogeorgou, Sabine Kahl, Cesare Granata, Geronimo Heilmann, Lucia Mastrototaro, Bedair Dewidar, Pavel Bobrov, Irene Esposito, Aslihan Yavas, Sandra Trenkamp, Frank A Granderath, Matthias Schlensak, Christos S Mantzoros, Michael Roden, Patrick Schrauwen.

   BACKGROUND AND PURPOSE: Preclinical studies reported elevated growth differentiation factor 15 (GDF15) when mitochondrial function is reduced. In humans, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) exhibit different hepatic mitochondrial adaptation. We hypothesized that circulating GDF15 differently correlates with hepatic mitochondrial respiration in obesity and/or MASLD/MASH.
METHODS: Humans without (n = 20) and with biopsy-confirmed MASLD (n = 20) or MASH (n = 20) underwent hyperinsulinemic-euglycemic clamps to assess whole-body (M-value) and adipose-tissue (insulin-induced NEFA suppression) insulin sensitivity. Fasting serum GDF15 and glucagon were quantified by ELISA. Mitochondrial respiration was measured in liver obtained during bariatric surgery by high-resolution respirometry. Associations were assessed with Spearman's nonparametric correlation.
RESULTS: Serum GDF15 correlated negatively with M-value (r = -0.35, p = 0.017) and NEFA suppression (r = -0.29, p = 0.046), but not with hepatic mitochondrial respiration across the whole cohort. However, correlations were found upon stratification into groups based on the presence (n = 37, age: 41 ± 2y, BMI: 49 ± 1 kg/m2) or absence of hepatic fibrosis (n = 23, 44 ± 2 years, BMI: 49 ± 1 kg/m2). In persons without fibrosis, GDF15 correlated positively with fatty acid oxidation-linked (FP; r = 0.35, p = 0.035) and maximal coupled (FNSP; r = 0.42, p = 0.010) mitochondrial respiration. Conversely, GDF15 correlated negatively with hepatic FNP in persons with fibrosis (r = -0.48, p = 0.022).
CONCLUSIONS: In humans with obesity, serum GDF15 correlates positively with hepatic mitochondrial respiration in persons without, but negatively in persons with hepatic fibrosis. Future studies are needed to investigate whether and how GDF15 affects hepatic mitochondrial respiration in a fibrosis-dependent manner and/or, conversely, how fibrosis might modulate hepatic GDF15 secretion through altered mitochondrial function.

Keywords:  Fibrosis; Growth differentiation factor 15; Insulin resistance; Liver; Mitochondria; Obesity

DOI:  https://doi.org/10.1016/j.metabol.2025.156391
Reprod Biol. 2025 Sep 17. pii: S1642-431X(25)00082-8. [Epub ahead of print]25(4): 101075

Decoding ovarian aging in women: Cellular damage, signaling networks, and treatment frontiers.

Shivani Ingole, Kanchan Khare, Veepin Dwivedi, Brijesh Taksande, Milind Umekar, Shubhada Mangrulkar.

  Ovarian aging is a significant biological process characterized by the gradual decline of ovarian function and fertility in women as they age. It is a multifaceted process that involves various molecular mechanisms. This review article delves into the complex nature of ovarian aging, marked by reductions in both the quantity and quality of oocytes, hormonal imbalances, and heightened risks of infertility and pregnancy complications. It consolidates current understanding of the physiological, cellular, and molecular mechanisms driving ovarian aging, such as mitochondrial dysfunction, oxidative stress, telomere shortening, DNA (Deoxyribonucleic Acid) damage, inflammation, and apoptosis. This review primarily focuses on human ovarian aging, while also integrating relevant insights from animal models particularly rodent studies that have contributed to our understanding of underlying mechanisms. It explores key signaling pathways involved in aging, including AMPK (AMP-Activated Protein Kinase), mTOR (mammalian target of rapamycin), Nrf2 (Nuclear Factor Erythroid 2-Related Factor 2), SIRT1 (Sirtuin 1), and FOXO3 (Forkhead Box O Transcription Factor) pathways. The review also discusses emerging therapeutic strategies designed to delay or reverse ovarian aging, which include antioxidants, hormone replacement therapy, stem cell-based treatments, CRMs (CR mimetics), gene therapy, and traditional medicines. Additionally, the article examines the potential role of polyamines in ovarian function and aging. By thoroughly analyzing the current research landscape and identifying future research directions, this review offers valuable insights for researchers and clinicians dedicated to improving reproductive health and quality of life for aging women.

Keywords:  DNA damage; Mitochondrial dysfunction; Ovarian aging; Oxidative stress; Telomere shortening

DOI:  https://doi.org/10.1016/j.repbio.2025.101075
Front Vet Sci. 2025 ;12 1577408

Astaxanthin alleviates oxidative stress and skeletal muscle damage by promoting mitochondrial biogenesis.

Chengmu Li, Yining Yan, Kai Wang, Tao Jiang.

   Introduction: This study aimed to investigate the damaging effects of a high-fat diet (HFD) on mitochondria and skeletal muscle and to evaluate the protective role of astaxanthin (Asta), with a focus on mitochondrial biogenesis, oxidative stress, and inflammation under metabolic stress.
Methods: HFD-fed mice and palmitate acid (PA)-stimulated C2C12 cells were treated with Asta. Skeletal muscle function, pathology, mitochondrial ultrastructure, inflammatory responses, and oxidative stress levels were assessed using behavioral tests, histology, quantitative reverse transcription-polymerase chain reaction, western blotting, transmission electron microscopy, and biochemical assays.
Results: Asta did not alter body weight or serum lipid levels in HFD-fed mice but markedly alleviated skeletal muscle damage and improved function. In both in vivo and in vitro models, Asta suppressed inflammatory gene expression, enhanced mitochondrial biogenesis-related proteins, reduced lipid accumulation and mitochondrial damage, increased antioxidant enzyme activity, and promoted ATP production. Furthermore, Asta inhibited mitochondrial fission and lipid peroxidation in PA-stimulated C2C12 cells.
Discussion: Asta mitigates oxidative stress, lipid accumulation, and inflammation in skeletal muscle cells by promoting mitochondrial biogenesis, thereby preserving muscle structure and function. These findings highlight Asta's potential as a therapeutic agent for skeletal muscle protection in metabolic stress conditions.

Keywords:  astaxanthin; high-fat diet; mitochondrial biogenesis; oxidative stress; skeletal muscle

DOI:  https://doi.org/10.3389/fvets.2025.1577408
Aging Cell. 2025 Sep 17. e70235

Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease.

Sheeja Navakkode, Brian K Kennedy.

  Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by a progressive decline in cognitive function. Increasing evidence indicates that alpha-ketoglutarate (AKG), a key metabolite in the tricarboxylic acid (TCA) cycle, can extend lifespan and healthspan across various animal models, raising interest in its potential neuroprotective effects in age-related disorders such as AD. Our previous research found that dietary supplementation with calcium alpha-ketoglutarate (CaAKG), a calcium derivative of AKG, enhances both lifespan and healthspan in mice. However, little is known about the neuroprotective role of AKG/CaAKG in AD. Here, we show that CaAKG could rescue synaptic deficits that are associated with AD. Treatment with AKG or CaAKG ameliorates long-term potentiation (LTP) at hippocampal CA1 synapses in APP/PS1 mice, with a more profound effect in female AD mice than in males. The effects of CaAKG were mediated through an NMDA receptor-independent mechanism involving L-type calcium channels (LTCC) and calcium-permeable AMPA receptors (CP-AMPARs). Analysis of protein expression showed that AD hippocampal slices treated with CaAKG exhibited increased LC3-II levels, indicating enhanced autophagy. Similarly, rapamycin, an mTOR inhibitor, also rescued LTP deficits in AD mice, suggesting that the observed increase in autophagy may contribute to neuroprotection. Interestingly, rapamycin showed differential effects, as it rescued LTP in AD mice but blocked LTP in WT mice. We also observed that CaAKG facilitated synaptic tagging and capture (STC), a widely studied cellular model for associative memory, indicating its potential to facilitate associative memory. Overall, our findings suggest that CaAKG has neuroprotective effects in APP/PS1 mice. We propose CaAKG as a promising therapeutic target not only for aging but also for AD and potentially other age-associated neurodegenerative diseases, highlighting geroprotective strategies as viable alternatives for the prevention and treatment of AD.

Keywords:  Alzheimer's disease; CP‐AMPA; CaAKG; NMDA; alpha‐ketoglutarate; autophagy; hippocampus; long‐term potentiation; rapamycin; synaptic plasticity

DOI:  https://doi.org/10.1111/acel.70235
3 Biotech. 2025 Oct;15(10): 341

Curcumin improves diabetic vascular aging rats and high glucose-induced cells aging by promoting mitophagy.

Jinlin Wu, Xi Mei, Yong Li, Fang Liu, Dongfang Liu.

  Vascular aging was reported to be closely related to diabetes. This study investigates the inhibitory effects and mechanism of curcumin on diabetic vascular aging by regulating mitophagy through the PINK1 pathway. The diabetic rat model was established by feeding with a high-fat diet and intraperitoneal injection of streptozotocin (STZ), and treated with high-dose (200 mg/kg), low-dose (50 mg/kg) curcumin, or metformin (200 mg/kg), respectively. The role of mitophagy in high glucose (HG)-induced human aortic smooth muscle cells (HASMCs) aging in vitro were investigated. The results indicated that curcumin ameliorated weight loss and improved elevated blood glucose levels in diabetic rats. Curcumin also improved the vascular pathological changes of the common carotid artery, decreased the vascular interstitial collagen fiber and vascular calcium salt deposition, and improved vascular ultrastructure. Furthermore, curcumin significantly decreased ET-1, VCAM-1, and p16 expressions. In addition, curcumin increased the expression of LC3II/I, Beclin1, and PINK1 proteins, while decreasing p62 expression. High-dose curcumin could improve mitochondrial morphology and increase mitochondrial autophagy. Additionally, curcumin increased HASMCs viability and inhibited HG-induced vascular aging by promoting mitophagy in vitro. WB confirmed that LC3II/I, Beclin1, and PINK1 levels were increased, while p62 and p16 levels were decreased. The improvement effect of curcumin on vascular aging was reversed by the mitophagy inhibitor Mdivi-1 or PINK1 siRNA. In conclusion, curcumin alleviates vascular aging in diabetic rats and HG-induced senescence in HASMCs by enhancing mitochondrial autophagy. These results suggest that curcumin has therapeutic potential in alleviating diabetic vascular aging.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-025-04510-3.

Keywords:  Curcumin; Diabetes; Mitophagy; PINK1; Vascular aging

DOI:  https://doi.org/10.1007/s13205-025-04510-3
Front Pharmacol. 2025 ;16 1460643

Biochemical changes associated with non-alcoholic fatty liver disease in response to berberine treatment: a systematic review and meta-analysis of clinical and preclinical research.

Wenyu Zhu, Lele Yang, Yufan Dai, Hanyang Wang, Jiaxuan Zhou, Lina Xia, Tao Shen.

   Background: Non-alcoholic fatty liver disease (NAFLD) represents a global health challenge. Berberine, an isoquinoline alkaloid traditionally used for metabolic disorders, has garnered attention for its potential therapeutic interventions.
Objective: To comprehensively review and perform a meta-analysis of berberine's effects on NAFLD across clinical and preclinical studies.
Methods: A comprehensive literature search was conducted across five databases from their inception to May 2024. We included randomized controlled trials and animal studies that evaluated berberine's impact on NAFLD using specified biochemical markers.
Results: Out of 487 screened studies, 22 (4 clinical and 18 preclinical) were included. Clinically, berberine significantly reduced fasting blood glucose (FBG) levels, with an effect size of 0.53 (95% CI: 0.04-1.01). In preclinical settings, berberine consistently demonstrated benefits across several markers, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipid profiles, despite significant heterogeneity in some outcomes.
Conclusion: Berberine presents promising therapeutic avenues for NAFLD management, especially in terms of glucose metabolism. Further rigorous, well-designed trials are needed to substantiate these findings.
Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, Identifier CRD42023459618.

Keywords:  berberine; clinical study; meta-analysis; non-alcoholic fatty liver disease; preclinical research

DOI:  https://doi.org/10.3389/fphar.2025.1460643
Int J Med Sci. 2025 ;22(14): 3664-3681

Temporal Effects of Lipid Oversupply on Energy Metabolism and Mitochondrial Homeostasis in Hepatocytes.

Cheng-Chieh Chuang, Ying-Hao Chen, Fang-Yeh Chu, Ching-Ping Yang, Hsiang-Ling Ho, Fu-Pang Chang, Yu-Li Lo, Chun-Jung Chen, Yih-Hsin Chang.

  Obesity is closely associated with multiple metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). Patients with NAFLD are susceptible to develop irreversible life-threatening diseases, however, the evolution concerning mitochondrial and metabolic alterations during NAFLD development and progression remain elusive. This study focused on uncovering the sequential events of energy metabolism and mitochondrial homeostasis of hepatocytes under the environment of lipid oversupply by in vitro and in vivo strategies. Long-chain fatty acid (FA) synthesis and lipid storage were first induced by providing hepatocytes with sufficient energy source, followed by suppressed glucose metabolic efficiency and decreased mitochondrial mass. Intriguingly, distinctive features of hepatic cancer cells in response to FA oversupply were characterized. Insulin signaling and glucose uptake were rapidly deterred while lipid β-oxidation was significantly boosted. Enhanced mitochondrial biogenesis was identified as compensatory feedback for mitochondrial dysfunction. FA-induced mitophagy, cell morphological transition and higher N-cadherin expression potentiates epithelial-mesenchymal transition (EMT) which confers the cells with higher plasticity and accelerates NAFLD progression to irreversible hepatic diseases. This study provides evidence elucidating the temporal events caused by FA oversupply, moreover, delineates the facilitative role of excess nutrients in shaping the environment for lipid-laden hepatocytes to acquire malignant traits. Given the rapidly increasing global prevalence of metabolic disorders and the heterogeneous manifestations exhibited by NAFLD during disease progression, better understanding of the sequential events caused by FA overload aids in identifying promising targets and developing tailor-made treatment protocol according to individual disease status and conditions.

Keywords:  energy metabolism; hepatocytes; lipid oversupply; mitochondrial homeostasis; obesity

DOI:  https://doi.org/10.7150/ijms.104128
EPMA J. 2025 Sep;16(3): 541-553

Creatine as a mitochondrial theranostic in predictive, preventive, and personalized medicine.

Sergej M Ostojic, László Rátgéber.

  Creatine, traditionally recognized for its role in skeletal muscle energy metabolism, is increasingly emerging as a mitochondria-targeted theranostic agent with significant relevance to the framework of predictive, preventive, and personalized medicine (PPPM). However, several critical gaps currently limit its translation into clinical practice: (1) the lack of sensitive and standardized biomarkers for early detection of bioenergetic deficits, (2) limited incorporation of creatine profiling into predictive risk models, (3) insufficient personalization of supplementation strategies despite known interindividual variability in transporter function, endogenous synthesis, and tissue kinetics, and (4) underdeveloped clinical validation of advanced creatine formulations and delivery systems. This mini review addresses these unmet needs by consolidating evidence on creatine's multifaceted biological functions-including stabilization of mitochondrial membranes, regulation of oxidative stress, support of mitochondrial biogenesis, and modulation of apoptotic signaling-across physiological and pathological states. By sustaining ATP homeostasis via the creatine kinase-phosphocreatine system and influencing mitochondrial dynamics and redox balance, creatine represents both a therapeutic and diagnostic candidate for diseases characterized by impaired bioenergetics. From a PPPM perspective, creatine profiling through biofluids, tissue sampling, and advanced imaging (e.g., proton magnetic resonance spectroscopy) offers a minimally invasive approach for early detection, patient stratification, and monitoring of mitochondrial function. Personalized intervention strategies-guided by molecular and phenotypic profiling-have the potential to maximize efficacy and minimize risk, while creatine loading or depletion tests may serve as functional biomarkers of mitochondrial reserve capacity and supplementation responsiveness. Finally, integration of creatine-centered diagnostics and therapeutics with multi-omics data, computational modeling, and digital health monitoring could overcome existing translational barriers. By reframing creatine from a sports nutrition supplement to a scalable, safe, and cost-effective component of mitochondrial medicine, this review outlines a pathway to address current diagnostic, predictive, and therapeutic deficits, ultimately supporting proactive, systems-level approaches to health maintenance and disease prevention.

Keywords:  Bioenergetics; Creatine; Digital health platform; Metabolic; Mitochondria; Neurodegenerative; Predictive preventive personalized medicine (PPPM / 3PM); Real-time monitoring; Sports nutrition; Theranostics; Wearable biosensors

DOI:  https://doi.org/10.1007/s13167-025-00420-9