bims-mistre 2025-05-11 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–05–11
fifteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial Dysfunction in Cardiac Diseases: Insights into Pathophysiology and Clinical Outcomes.
Mitochondrial fatty acid oxidation dysfunction impairs autophagic flux through ATP deficiency-caused lysosomal pH abnormity.
Say hello to my little friend… micronutraceuticals in neuroenergetics, neuronal health, and neurodegenerative diseases.
Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.
Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise.
Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.
The role of ferroptosis in Alzheimer's disease: Mechanisms and therapeutic potential (Review).
Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.
The Role of N6-Methyladenosine in Mitochondrial Dysfunction and Pathology.
(-)-Epigallocatechin-3-gallate and chlorogenic acid in combination with vitamin D as a Therapeutic Approach for Letrozole-Induced Polycystic ovary syndrome (PCOS) rats: Biochemical and Hormonal Modulation.
Unlocking the Potential of Curcumae Rhizoma Aqueous Extract in Stress Resistance and Extending Lifespan in Caenorhabditis elegans.
Oleoylethanolamine precursor triggers lipolysis during Time-Restricted Intermittent Fasting and promotes longevity and healthy aging of Caenorhabditis elegans.
Fenofibrate inhibits activation of cGAS-STING pathway by alleviating mitochondrial damage to attenuate inflammatory response in diabetic dry eye.
The Power Struggle: Kynurenine Pathway Enzyme Knockouts and Brain Mitochondrial Respiration.
Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.

Curr Cardiol Rev. 2025 May 06.

Mitochondrial Dysfunction in Cardiac Diseases: Insights into Pathophysiology and Clinical Outcomes.

Syed Shadab Ahmad, Javed Akhtar Ansari, Tarique Mahmood Ansari, Syed Mehdi Hasan Zaidi.

  Mitochondrial dysfunction plays a crucial role in the pathogenesis of various cardiac diseases, including heart failure, ischemic cardiomyopathy, and drug-induced cardiotoxicity. Mitochondria are essential for cellular energy production, calcium homeostasis, redox balance, and apoptotic regulation, making their proper function vital for cardiac health. Dysfunctional mitochondria contribute to excessive reactive oxygen species (ROS) production, impaired ATP synthesis, and disruption of mitochondrial dynamics, leading to cardiomyocyte damage and cell death. Emerging research highlights mitochondrial dynamics, including fission, fusion, mitophagy, and biogenesis, as critical determinants of cardiac homeostasis. Perturbations in these processes exacerbate myocardial injury and heart failure progression. Additionally, chemotherapy-induced cardiotoxicity, primarily from anthracyclines, is closely linked to mitochondrial damage, underscoring the need for targeted therapeutic strategies. Pharmacological interventions, such as antioxidants, mitochondrial-targeted drugs, and cardioprotective agents, have shown promise in mitigating mitochondrial dysfunction-related cardiac toxicity. Furthermore, lifestyle modifications, including exercise and dietary interventions, are being explored to enhance mitochondrial resilience in cardiac tissues. Advanced imaging techniques and biomarker-based diagnostics are improving the early detection of mitochondrial dysfunction in cardiac diseases. Emerging therapeutic strategies, such as mitochondrial transplantation, gene therapy, and precision medicine approaches, hold potential for targeted intervention. Despite these advances, challenges remain in translating mitochondrial-targeted therapies into clinical practice due to complexities in mitochondrial regulation and inter-organ communication. Future research should focus on optimizing mitochondrial-targeted interventions, improving diagnostic precision, and exploring novel molecular pathways to mitigate cardiac mitochondrial dysfunction. A comprehensive understanding of mitochondrial pathophysiology in cardiac diseases will pave the way for innovative treatment strategies aimed at preserving cardiac function and reducing the burden of heart failure.

Keywords:  Mitochondrial dysfunction; cardiac toxicity; cardiomyopathy; cardiovascular diseases; disease.; health

DOI:  https://doi.org/10.2174/011573403X379197250417061904
J Nutr Biochem. 2025 May 02. pii: S0955-2863(25)00106-8. [Epub ahead of print] 109943

Mitochondrial fatty acid oxidation dysfunction impairs autophagic flux through ATP deficiency-caused lysosomal pH abnormity.

Yan-Yu Zhang, Ze-Dong Lv, Mai Wang, Jun-Xian Wang, Samwel Mchele Limbu, Fang Qiao, Li-Qiao Chen, Mei-Ling Zhang, Yuan Luo, Zhen-Yu Du.

  Autophagy, a pivotal lysosomal degradation process, plays crucial roles in cellular homeostasis and energy metabolism. Mitochondrial fatty acid oxidation (FAO), a key mitochondrial function, is crucial for energy production. Generally, mitochondrial dysfunction exerts negative effects on autophagy, but the regulatory role of mitochondrial FAO dysfunction on the autophagic process remains unclear. The present study aimed to elucidate the role and mechanism of mitochondrial FAO in regulating autophagy process. We used Nile tilapia (Oreochromis niloticus) as a model and inhibited mitochondrial FAO by dietary mildronate feeding or knocking down carnitine palmitoyltransferase 1a. We found that mitochondrial FAO inhibition enhanced autophagy initiation and lysosomal proliferation accompanied by decreased autophagy degradation activity due to lysosomal acidification abnormity. Moreover, mitochondrial FAO inhibition decreased adenosine triphosphate (ATP) production and elevated adenosine monophosphate (AMP)/ATP promoted autophagy initiation via the AMP-activated protein kinase-serine/threonine kinase 1 pathway. Furthermore, mitochondrial FAO inhibition upregulated peroxisome proliferator-activated receptor alpha and retinoid X receptor alpha protein expression, which promoted transcription factor EB mRNA and its protein expression. Meanwhile, mitochondrial FAO inhibition led to lysosomal alkalinization, which is due to a pH increase caused by v-ATPase V1/V0 imbalance and ATP deficiency from mitochondrial dysfunction. Collectively, our results highlight the role of mitochondrial FAO in maintaining lysosomal homeostasis and autophagic flux through stabilizing lysosomal acidification.

Keywords:  autophagy; fatty acid oxidation inhibition; lysosome; mitochondrial dysfunction; vacuolar ATPase

DOI:  https://doi.org/10.1016/j.jnutbio.2025.109943
Front Neurosci. 2025 ;19 1498655

Say hello to my little friend… micronutraceuticals in neuroenergetics, neuronal health, and neurodegenerative diseases.

Shayne Mason.

  Vitamins and minerals (micronutraceuticals) maintain good health. However, the specific effects of these micronutraceuticals on brain health are often overlooked, or not even known. In this review, an overview of the direct and indirect effects of micronutraceuticals on brain energy metabolism (neuroenergetics) and neuronal health is provided. Thereafter, a holistic summary of the existing studies that have shown the impact of micronutraceuticals on neurodegenerative diseases. Lastly, this review concludes by identifying several research gaps that remain and provides suggestions for future research on these hot topics.

Keywords:  brain; energy metabolism; neurodegenerative disease; neuroenergetics; neurons; vitamins

DOI:  https://doi.org/10.3389/fnins.2025.1498655
Ageing Res Rev. 2025 May 02. pii: S1568-1637(25)00108-4. [Epub ahead of print]109 102762

Sestrin2 is a central regulator of mitochondrial stress responses in disease and aging.

Ivo F Machado, Carlos M Palmeira, Anabela P Rolo.

  Mitochondria supply most of the energy for cellular functions and coordinate numerous cellular pathways. Their dynamic nature allows them to adjust to stress and cellular metabolic demands, thus ensuring the preservation of cellular homeostasis. Loss of normal mitochondrial function compromises cell survival and has been implicated in the development of many diseases and in aging. Although exposure to continuous or severe stress has adverse effects on cells, mild mitochondrial stress enhances mitochondrial function and potentially extends health span through mitochondrial adaptive responses. Over the past few decades, sestrin2 (SESN2) has emerged as a pivotal regulator of stress responses. For instance, SESN2 responds to genotoxic, oxidative, and metabolic stress, promoting cellular defense against stress-associated damage. Here, we focus on recent findings that establish SESN2 as an orchestrator of mitochondrial stress adaptation, which is supported by its involvement in the integrated stress response, mitochondrial biogenesis, and mitophagy. Additionally, we discuss the integral role of SESN2 in mediating the health benefits of exercise as well as its impact on skeletal muscle, liver and heart injury, and aging.

Keywords:  Aging; Liver; Mitochondria; Mitohormesis; Muscle; Sestrin2

DOI:  https://doi.org/10.1016/j.arr.2025.102762
Am J Physiol Heart Circ Physiol. 2025 May 06.

Loss of RET-ROS at complex I induces diastolic dysfunction in mice that is reversed by aerobic exercise.

Ana Vujic, Amy Koo, Guillaume Bidault, Jan Lj Miljkovic, Andrew M James, Andreas Dannhorn, Xiaowen Duan, Lucy M Davis, Jiro Abe, Joyce Valadares, Jordan J Lee, Alexis Diaz-Vegas, Keira Turner, Richard Goodwin, Daniel J Fazakerley, Antonio Vidal Puig, Michael P Murphy, Thomas Krieg.

  Central to the development of heart failure with preserved ejection fraction (HFpEF) is the redox disruption of metabolic processes, however, the underlying mechanisms are not fully understood. This study utilized a murine model (ND6) carrying a homoplasmic mitochondrial DNA point mutation (ND6 G13997A), which maintains functional NADH oxidation but lacks the site-specific reactive oxygen species (ROS) generation via reverse electron transport (RET). We demonstrate that mice with RET-ROS deficiency have reduced exercise capacity despite higher lean body mass, impaired resilience to high-fat/high-sucrose dietary stress, and cardiac hypertrophy with diastolic dysfunction. Importantly, dobutamine-induced stress elevated succinate levels in the heart, accompanied by RET-ROS production in WT but not in ND6 mice. Furthermore, ND6 mice showed perturbation in metabolite profiles following dobutamine stress. Mechanistically, the ND6 heart had an upregulated expression of fatty acid transport, oxidation, and synthesis genes (CD36, Cpt1b, Acly, Fas, Elovl6 and Scd1) and increased protein levels of lipid metabolism regulators (acetyl-CoA carboxylase and perilipin 2). Interestingly, 8 weeks of forced treadmill running increased acetyl-CoA abundance, alleviated metabolic stress, and improved diastolic function in RET-ROS mutant hearts. In summary, these findings reveal a critical role for RET-ROS in regulating exercise capacity and cardiometabolic health, identifying it as a potentially selective target for modulating cardiac metabolism.

Keywords:  HFpEF; RET-ROS; exercise; lipid metabolism; mitochondria

DOI:  https://doi.org/10.1152/ajpheart.00482.2024
J Appl Physiol (1985). 2025 May 08.

Effect of aging, endurance training, and denervation on innate immune signaling in skeletal muscle.

Priyanka Khemraj, Anastasiya Kuznyetsova, David A Hood.

  Skeletal muscle function relies on mitochondria for energy and for mediating its unique adaptive plasticity. The NLRP3 inflammasome complex is an innate immune mechanism that responds to mitochondrial damage-associated molecular patterns (DAMPS), however its activity relative to mitochondrial dysfunction in muscle requires exploration. The purpose of this study was to characterize immune signaling and mitochondrial function in muscle during aging, endurance training, and disuse induced by denervation. Denervation led to decreases in muscle mass, mitochondrial content, and impaired respiration. Protein analyses revealed increases in NF-κB p65 and downstream inflammatory markers including NLRP3, caspase-1, GSDMD-N, STING and IL-1β, along with pro-apoptotic BAX and AIF. When assessing potential DAMPS, denervation led to increased ROS production but no changes in cytosolic mtDNA levels, relative to total mtDNA. Since we hypothesized that inflammasome activation would be increased with age, we studied young (6-8 months) and aged (21-22 months) mice that remained sedentary or underwent a 6-week voluntary running protocol. Aging resulted in marked increases in the expression of multiple pro-inflammatory and pro-apoptotic proteins. Remarkably, training uniformly attenuated age-related increases in BAX, NLRP3, caspase-1, STING, and GSDMD protein expression, and tended to reduce the elevated level of cytosolic mtDNA evident in aged muscle. Training adaptations were evident also in the aged animals by the preservation of muscle mass and improvements in oxygen consumption and endurance performance and were achieved despite a lower training distance than in young animals. Our results strongly implicate endurance training as a promising therapeutic for combatting disuse and age-related inflammation in skeletal muscle.

Keywords:  NLRP3 Inflammasome; exercise; mitochondria; mitochondrial biogenesis; muscle disuse

DOI:  https://doi.org/10.1152/japplphysiol.00038.2025
Mol Med Rep. 2025 Jul;pii: 192. [Epub ahead of print]32(1):

The role of ferroptosis in Alzheimer's disease: Mechanisms and therapeutic potential (Review).

Heng Zeng, Zhaohui Jin.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by insidious onset and progressive symptom deterioration. It extends beyond a simple aging process, involving irreversible and progressive neurological degeneration that impairs brain function through multiple etiologies. Iron dysregulation is implicated in the pathophysiology of AD; however, the precise mechanisms remain unclear. Additionally, vitamin E and selenium are key in regulating ferroptosis through their antioxidant properties. The present review examined the mechanistic pathways by which ferroptosis contributes to AD, the regulatory roles of vitamin E, selenium, ferrostatin‑1, N‑acetylcysteine and curcumin, and their potential as therapeutic agents to mitigate neurodegeneration.

Keywords:  Alzheimer's disease; drug; ferroptosis; pathophysiology

DOI:  https://doi.org/10.3892/mmr.2025.13557
Basic Res Cardiol. 2025 May 07.

Altered protein homeostasis in cardiovascular diseases contributes to Alzheimer's-like neuropathology.

Nirjal Mainali, Meenakshisundaram Balasubramaniam, Sonu Pahal, W Sue T Griffin, Robert J Shmookler Reis, Srinivas Ayyadevara.

  Cardiovascular diseases (CVDs) are the leading cause of death worldwide. CVD is known to increase the risk of subsequent neurodegeneration but the mechanism(s) and proteins involved have yet to be elucidated. We previously showed that myocardial infarction (MI), induced in mice and compared to sham-MI mice, leads to increases in protein aggregation, endoplasmic reticulum (ER) stress in both heart and brain, and changes in proteostatic pathways. In this study, we further investigate the molecular mechanisms altered by induced MI in mice, which were also implicated by proteomics of postmortem human hippocampal aggregates from Alzheimer's disease (AD) and cardiovascular disease (CVD) patients, vs. age-matched controls (AMC). We utilized intra-aggregate crosslinking to identify protein-protein contacts or proximities, and thus to reconstruct aggregate "contactomes" (nonfunctional interactomes). We used leave-one-out analysis (LOOA) to determine the contribution of each protein to overall aggregate cohesion, and gene ontology meta-analyses of constituent proteins to define critical organelles, processes, and pathways that distinguish AD and/or CVD from AMC aggregates. We identified influential proteins in both AD and CVD aggregates, many of which are associated with pathways or processes previously implicated in neurodegeneration such as mitochondrial, oxidative, and endoplasmic-reticulum stress; protein aggregation and proteostasis; the ubiquitin proteasome system and autophagy; axonal transport; and synapses.

Keywords:  Alzheimer’s disease; Cardiovascular disease; Crosslinking studies; Leave-one-out analysis; Protein aggregates

DOI:  https://doi.org/10.1007/s00395-025-01109-w
Int J Mol Sci. 2025 Apr 11. pii: 3624. [Epub ahead of print]26(8):

The Role of N6-Methyladenosine in Mitochondrial Dysfunction and Pathology.

Wenxin Yan, Saqirile, Ke Li, Kexin Li, Changshan Wang.

  Mitochondria are indispensable in cells and play crucial roles in maintaining cellular homeostasis, energy production, and regulating cell death. Mitochondrial dysfunction has various manifestations, causing different diseases by affecting the diverse functions of mitochondria in the body. Previous studies have mainly focused on mitochondrial-related diseases caused by nuclear gene mutations or mitochondrial gene mutations, or mitochondrial dysfunction resulting from epigenetic regulation, such as DNA and histone modification. In recent years, as a popular research area, m6A has been involved in a variety of important processes under physiological and pathological conditions. However, there are few summaries on how RNA methylation, especially m6A RNA methylation, affects mitochondrial function. Additionally, the role of m6A in pathology through influencing mitochondrial function may provide us with a new perspective on disease treatment. In this review, we summarize several manifestations of mitochondrial dysfunction and compile examples from recent years of how m6A affects mitochondrial function and its role in some diseases.

Keywords:  N6-methydenosine; cancer; mitochondrial dysfunction

DOI:  https://doi.org/10.3390/ijms26083624
J Steroid Biochem Mol Biol. 2025 May 05. pii: S0960-0760(25)00100-1. [Epub ahead of print] 106772

(-)-Epigallocatechin-3-gallate and chlorogenic acid in combination with vitamin D as a Therapeutic Approach for Letrozole-Induced Polycystic ovary syndrome (PCOS) rats: Biochemical and Hormonal Modulation.

Sana Siddiqui, Rizwan Ahmad, Tariq Aziz, Aijaz Ahmed Khan, Hamid Ashraf, Shagufta Moin.

  Treatment with phytochemicals have shown promising results in managing various diseases including Polycystic ovary syndrome (PCOS) which is an endocrine gynecological disorder affecting reproductive aged women. This study has demonstrated that Epigallocatechin-3-gallate (EGCG) and chlorogenic acid (CGA) in combination with vitamin D can significantly reduce PCOS like characteristics including ovarian cysts, hyperandrogenism, fasting blood glucose level, insulin resistance, hyperlipidaemia, ROS formation, oxidative stress, DNA damage, and ovarian histomorphology in letrozole induced PCOS rats. PCOS was induced in female Wistar rats by giving 1mg/kg/day letrozole for 21 days through oral gavage. EGCG (100mg/kg/day) and CGA (120mg/kg/day) in combination with vitamin D (25mcg/kg/day) was given orally for 15 days, from day 21 to 35. Metformin treatment was used as a positive control. Histological, microscopic analysis, and chemiluminescent immunoassays were performed to evaluate decrement in PCOS like symptoms. Nitric oxide (RNS) production, antioxidant status, and the generation of reactive oxygen species (ROS) were also assessed. Ovary homogenates and plasma samples of rats were also examined for markers of protein, lipid, and DNA oxidation. Activities of enzymatic antioxidants (superoxide dismutase, catalase, glutathione reductase, Paraoxonase-1 status) were also evaluated. EGCG + vitamin D and CGA + vitamin D has been found to restore hormonal balance by modulating steroidogenic enzymes, they also improved antioxidant enzyme activity including SOD, catalase, glutathione reductase, PON-1 arylesterase, PON-1 CMPAase, etc. Similarly, EGCG + vitamin D and CGA + vitamin D treatment have shown efficacy in normalizing the estrus cycle, reducing ovarian cysts, and improving ovarian histomorphology. They also assisted in alleviating triglycerides and cholesterol levels and maintained liver function enzymes level. However, EGCG + vitamin D proves to have better therapeutic potential modulates glucose metabolic pathways, by reducing blood glucose levels, advanced glycation end product formation, decreasing ROS generation and oxidative stress; consequently, lowers hyperandrogenism and insulin resistance. Overall, EGCG + vitamin D treatment offers a comprehensive approach in managing PCOS by targeting multiple pathways associated with this disorder, making it a potential alternative to conventional therapies.

Keywords:  Polycystic ovary syndrome (PCOS); histology; hormone profile; insulin resistance; lipid profile; oxidative stress index

DOI:  https://doi.org/10.1016/j.jsbmb.2025.106772
Molecules. 2025 Apr 08. pii: 1668. [Epub ahead of print]30(8):

Unlocking the Potential of Curcumae Rhizoma Aqueous Extract in Stress Resistance and Extending Lifespan in Caenorhabditis elegans.

Linyao Jing, Yanlin Zhao, Lijun Jiang, Fei Song, Lu An, Edmund Qi, Xueqi Fu, Jing Chen, Junfeng Ma.

  The enhancement of stress resistance is crucial for delaying aging and extending a healthy lifespan. Traditional Chinese medicine (TCM), a cherished treasure of Chinese heritage, has shown potential in mitigating stress and promoting longevity. This study integrates network pharmacology and in vivo analysis to investigate the mechanisms and effects of Curcumae Rhizoma (C. Rhizoma), known as "E Zhu" in Chinese. Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS) identified 10 active compounds in its aqueous extract, interacting with 128 stress-related targets. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed pathways such as stress response, FoxO signaling, and insulin resistance. In Caenorhabditis elegans, 10 mg/mL of C. Rhizoma aqueous extract improved resistance to UV, thermal, oxidative, and pathogen-induced stress, extending lifespan in a dose-dependent manner. Mechanistically, it reduced reactive oxygen species (ROS), increased superoxide dismutase (SOD) activity, and enhanced UV resistance via the insulin/IGF-1 pathway and DAF-16 translocation. Molecular docking highlighted hexahydrocurcumin (HHC) and related compounds as key bioactives. Furthermore, we also observed that C. Rhizoma aqueous extract significantly extended both the lifespan and healthspan of nematodes. These findings highlight the potential of C. Rhizoma in stress mitigation and longevity promotion, offering valuable insights into the therapeutic applications of TCM.

Keywords:  Caenorhabditis elegans; IIS; ROS; molecular docking; network pharmacology; stress resistance

DOI:  https://doi.org/10.3390/molecules30081668
J Physiol Biochem. 2025 May 07.

Oleoylethanolamine precursor triggers lipolysis during Time-Restricted Intermittent Fasting and promotes longevity and healthy aging of Caenorhabditis elegans.

Thondimuthu Vinitha, Rajasekharan Sharika, Krishnaswamy Balamurugan.

  Intermittent fasting (IF), Time-Restricted Intermittent Fasting (TRIF), and fasting-mimicking diets have gained popularity among weight loss programs. The body efficiently utilizes its energy reserves to activate metabolic processes in response to food intake. Modifying food regimens can alter/extend life span and promote healthy aging by activating specific metabolic processes. However, changes in general lipid metabolism, especially the alteration in N-acylethanolamide (NAE) regulation and their role in promoting lipolysis and extending life span during TRIF, are still inadequately explored. To bridge the knowledge gap, this study focuses on enhancing Oleoylethanolamine (OEA), a precursor molecule that instigates satiety, promotes lipolysis and extends the life span of model system, Caenorhabditis elegans. TRIF regimen in C. elegans induces OEA, which in turn lead to satiety followed by lipolysis and ATP synthesis. Lipolysis is stimulated by the increase in Adipose Tissue Triglyceride Lipase-1 (ATGL-1) activity that results from the enrichment in OEA precursor. In addition, the TRIF regimen induces oxidative stress resistance in C. elegans. Subsequently, this promotes longevity and slow aging in C. elegans by altering the insulin/ insulin-like growth factor signaling (IIS) pathway. The present study suggested the beneficial effects of time-restricted fasting in the eukaryotic model nematodes through the activation of lipid metabolism that involves enhanced production of OEA precursors which promotes lipolysis. In addition, the data revealed that the increased ATP production resulted in oxidative stress tolerance that promoted longevity and slow aging processes.

Keywords:   C. elegans ; GC-MS analysis; Lipolysis; Longevity; Oleic acid; Time- Restricted Intermittent Fasting

DOI:  https://doi.org/10.1007/s13105-025-01087-6
Free Radic Biol Med. 2025 May 06. pii: S0891-5849(25)00658-6. [Epub ahead of print]

Fenofibrate inhibits activation of cGAS-STING pathway by alleviating mitochondrial damage to attenuate inflammatory response in diabetic dry eye.

Xia Sun, Jingyi Zhang, Xiaoxia Li, Yansheng Li, Xinmei Zhao, Xiaowei Sun, Yuanbin Li.

  The cyclic GMP-AMP synthase (cGAS) and Stimulator of Interferon Genes (STING) signaling pathway are critical regulators of inflammation. This study aims to investigate the role of the cGAS-STING signaling pathway in diabetic dry eye disease (DDE) and further explore the therapeutic efficacy and underlying mechanism of fenofibric acid in DDE. Using single-cell RNA sequencing data from the Gene Expression Omnibus (GEO) database, combined with the STZ-induced DDE mouse model and high-glucose conditions in immortalized human corneal epithelial cells (HCE-T), we observed mitochondrial dysfunction in the diabetic cornea, and identified that the cGAS-STING signaling pathway plays a pivotal role in the pathogenesis of DDE. Notably, we found that the inhibitor H151 reversed the ocular surface inflammatory response via the cGAS-STING pathway. Further investigation revealed that fenofibrate alleviated corneal inflammation in diabetic mice by inhibiting reactive oxygen species (ROS) production, restoring mitochondrial membrane potential, and suppressing the activation of the cGAS-STING signaling pathway. In conclusion, this study highlights the crucial role of the cGAS-STING signaling pathway in DDE and proposes that fenofibrate alleviates mitochondrial damage to inhibit this pathway, offering novel strategy for the treatment of DDE.

Keywords:  cGAS-STING pathway; diabetic-related dry eye; fenofibrate; mitochondrial damage; ocular surface inflammation

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.383
J Neurochem. 2025 May;169(5): e70075

The Power Struggle: Kynurenine Pathway Enzyme Knockouts and Brain Mitochondrial Respiration.

László Juhász, Krisztina Spisák, Boglárka Zsuzsa Szolnoki, Anna Nászai, Ágnes Szabó, Attila Rutai, Szabolcs Péter Tallósy, Andrea Szabó, József Toldi, Masaru Tanaka, Keiko Takeda, Kinuyo Ozaki, Hiromi Inoue, Sayo Yamamoto, Etsuro Ono, Mihály Boros, József Kaszaki, László Vécsei.

  Numerous illnesses, including neurological and mental disorders, have been associated with mitochondrial dysfunction. Disruptions in mitochondrial respiration and energy production have been linked to dysmetabolism of the tryptophan (Trp)-kynurenine (KYN) pathway, which produces a diverse array of bioactive metabolites. Kynurenic acid (KYNA) is a putative neuroprotectant. The exact mechanisms through which Trp-KYN metabolic dysregulation affects mitochondrial function remain largely unclear. This study investigates the impact of the genetic deletion of kynurenine aminotransferase (KAT) enzymes, which are responsible for KYNA synthesis, on mitochondrial function, specifically mitochondrial respiration and ATP synthesis, and its potential role in neuropsychiatric pathology. CRISPR/Cas9-induced knockout mouse strains kat1-/-, kat2-/-, and kat3-/- were generated. Eight-to-ten-week-old male mice were used, and cerebral and hepatic respiration, complex I- and II-linked oxidative phosphorylation (CI and CII OXPHOS), and complex IV (CIV) activity were measured using high-resolution respirometry. Mitochondrial membrane potential changes were measured with Fluorescence-Sensor Blue and safranin dye. KAT knockout mice exhibited significantly lower cerebellar respiration (CI OXPHOS, CII OXPHOS, and CIV activity) compared to wild-type mice. Lower baseline respiration and attenuated OXPHOS activities were observed in the hippocampus and striatum, particularly in kat2-/- and kat3-/- mice. Non-neuronal tissues showed reduced CIV activity, while ADP-stimulated CI and CII OXPHOS remained unchanged. The deletion of the KAT genes significantly impairs mitochondrial respiration and ATP synthesis, potentially contributing to pathogenesis. This study highlights the importance of KYNA in mitochondrial function, offering new insights into potential therapeutic targets for various disorders. Targeting the KYN pathway could mitigate mitochondrial dysfunction in a variety of diseased conditions.

Keywords:  kynurenic acid; kynurenine aminotransferase; mitochondrial dysfunction; neurodegenerative diseases; psychiatric diseases; transgenic mice; tryptophan

DOI:  https://doi.org/10.1111/jnc.70075
J Diabetes Investig. 2025 May 07.

Revisiting the thrifty substrate hypothesis: Ketone bodies as cardioprotective fuels in diabetes and SGLT2 inhibitor therapy.

Yoriyasu Suzuki, Tetsuya Amano.

SGLT2 inhibitors increase circulating β-hydroxybutyrate (β-OH-B), a ketone body that may enhance cardiac efficiency in HFrEF. The "thrifty substrate hypothesis" suggests β-OH-B provides more ATP per oxygen consumed than glucose or fatty acids. Clinical studies by Nielsen et al. and Solis-Herrera et al. show that β-OH-B infusion improves cardiac output, ejection fraction, and myocardial blood flow in HFrEF patients-with and without diabetes-without increasing oxygen demand or reducing glucose uptake. These findings support β-OH-B as an additive metabolic fuel, highlighting the therapeutic potential of enhancing cardiac metabolic flexibility.

DOI: https://doi.org/10.1111/jdi.70068