bims-mistre 2025-04-06 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–04–06
fifteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.
The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.
Cardiac-specific overexpression of serum response factor regulates age-associated decline in mitochondrial function.
Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.
Multi-target approach to Alzheimer's disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid- modulating mechanisms.
The Role of Mitochondrial Dysfunction-Mediated Changes in Immune Cytokine Expression in the Pathophysiology and Treatment of Major Depressive Disorder.
Pre-clinical evidence for mitochondria as a therapeutic target for luteolin: A mechanistic view.
Upstream Stimulatory Factor 2 Protects Cardiomyocytes by Regulating Mitochondrial Homeostasis.
α‑ketoglutarate protects against septic cardiomyopathy by improving mitochondrial mitophagy and fission.
APOE4 impairs autophagy and Aβ clearance by microglial cells.
Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.
Strategic approaches to assess and quantify the oxidative stress biomarkers in complex biological systems.
Ginsenoside CK modulates glucose metabolism via PPARγ to ameliorate SCOP-induced cognitive dysfunction.
Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue.
Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.

Naunyn Schmiedebergs Arch Pharmacol. 2025 Mar 31.

Mitochondrial-based therapies for neurodegenerative diseases: a review of the current literature.

Al-Hassan Soliman Wadan, Ahmed H Shaaban, Mohamed Z El-Sadek, Salah Abdelfatah Mostafa, Ahmed Sherief Moshref, Ahmed El-Hussein, Doha El-Sayed Ellakwa, Samah S Mehanny.

  Neurodegenerative disorders present significant challenges to modern medicine because of their complex etiology, pathogenesis, and progressive nature, which complicate practical treatment approaches. Mitochondrial dysfunction is an important contributor to the pathophysiology of various neurodegenerative illnesses, including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). This review paper examines the current literature highlighting the multifaceted functions of mitochondria, including energy production, calcium signaling, apoptosis regulation, mitochondrial biogenesis, mitochondrial dynamics, axonal transport, endoplasmic reticulum-mitochondrial interactions, mitophagy, mitochondrial proteostasis, and their crucial involvement in neuronal health. The literature emphasizes the increasing recognition of mitochondrial dysfunction as a critical factor in the progression of neurodegenerative disorders, marking a shift from traditional symptom management to innovative mitochondrial-based therapies. By discussing mitochondrial mechanisms, including mitochondrial quality control (MQC) processes and the impact of oxidative stress, this review highlights the need for novel therapeutic strategies to restore mitochondrial function, protect neuronal connections and integrity, and slow disease progression. This comprehensive review aims to provide insights into potential interventions that could transform the treatment landscape for neurodegenerative diseases, addressing symptoms and underlying pathophysiological changes.

Keywords:  Mitochondria-focused therapies; Mitochondrial dysfunction; Neurodegenerative diseases; Oxidative stress; Therapeutic strategies

DOI:  https://doi.org/10.1007/s00210-025-04014-0
bioRxiv. 2025 Mar 27. pii: 2025.03.19.644244. [Epub ahead of print]

The Silent Saboteur: How Mitochondria Shape the Long-Term Fate of the Injured Brain.

Sahan Bs Kansakar, Sydney P Sterben, Charitha C Anamala, Mitchell D Thielen, Volha Liaudanskaya.

Traumatic brain injury (TBI) is a major risk factor for neurodegenerative diseases, including Alzheimer's disease (AD), yet the mechanistic link remains unclear. Here, we integrated human patient-derived transcriptomics with a 3D in vitro brain injury model to dissect cell-specific mitochondrial dysfunction as a driver of injury-induced neurodegeneration. Comparative transcriptomic analysis at 6 and 48 hours post-injury revealed conserved mitochondrial impairments across excitatory neurons, interneurons, astrocytes, and microglia. Using a novel cell-specific mitochondria tracking system, we demonstrate prolonged neuronal mitochondrial fragmentation, bioenergetic failure, and metabolic instability, coinciding with the emergence of AD markers, including pTau, APP, and Aβ42/40 dysregulation. Glial mitochondria exhibited delayed but distinct metabolic dysfunctions, with astrocytes impaired metabolic support and microglia sustained chronic inflammation. These findings establish neuronal mitochondrial failure as an early trigger of injury-induced neurodegeneration, reinforcing mitochondrial dysfunction as a therapeutic target for preventing TBI-driven AD pathology.

DOI: https://doi.org/10.1101/2025.03.19.644244
Geroscience. 2025 Mar 31.

Cardiac-specific overexpression of serum response factor regulates age-associated decline in mitochondrial function.

Pankaj Patyal, Gohar Azhar, Xiaomin Zhang, Ambika Verma, Jeanne Y Wei.

  Cardiac aging is an intrinsic process that leads to impaired heart function, along with cellular and molecular changes. Recent research highlights the important role of mitochondria in cardiac function, due to the heart's high energy demands. Serum response factor (SRF), a transcription factor involved in regulating actin and smooth muscle gene expression, is well known as a regulator of various aspects of cardiac function. However, its role in mitochondrial regulation and cardiac aging is poorly understood. Our laboratory generated a transgenic mouse model with cardiac-specific overexpression of SRF, which exhibits characteristics of diastolic dysfunction and accelerated cardiac aging in young adult transgenic mice. In this study, we tested how cardiac-specific overexpression of SRF affects age associated mitochondrial dysfunction in the heart. Our results showed that cardiac specific SRF overexpression reduced the lifespan of mice and induced cardiomyopathy. Histological analysis revealed cardiac hypertrophy and fibrosis in transgenic mice hearts. SRF overexpression led to significant alterations in mitochondrial structure and function, including reduced mitochondrial biogenesis and dysregulation of oxidative phosphorylation. These changes were accompanied by increased oxidative stress, a decline in antioxidant enzyme activity, and disrupted calcium handling. Moreover, cardiac-specific SRF overexpression activated the MAPK signaling pathway. Our findings were further corroborated by similar mitochondrial dysfunction observed in a human cardiomyocyte cells transfected with SRF plasmid. Taken together, these findings suggest that SRF plays a novel role in cardiac aging, thus establishing SRF as a potential therapeutic target for mitigating age-associated decline in mitochondrial function and preserving cardiac health in older adults.

Keywords:  Calcium homeostasis; Cardiac aging; MAPK; Mitochondria; Oxidative stress; Serum response factor

DOI:  https://doi.org/10.1007/s11357-025-01629-2
Mitochondrion. 2025 Mar 28. pii: S1567-7249(25)00033-9. [Epub ahead of print]83 102036

Therapeutic potential of DDQ in enhancing mitochondrial health and cognitive function in Late-Onset Alzheimer's disease.

Sudhir Kshirsagar, Rainier Vladlen Alvir, Jangampalli Adi Pradeepkiran, Arubala P Reddy, P Hemachandra Reddy.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, mitochondrial dysfunction, and neuroinflammation. This study evaluates the therapeutic potential of DDQ, a small molecule in the humanized Abeta knockin (hAbKI) mice that represents late-onset AD. Our findings demonstrate that DDQ treatment significantly improves cognitive performance as assessed through behavioral tests, including the rotarod, open field, Y-maze, and Morris water maze, compared to untreated hAbKI mice. At the molecular level, DDQ promoted mitochondrial biogenesis, as evidenced by enhanced expression of key proteins like PGC1α, NRF1, and TFAM. Additionally, DDQ treatment facilitated mitophagy, as indicated by elevated levels of PINK1 and Parkin, and reduced neuroinflammation, reflected by decreased Iba1 and GFAP levels. Transmission electron microscopy analysis revealed a marked improvement in mitochondrial morphology, with increased mitochondrial length and reduced mitochondrial numbers in DDQ-treated mice. Furthermore, DDQ treatment led to an increase in mitophagic vacuoles, suggesting that it effectively removes dysfunctional mitochondria. Taken together, for the first time, our study results support the potential of DDQ as a promising neuroprotective agent for late-onset AD, addressing mitochondrial dysfunction, neuroinflammation, and cognitive decline. Our study focused on developing small molecules that modulate mitophagy, mitochondrial dynamics and neuroinflammatory pathways for aging, AD and other neurodegenerative disorders.

Keywords:  Alzheimer’s disease; Behavioral tests; Cognitive function; DDQ; Mitochondrial biogenesis; Mitochondrial dysfunction; Mitophagy; Neurodegenerative disorders; Neuroinflammation; Neuroprotection; Transmission electron microscopy; hAbKI mouse model

DOI:  https://doi.org/10.1016/j.mito.2025.102036
Neurogenetics. 2025 Apr 01. 26(1): 39

Multi-target approach to Alzheimer's disease prevention and treatment: antioxidant, anti-inflammatory, and amyloid- modulating mechanisms.

Kashif Abbas, Mohd Mustafa, Mudassir Alam, Safia Habib, Waleem Ahmad, Mohd Adnan, Md Imtaiyaz Hassan, Nazura Usmani.

  Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaque accumulation, neurofibrillary tangles, neuroinflammation, and progressive cognitive decline, posing a significant global health challenge. Growing evidence suggests that dietary polyphenols may reduce the risk and progression of AD through multifaceted neuroprotective mechanisms. Polyphenols regulate amyloid proteostasis by inhibiting β/γ-secretase activity, preventing Aβ aggregation, and enhancing clearance pathways. Their strong antioxidant properties neutralize reactive oxygen species, chelate redox-active metals, and activate cytoprotective enzymes via Nrf2 signaling. This review examines the potential therapeutic targets, signaling pathways, and molecular mechanisms by which dietary polyphenols exert neuroprotective effects in AD, focusing on their roles in modulating amyloid proteostasis, oxidative stress, neuroinflammation, and cerebrovascular health. Polyphenols mitigate neuroinflammation by suppressing NF-κB signaling and upregulating brain-derived neurotrophic factor, supporting neuroplasticity and neurogenesis. They also enhance cerebrovascular health by improving cerebral blood flow, maintaining blood-brain barrier integrity, and modulating angiogenesis. This review examines the molecular and cellular pathways through which polyphenols exert neuroprotective effects, focusing on their antioxidant, anti-inflammatory, and amyloid-modulating roles. We also discuss their influence on key AD pathologies, including Aβ deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. Insights from clinical and preclinical studies highlight the potential of polyphenols in preventing or slowing AD progression. Future research should explore personalized dietary strategies that integrate genetic and lifestyle factors to optimize the neuroprotective effects of polyphenols.

Keywords:  Alzheimer’s; Antioxidants; Dementia; Neuroinflammation; Polyphenols; Tau hyperphosphorylation

DOI:  https://doi.org/10.1007/s10048-025-00821-y
Mol Neurobiol. 2025 Mar 31.

The Role of Mitochondrial Dysfunction-Mediated Changes in Immune Cytokine Expression in the Pathophysiology and Treatment of Major Depressive Disorder.

Wanjun Zhang, Tianyi Wang, Lei Li, Jiyi Xu, Jing Wang, Gang Wang, Jing Du.

  Recent studies have demonstrated an association between major depressive disorder (MDD) and both mitochondrial dysfunction and alterations in pro-inflammatory cytokine expression, suggesting that such changes may be key drivers of MDD pathogenesis. Mechanistically, changes in mitochondrial function are related to endoplasmic reticulum stress, reactive oxygen species production, oxidative phosphorylation, apoptosis, and disrupted calcium ion homeostasis, all of which trigger the activation of signaling cascades that affect the expression of pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferons. Certain factors present in the gut microbiota ecosystem can influence communication between microorganisms and the brain through the neuroendocrine, immune, and autonomic nervous systems, thereby altering mitochondrial function and cytokine production. This review article explores the means through which mitochondria regulate immune cytokine expression and the role of mitochondrial dysfunction in the pathogenesis and treatment of MDD to provide new perspectives for the diagnosis of this disease and the development of novel therapeutic interventions with greater efficacy and improved safety profiles.

Keywords:  Endoplasmic reticulum; Gut–brain axis; Immune cytokines; Major depressive disorder; Mitochondria; Reactive oxygen species

DOI:  https://doi.org/10.1007/s12035-025-04872-y
Chem Biol Interact. 2025 Mar 26. pii: S0009-2797(25)00122-X. [Epub ahead of print]413 111492

Pre-clinical evidence for mitochondria as a therapeutic target for luteolin: A mechanistic view.

Marcos Roberto de Oliveira.

  Pre-clinical evidence indicates that mitochondria may be a therapeutic target for luteolin (3',4',5,7-tetrahydroxyflavone; LUT) in different conditions. LUT modulates mitochondrial physiology in in vitro, ex vivo, and in vivo experimental models. This flavone exerted mitochondria-related antioxidant and anti-apoptotic effects, stimulated mitochondrial fusion and fission, induced mitophagy, and promoted mitochondrial biogenesis in human and animal cells and tissues. Moreover, LUT modulated the activity of components of the oxidative phosphorylation (OXPHOS) system, improving the ability of mitochondria to produce adenosine triphosphate (ATP) in certain circumstances. The mechanism of action by which LUT promoted mitochondrial benefits and protection are not completely clear yet. Nonetheless, LUT is a potential candidate to be utilized in mitochondrial therapy in the future. In this work, it is explored the mechanisms of action by which LUT modulates mitochondrial physiology in different pre-clinical experimental models.

Keywords:  Bioenergetics; Luteolin; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Mitophagy

DOI:  https://doi.org/10.1016/j.cbi.2025.111492
Int Heart J. 2025 ;66(2): 302-312

Upstream Stimulatory Factor 2 Protects Cardiomyocytes by Regulating Mitochondrial Homeostasis.

Wenbin Wu, Kexin Zhao, Kejuan Li, Ziwei Zhu, Yongnan Li, Jianshu Chen, Hong Ding, Xiaowei Zhang.

  Myocardial ischemia and hypoxia are the main causes of heart failure, and cardiomyocyte apoptosis induced by mitochondrial injury is the basis of adverse heart remodeling and heart failure. Upstream stimulatory factor 2 (USF2), a transcription factor involved in multiple cellular processes, was recently shown to play an active role in mitochondrial function and energy homeostasis. However, its involvement in cardiovascular disease has not been previously reported. In this study, we demonstrated that under hypoxic conditions, USF2 protein expression can be degraded via the ubiquitin-proteasome pathway in cardiomyocytes. The deletion of USF2 results in mitochondrial dysfunction and exacerbates mitochondrial damage, ultimately promoting apoptosis. Mechanistically, we demonstrated that USF2 deficiency induces apoptosis in cells by modulating the AMPK/mTOR signaling pathway. In conclusion, this study provides new insights into the protective role of USF2 in hypoxic cardiomyocyte injury and indicates that USF2 could be a potential therapeutic target for myocardial hypoxia.

Keywords:  Heart failure; Reactive oxygen species; mTOR signaling pathway

DOI:  https://doi.org/10.1536/ihj.23-619
Mol Med Rep. 2025 Jun;pii: 146. [Epub ahead of print]31(6):

α‑ketoglutarate protects against septic cardiomyopathy by improving mitochondrial mitophagy and fission.

Wei Wu, Qiong Ma, Bo-Tao Li, Shuang Shi, Gong-Chang Guan, Jun-Kui Wang, Bao-Yao Xue, Zhong-Wei Liu.

  Septic cardiomyopathy is a considerable complication in sepsis, which has high mortality rates and an incompletely understood pathophysiology, which hinders the development of effective treatments. α‑ketoglutarate (AKG), a component of the tricarboxylic acid cycle, serves a role in cellular metabolic regulation. The present study delved into the therapeutic potential and underlying mechanisms of AKG in ameliorating septic cardiomyopathy. A mouse model of sepsis was generated and treated with AKG via the drinking water. Cardiac function was assessed using echocardiography, while the mitochondrial ultrastructure was examined using transmission electron microscopy. Additionally, in vitro, rat neonatal ventricular myocytes were treated with lipopolysaccharide (LPS) as a model of sepsis and then treated with AKG. Mitochondrial function was evaluated via ATP production and Seahorse assays. Additionally, the levels of reactive oxygen species were determined using dihydroethidium and chloromethyl derivative CM‑H2DCFDA staining, apoptosis was assessed using a TUNEL assay, and the expression levels of mitochondria‑associated proteins were analyzed by western blotting. Mice subjected to LPS treatment exhibited compromised cardiac function, reflected by elevated levels of atrial natriuretic peptide, B‑type natriuretic peptide and β‑myosin heavy chain. These mice also exhibited pronounced mitochondrial morphological disruptions and dysfunction in myocardial tissues; treatment with AKG ameliorated these changes. AKG restored cardiac function, reduced mitochondrial damage and corrected mitochondrial dysfunction. This was achieved primarily through increasing mitophagy and mitochondrial fission. In vitro, AKG reversed LPS‑induced cardiomyocyte apoptosis and dysregulation of mitochondrial energy metabolism by increasing mitophagy and fission. These results revealed that AKG administration mitigated cardiac dysfunction in septic cardiomyopathy by promoting the clearance of damaged mitochondria by increasing mitophagy and fission, underscoring its therapeutic potential in this context.

Keywords:  AKG; fission; mitochondria; mitophagy; septic cardiomyopathy

DOI:  https://doi.org/10.3892/mmr.2025.13511
Inflamm Res. 2025 Apr 01. 74(1): 61

APOE4 impairs autophagy and Aβ clearance by microglial cells.

Rawan Bassal, Maria Rivkin-Natan, Alon Rabinovich, Daniel Moris Michaelson, Dan Frenkel, Ronit Pinkas-Kramarski.

  Alzheimer's disease (AD) is a predominant form of dementia in elderly. In sporadic AD and in families with higher risk of AD, correlation with apolipoprotein E4 (APOE) allele expression has been found. How APOE4 induces its pathological effects is still unclear. Several studies indicate that autophagy, a major degradation pathway trough the lysosome, may be compromised in AD. Here we studied, the effects of APOE isoforms expression in microglia cells. By using an in-situ model, the clearance of Aβ plaques from brain sections of transgenic 5xFAD mice by the APOE expressing microglia was examined. The results show that APOE4 microglia has Impairment In clearance of insoluble Aβ plaques as compared to APOE3 and APOE2 microglia. Furthermore, APOE4 affect the uptake of soluble Aβ. We found that microglia expressing APOE4 exhibit reduced autophagic flux as compared to those expressing APOE3. The autophagy inhibitor chloroquine also blocked Aβ plaque uptake in APOE3 expressing cells. Furthermore, we found that APOE4 expressing microglia have altered mitochondrial dynamics protein expression, mitochondrial morphology and mitochondrial activity compared to those expressing APOE2, and APOE3. Rapamycin treatment corrected Mitochondrial Membrane Potential in APOE4-expressing cells. Taken together, these findings suggest that APOE4 impairs the activation of autophagy, mitophagy, and Aβ clearance and that autophagy-inducing treatments, such as rapamycin, can enhance autophagy and mitochondrial functions in APOE4 expressing microglia. Our results reveal a direct link between APOE4 to autophagy activity in microglia, suggesting that the pathological effects of APOE4 could be counteracted by pharmacological treatments inducing autophagy, such as rapamycin.

Keywords:  Alzheimer's disease (AD); Amyloid β; Apolipoprotein E4 (apoE4); Autophagy

DOI:  https://doi.org/10.1007/s00011-025-02016-5
Int Immunopharmacol. 2025 Mar 28. pii: S1567-5769(25)00541-7. [Epub ahead of print]154 114551

Mitochondria-dependent innate immunity: A potential therapeutic target in Flavivirus infection.

Saurabh Losarwar, Bhaskaranand Pancholi, Raja Babu, Debapriya Garabadu.

  Mitochondria, known as the powerhouse of cells, play a crucial role in host innate immunity during flavivirus infections such as Dengue, Zika, West Nile, and Japanese Encephalitis Virus. Mitochondrial antiviral signaling protein (MAVS) resides on the outer mitochondrial membrane which is triggered by viral RNA recognition by RIG-I-like receptors (RLRs). This activation induces IRF3 and NF-κB signaling, resulting in type I interferon (IFN) production and antiviral responses. Upon flavivirus infection, mitochondrial stress and dysfunction may lead to the release of mitochondrial DNA (mtDNA) into the cytoplasm, which serves as a damage-associated molecular pattern (DAMP). Cytosolic mtDNA is sensed by cGAS (cyclic GMP-AMP synthase), leading to the activation of the STING (Stimulator of Interferon Genes) pathway to increase IFN production and expand inflammation. Flaviviral proteins control mitochondrial morphology by controlling mitochondrial fission (MF) and fusion (MFu), disrupting mitochondrial dynamics (MD) to inhibit MAVS signaling and immune evasion. Flaviviral proteins also cause oxidative stress, resulting in the overproduction of reactive oxygen species (ROS), which triggers NLRP3 inflammasome activation and amplifies inflammation. Additionally, flaviviruses drive metabolic reprogramming by shifting host cell metabolism from oxidative phosphorylation (OxPhos) to glycolysis and fatty acid synthesis, creating a pro-replicative environment that supports viral replication and persistence. Thus, the present review explores the complex interaction between MAVS, mtDNA, and the cGAS-STING pathway, which is key to the innate immune response against flavivirus infections. Understanding these mechanisms opens new avenues in therapeutic interventions in targeting mitochondrial pathways to enhance antiviral immunity and mitigate viral infection.

Keywords:  Flavivirus; Innate immunity; Mitochondria; Mitochondrial antiviral signaling protein (MAVS); Mitochondrial dynamics (MD); RIG-I-like receptors (RLRs)

DOI:  https://doi.org/10.1016/j.intimp.2025.114551
Bioanalysis. 2025 Apr 04. 1-14

Strategic approaches to assess and quantify the oxidative stress biomarkers in complex biological systems.

Padmasri Sai Nandana Aravapally, Naveen Chandrasekar, Arvind Verma, Ravi P Shah.

  Oxidative stress (OS) is an emerging research area in clinical and biological sciences due to its association with various diseases and physiological processes. OS occurs when there is an imbalance between the production of reactive oxygen species (ROS) and the body's ability to neutralize or repair the damage caused. Chronic oxidative stress is linked to diseases like diabetes, cardiovascular diseases, cancer, and neurodegenerative disorders. Accurate monitoring of OS is crucial for diagnosing diseases, evaluating disease progression, and predicting clinical results. Despite challenges in measuring free radicals due to their short half-life and low concentrations, it can be indirectly assessed through biomarkers like lipid peroxidation, DNA damage, and protein oxidation. The most effective analytical techniques for assessing OS biomarkers in various biological fluids were developed. Furthermore, an in-depth exploration of these various analytical methodologies, underscoring their sensitivity, specificity, and reliability in detecting low concentrations of biomarkers across complex matrices is necessary. A comprehensive literature search was conducted using databases such as Google Scholar, PubMed and Reaxys to identify relevant studies on OS biomarkers. This review explores the evolution of these techniques, highlighting advancements in sample preparation procedures and the specifications of each technique, offering a thorough evaluation of biomarker analysis.

Keywords:  Oxidative stress; biological fluids; biomarkers; matrix components; quantification; reactive oxygen species

DOI:  https://doi.org/10.1080/17576180.2025.2486929
Metab Brain Dis. 2025 Apr 03. 40(4): 168

Ginsenoside CK modulates glucose metabolism via PPARγ to ameliorate SCOP-induced cognitive dysfunction.

Na Li, Xingyu Fang, Hui Li, Jian Liu, Nan Chen, Xiaohui Zhao, Qing Yang, Xijun Chen.

  Ginsenoside compound K (CK) exhibits neuroprotective properties; however, the underlying mechanisms behind these effects have not been investigated thoroughly. CK is the primary active compound derived from ginseng and is metabolized in the gut. It enhances neuronal function by modulating the gut microflora. Therefore, the present study aimed to elucidate the mechanism through which CK enhances cognitive function, employing gut microbiome and microarray analyses. The results revealed that CK upregulated the expression of peroxisome proliferator-activated receptor gamma (PPARγ), suppressed amyloid-β (Aβ) aggregation in hippocampal neurons, and influenced the expression of cyclin-dependent kinase-5 (CDK5), (including insulin receptor substrate 2) IRS2, insulin-degrading enzyme (IDE), glycogen synthase kinase-3 beta (GSK-3β), glucose transporter type 1 (GLUT1), and glucose transporter type 3 (GLUT3) proteins. These proteins play crucial roles in regulating brain glucose metabolism, increasing neuronal energy, and reducing neuronal apoptosis, thereby ameliorating cognitive impairment in mice.

Keywords:  Cognitive impairment; Ginsenoside CK; Glucose metabolism; PPARγ

DOI:  https://doi.org/10.1007/s11011-025-01596-9
Mitochondrion. 2025 Mar 27. pii: S1567-7249(25)00031-5. [Epub ahead of print]83 102034

Loss of PGC-1α causes depot-specific alterations in mitochondrial capacity, ROS handling and adaptive responses to metabolic stress in white adipose tissue.

Anders Gudiksen, Eva Zhou, Louise Pedersen, Catherine A Zaia, Cecilie E Wille, Elisabeth V Eliesen, Henriette Pilegaard.

  White adipose tissue (WAT) delivers lipid-fueled metabolic support to systemic energy expenditure through control of lipolytic and re-esterifying regulatory pathways, facilitated by mitochondrial bioenergetic support. Mitochondria are important sources of reactive oxygen species (ROS) and oxidative damage may potentially derail adipocyte function when mitochondrial homeostasis is challenged by overproduction of ROS. Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α is a transcriptional co-activator that in skeletal muscle plays a central role in mitochondrial biogenesis and function but whether PGC-1α is equally important for mitochondrial function and adaptations in white adipose tissue remains to be fully resolved. The aim of the present study was to characterize the necessity of adipocyte PGC-1α for adaptive regulation of mitochondrial function in distinct white adipose depots. PGC-1α adipose tissue-specific knockout (ATKO) and floxed littermate control mice (CTRL) were subjected to either 24 h of fasting or 48 h of cold exposure. Bioenergetics, ROS handling, basal and adaptive protein responses, markers of protein damage as well as lipid cycling capacity and regulation were characterized in distinct WAT depots. ATKO mice demonstrated impairments in respiration as well as reduced OXPHOS protein content in fed and fasted conditions. Increased ROS emission in tandem with diminished mitochondrial antioxidant defense capacity resulted in increased protein oxidation in ATKO WAT. Adipose tissue PGC-1α knockout also led to changes in regulation of lipolysis and potentially triglyceride reesterification in WAT. In conclusion, PGC-1α regulates adipose tissue mitochondrial respiration and ROS balance as well as lipid cycling during metabolic challenges in a depot specific manner.

Keywords:  Bioenergetics; Cold exposure; Fasting; Mitochondria; PGC-1α; ROS; White adipose tissue

DOI:  https://doi.org/10.1016/j.mito.2025.102034
Neurobiol Aging. 2025 Mar 24. pii: S0197-4580(25)00057-0. [Epub ahead of print]151 1-12

Sex-specific decline in prefrontal cortex mitochondrial bioenergetics in aging baboons correlates with walking speed.

Daniel A Adekunbi, Hillary F Huber, Gloria A Benavides, Ran Tian, Cun Li, Peter W Nathanielsz, Jianhua Zhang, Victor Darley-Usmar, Laura A Cox, Adam B Salmon.

  Mitochondria play a crucial role in brain homeostasis and changes in mitochondrial bioenergetics are linked to age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. We investigated changes in the activities of the electron transport chain (ETC) complexes in normally aging baboon brains and determined how these changes relate to donor sex, morning cortisol levels, and walking speed. We assessed mitochondrial bioenergetics from archived prefrontal cortex (PFC) tissues from a large cohort (60 individuals) of well-characterized aging baboons (6.6-22.8 years, approximately equivalent to 26.4-91.2 human years). Aging was associated with a decline in mitochondrial ETC complexes in the PFC, which was more pronounced when normalized for citrate synthase activity, suggesting that the decline is predominantly driven by changes in the specific activity of individual complexes rather than global changes in mitochondrial content. When donor sex was used as a covariate, we found that ETC activity was preserved with age in females and declined in males. Males had higher activities of each individual ETC complex and greater lactate dehydrogenase activity at a given age relative to females. Circulating cortisol negatively correlated with walking speed when male and female data were combined. We also observed a robust positive predictive relationship between walking speed and respiration linked to complexes I, III, and IV in males but not in females. This data reveals a link between frailty and PFC bioenergetic function and highlights a potential molecular mechanism for sexual dimorphism in brain resilience.

Keywords:  Aging; Baboons; Cortisol; Mitochondrial respiration; Prefrontal cortex; Walking speed

DOI:  https://doi.org/10.1016/j.neurobiolaging.2025.03.010