bims-mihora 2025-11-09 papers

bims-mihora

Biomed News

on Mitohormesis, repair and aging

Issue of 2025–11–09
twenty-one papers selected by
Lisa Patel, Istesso

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.
Unraveling the Interactive Role of Mitochondrial Dysfunction in Promoting Macrophage Polarization in Pulmonary Fibrosis.
Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.
Interactome quantitation reveals non-energetic mitochondrial roles in cell type specialization in murine kidney.
Integrated stress response-mediated metabolic reprogramming drives hepatic stellate cell activation and liver fibrosis via the noncanonical EIF3d-ATF4-S100P signaling pathway.
Innate Immunity and Inflammation: Conuersim Between PAMPS and DAMPS.
Germline regulation of the intestinal mitochondrial unfolded protein response.
Heat stress-induced mitochondrial damage and its impact on leukocyte function.
Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.
A novel esculin-loaded bacterial nanocellulose wound dressing enhances cutaneous wound healing via modulation of inflammation, oxidative stress, and growth factor expression.
Involvement of Integrated Stress Response in Drug-Induced Secondary Dystonia.
The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.
Cell-type-specific dysregulation of mitochondrial calcium signaling in Alzheimer's disease.
Extracellular matrix and immune dysfunction: An overlooked relationship in idiopathic pulmonary fibrosis.
Mitochondrial quality control disorder: a potential mechanism of male infertility.
Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.
The Mechanism and Potential Therapeutic Strategies of Vascular Aging.
Distinct profiles of mitochondrial bioenergetics and redox balance in left atrial and ventricular myocardium in the healthy rat heart.
Srpx2 exerts multifaceted cardio-protection in septic cardiomyopathy: PI3K/AKT-dependent attenuation of mitochondrial oxidative stress, apoptotic signaling, and inflammatory response.
The Role of Mitochondrial Dysfunction and Inflammatory Response in the Pathogenesis of Sepsis-Induced Myocardial Injury: A Mechanistic Study.
Cell-free strategies for cardiomyocyte proliferation and heart repair.

Geroscience. 2025 Nov 04.

Transcriptomic analysis of mitohormesis associated with lifespan extension in Caenorhabditis elegans.

Juri Kim, Naibedya Dutta, Gilberto Garcia, Ryo Higuchi-Sanabria.

  Non-lethal exposure to mitochondrial stress has been shown to have beneficial effects due to activation of signaling pathways, including the mitochondrial unfolded protein response (UPRmt). Activation of UPRmt restores the function of the mitochondria and improves general health and longevity in multiple model systems, termed mitohormesis. In C. elegans, mitohormesis can be accomplished by electron transport chain inhibition, a decline in mitochondrial translation, decreased mitochondrial import, and numerous other methods that activate UPRmt. However, not all methods that activate UPRmt promote longevity. These and other studies have started to question whether UPRmt is directly correlated with longevity. Here, we attempt to address this controversy by unraveling the complex molecular regulation of longevity of the nematode under different mitochondrial stressors that induce mitochondrial stress by performing RNA sequencing to profile transcriptome changes. Using this comprehensive and unbiased approach, we aim to determine whether specific transcriptomic changes can reveal a correlation between UPRmt and longevity. Altogether, this study will provide mechanistic insights on mitohormesis and how it correlates with the lifespan of C. elegans.

Keywords:  Aging; Caenorhabditis elegans; Mitohormesis; UPRmt

DOI:  https://doi.org/10.1007/s11357-025-01912-2
J Biochem Mol Toxicol. 2025 Nov;39(11): e70586

Unraveling the Interactive Role of Mitochondrial Dysfunction in Promoting Macrophage Polarization in Pulmonary Fibrosis.

Jiajia Zou, Junling Jian, Dehua Ge, Bin Zhou, Jiaxiang Zhang.

  Pulmonary fibrosis (PF) is a chronic, irreversible interstitial lung disease. There is no effective treatment or drug that can completely cure this disease. The pathogenesis is still unclear. In recent years, several scholars have reported that the main cause of PF is an imbalance in the inflammatory response and abnormal repair after lung injury. Lung macrophages, as immune cells in vivo, play an important role in regulating the immune response and immune tolerance and promoting lung injury repair through polarization. Recent studies have highlighted the importance of mitochondria in lung fibrosis, safeguarding cellular homeostasis and metabolic roles, and their ability to influence the progression of lung fibrosis by mediating macrophage polarization within lung cells. However, the regulation of macrophage polarization by impaired mitochondrial function remains largely unknown. In this review, we intend to summarize the associations of mitochondrial dysfunction, including mitochondrial dynamics, increased ROS production, mitochondrial DNA (mtDNA) leakage, and inflammatory vesicle activation, with the key mechanisms driving the polarization of both M1-type and M2-type macrophages, as well as further explore the role of mitochondria as key control centers for macrophage polarization, which may lead to novel therapeutic approaches to target and/or reverse disease progression.

Keywords:  inflammation; macrophage; mitochondrial dysfunction; pulmonary fibrosis

DOI:  https://doi.org/10.1002/jbt.70586
Front Mol Neurosci. 2025 ;18 1639114

Targeting ER stress in skeletal muscle through physical activity: a strategy for combating neurodegeneration-associated muscle decline.

Zhanguo Su, Lijuan Xiang.

  The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.

Keywords:  ER stress; exercise; muscle function; neurodegenerative diseases; unfolded protein response

DOI:  https://doi.org/10.3389/fnmol.2025.1639114
Mol Cell Proteomics. 2025 Nov 03. pii: S1535-9476(25)00540-7. [Epub ahead of print] 101441

Interactome quantitation reveals non-energetic mitochondrial roles in cell type specialization in murine kidney.

A A Bakhtina, M D Campbell, B D Sibley, M Sanchez-Contreras, A Keller, M T Sweetwyne, J E Bruce.

Evolution of multicellular life forms has involved adaptation of organs that consist of multiple cell types, each with unique functional properties that as a collection, achieve complex organ function. Since each cell type is adapted to deliver specific functionality within the context of an organ, knowledge on functional landscapes occupied by individual cell types could improve comprehension of organ function at the molecular level. In kidney, podocytes and tubules are two cell types of the nephron, each with vastly different functional roles. Podocytes envelop the blood vessels in the glomerulus and act as filters while tubules, located downstream of the glomerulus, are responsible for reabsorption of important nutrients. Mitochondria hold a critical and well-studied role in tubules due to the high energetic requirements required to fulfill their function. In podocytes however, questions remain regarding the relevance of mitochondrial function in both normal physiology and pathology. Quantitative cross-linking mass spectrometry and proteomics together with a transgenic mitochondrial tagging strategy were used to investigate kidney cell-type specificity of mitochondria. These efforts revealed that despite similarities of podocyte and tubule mitochondrial proteomes, each contain unique features corresponding to known distinct functional roles. These include increased demand for energy production through the TCA cycle in tubules and increased detoxification demand in podocytes. Moreover, tubule and podocyte mitochondrial interactome differences revealed additional cell-type specific functional insights with alterations in betaine metabolism, lysine degradation, and other pathways not regulated through proteome abundance levels. Most importantly, these efforts illustrate that cell specific mitochondrial interactome differences within an organ can now be visualized. Therefore, this approach can generally be used to map cell-specific mitochondrial changes in disease, aging or even with therapy to better understand the roles and contributions of each cell type in normal physiology and pathology within an organ in ways not previously possible.

DOI: https://doi.org/10.1016/j.mcpro.2025.101441
Redox Biol. 2025 Oct 30. pii: S2213-2317(25)00418-5. [Epub ahead of print]88 103905

Integrated stress response-mediated metabolic reprogramming drives hepatic stellate cell activation and liver fibrosis via the noncanonical EIF3d-ATF4-S100P signaling pathway.

Simin Yang, Hongli Zhang, Xiaoyan Sun, Zhengyang Chen, Zhentian Nie, Yuting Li, Xiaohan Liu, Yawei Kong, Ziyu Wang, Wenjing Zai, Shan Gao, Wei Chen.

  Hepatic stellate cells (HSCs) trans-differentiation into myofibroblasts is central to liver fibrosis. Integrated stress response (ISR) signaling, including metabolic stress, plays a critical role in this process. However, the precise role of ISR signaling in HSCs activation-whether detrimental or protective-remains unclear. Here we identified that the noncanonical cap-binding protein EIF3d-mediated ATF4 expression is significantly upregulated in HSCs from both patients and mouse models of fibrotic livers, with its levels positively correlating with the degree of fibrosis. EIF3d-ATF4 signaling was induced by TGFβ1 in HSCs and was demonstrated to be both necessary and sufficient for promoting HSC survival, proliferation, activation, and extracellular matrix (ECM) production. Furthermore, genetic and pharmacological inhibition of EIF3d-ATF4 effectively prevented TGFβ1-induced HSC activation by suppressing mitochondrial activity and glycolysis. Mechanistically, EIF3d-ATF4 overexpression drove ATF4-dependent S100P transcription, which facilitated metabolic reprogramming and upregulated fibrogenic markers. This EIF3d-ATF4-S100P axis promoted liver fibrosis by activating JNK and NLRP3 signaling in HSCs, thereby inducing HSC activation and conferring resistance to apoptosis. Importantly, mice with HSC-specific ATF4 deletion or treated with our innovative ISR antagonist, ERMT1, were protected from three distinct mouse fibrotic models. These findings underscore the role of the EIF3d-ATF4-S100P signaling axis in liver fibrosis progression and HSC activation, presenting it as a promising therapeutic target for managing liver fibrosis and cirrhosis.

Keywords:  ATF4; Hepatic stellate cells; Integrated stress response; Liver fibrosis; Metabolic reprogramming

DOI:  https://doi.org/10.1016/j.redox.2025.103905
Scand J Immunol. 2025 Nov;102(5): e70060

Innate Immunity and Inflammation: Conuersim Between PAMPS and DAMPS.

Balachandran Ravindran.

  The current conundrum of inflammation is that exogenous pathogen-associated molecular patterns (PAMPs) from microbial sources or endogenous damage-associated molecular patterns (DAMPs) released during trauma/tissue injury generate host inflammatory response independently or in a synergistic manner. The 'discussion' highlights several confounders in the in vitro investigations reported in the literature and argues in favour of addressing the issue only in in vivo model systems, such as germ-free animals that are free of microbiota and hence PAMPs, in which response to DAMPs can be precisely studied. Based on the available literature, the 'discussion forum' proposes that host innate immune responses leading to the induction of inflammatory molecules by PAMPs and DAMPs are interdependent and biologically inactive in isolation, and that their threshold and context would be critical determining factors for acute or chronic inflammation.

Keywords:  DAMPs; PAMPs; inflammation; innate immunity; tissue damage; wound healing

DOI:  https://doi.org/10.1111/sji.70060
Geroscience. 2025 Nov 07.

Germline regulation of the intestinal mitochondrial unfolded protein response.

Anna C Foulger, Nathaniel A Jordan, Alyssa Castle, Dipa Bhaumik, Julie K Andersen, Gordon J Lithgow, Suzanne Angeli.

  The disposable soma theory posits that there is a trade-off between reproduction and somatic maintenance. In support of this theory, we previously identified that pharmacological inhibition of the germline has widespread protective cell non-autonomous effects on cellular protein homeostasis in the model organism Caenorhabditis elegans. However, the cell non-autonomous effects of the germline on mitochondrial protein homeostasis are not well defined. Here, we use pharmacological or genetic inhibition of the germline to determine its effects on intestinal mitochondrial protein homeostasis as measured by the mitochondrial unfolded protein response (UPRmt). We find that pharmacological inhibition of germline proliferation by 5-fluoro-2-deoxyuridine (FUdR), a DNA synthesis inhibitor, potently inhibits activation of the intestinal UPRmt as well as reverses lifespan effects induced by mitochondrial dysfunction. We find similar results with the genetic mutant (glp-1), which lacks germline proliferation. To further identify the reproductive processes required to regulate the intestinal UPRmt, we examined the genetic mutant fem-1, which contains an intact gonad with oocytes but lacks sperm. Like glp-1 mutants, fem-1 mutants do not activate the intestinal UPRmt due to mitochondrial dysfunction caused by loss of OXPHOS subunits. Restoring reproduction in fem-1 mutants by mating them with wild type males is sufficient to reactivate the intestinal UPRmt. Furthermore, loss of the FOXO transcription factor daf-16 is sufficient to reactivate the intestinal UPRmt in fem-1 mutants and partially in glp-1 mutants. These findings suggest that FOXO/daf-16 acts to limit UPRmt activation in the intestine. These findings also suggest that late-stage reproductive signals that include the maturation of oocytes and fertilization may play a critical role in cell non-autonomous intestinal UPRmt activation.

Keywords:   Caenorhabditis elegans ; Cell non-autonomous; Fertilization; Germline; Intestines; Mitochondrial unfolded protein response; Reproduction

DOI:  https://doi.org/10.1007/s11357-025-01890-5
J Intensive Care. 2025 Nov 04. 13(1): 61

Heat stress-induced mitochondrial damage and its impact on leukocyte function.

Toshiaki Iba, Julie Helms, Isao Nagaoka, Ricard Ferrer, Jerrold H Levy.

  Heatstroke is characterized by systemic inflammation, immune dysregulation, and multiorgan failure, in which mitochondrial damage in leukocytes plays a pivotal role. This review examines the mechanisms by which heat stress induces leukocyte mitochondrial dysfunction and its downstream effects on immunity, coagulation, and organ integrity. Exposure to heat stress activates leukocytes through damage-associated molecular patterns (DAMPs), triggering the release of proinflammatory cytokines, reactive oxygen species (ROS), and neutrophil extracellular traps (NETs). These responses disrupt endothelial integrity, promote microvascular thrombosis, and contribute to the development of disseminated intravascular coagulation (DIC). Prolonged heat exposure further shifts the immune landscape toward immunosuppression, marked by monocyte deactivation and lymphocyte apoptosis. Mitochondrial dysfunction is central to this biphasic immune response. Heat stress reduces mitochondrial membrane potential, increases ROS production, and promotes the release of mitochondrial DNA and cytochrome c, amplifying inflammation and initiating cell death pathways, including apoptosis, pyroptosis, and ferroptosis. Biomarkers such as reduced mitochondrial membrane potential (ΔΨm), elevated mitochondrial ROS, cytochrome c, circulating mitochondrial DNA (mtDNA), and altered expression of mitophagy regulators (e.g., PINK1 and Parkin) provide insights into mitochondrial integrity and function in leukocytes. In addition to immune disruption, mitochondrial injury exacerbates coagulation abnormalities by promoting platelet activation and endothelial dysfunction, fostering a prothrombotic environment. In the microcirculation, leukocyte adhesion, NET formation, and endothelial damage create a self-amplifying cycle of ischemia and inflammation, ultimately leading to organ dysfunction, including hepatic failure, acute kidney injury, acute lung injury, and gastrointestinal barrier breakdown. Therapeutic strategies aimed at preserving mitochondrial function include antioxidants (e.g., N-acetylcysteine and MitoQ), mitochondrial biogenesis inducers (e.g., PGC-1α activators), and mitophagy enhancers. Understanding the central role of leukocyte mitochondrial damage in heat stress provides a foundation for the development of targeted diagnostics and interventions to prevent organ failure and improve clinical outcomes.

Keywords:  Cell death; Heat stress; Leukocyte; Mitochondria; Organ dysfunction

DOI:  https://doi.org/10.1186/s40560-025-00832-9
Cell Death Differ. 2025 Nov 01.

Adaptive ER stress promotes mitochondrial remodelling and longevity through PERK-dependent MERCS assembly.

Jose C Casas-Martinez, Qin Xia, Penglin Li, Maria Borja-Gonzalez, Antonio Miranda-Vizuete, Emma McDermott, Peter Dockery, Leo R Quinlan, Katarzyna Goljanek-Whysall, Afshin Samali, Brian McDonagh.

The transfer of information and metabolites between the mitochondria and the endoplasmic reticulum (ER) is mediated by mitochondria-ER contact sites (MERCS), allowing adaptations in response to changes in cellular homeostasis. MERCS are dynamic structures essential for maintaining cell homeostasis through the modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Under stress conditions such as ER protein misfolding, the Unfolded Protein Response (UPRER) mediates PERK and IRE1 activation, both of which localise at MERCS. Adaptive UPRER signalling enhances mitochondrial function and calcium import, whereas maladaptive responses lead to excessive calcium influx and apoptosis. In this study, induction of mild acute ER stress with tunicamycin (TM) in myoblasts promoted myogenesis that required PERK for increased MERCS assembly, mitochondrial turnover and function. Similarly, treatment of C. elegans embryos with an acute low concentration of TM, promoted an extension in lifespan and health-span. The adaptive ER stress response following a low dose of TM in both myoblasts and C. elegans, increased MERCS assembly and activated autophagy machinery, ultimately promoting an increase in mitochondrial remodelling. However, these beneficial adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. In both models the adaptations to UPRER activation were dependent on PERK signalling and its interaction with the UPRmt. The results demonstrate PERK is required for the increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function.

DOI: https://doi.org/10.1038/s41418-025-01603-7
Int J Biol Macromol. 2025 Nov 05. pii: S0141-8130(25)09367-5. [Epub ahead of print] 148810

A novel esculin-loaded bacterial nanocellulose wound dressing enhances cutaneous wound healing via modulation of inflammation, oxidative stress, and growth factor expression.

Amir Emaminia, Mohammad Hashemnia, Hadi Cheraghi, Farid Rezaei.

  Wound healing is a complex biological process involving tightly regulated phases of inflammation, proliferation, and remodeling. Developing multifunctional wound dressings that can actively modulate these processes remains a key challenge in regenerative medicine. Wound healing is a complex biological process involving tightly regulated phases of inflammation, proliferation, and remodeling. Developing multifunctional wound dressings that can actively modulate these processes remains a key challenge in regenerative medicine. The BNC/Esc composite film was thoroughly characterized using SEM, FTIR, XRD, swelling behavior, drug release studies, and in vitro cytocompatibility assays. The in vivo therapeutic efficacy was evaluated in a full-thickness excisional wound model in rats over 21 days using histological, biochemical, and molecular analyses. The BNC/Esc film exhibited a uniform nanofibrous morphology, high swelling capacity and porosity, and sustained biphasic esculin release while maintaining excellent biocompatibility. In vivo, the dressing significantly accelerated wound contraction and re-epithelialization, enhanced collagen deposition and alignment, promoted fibroblast proliferation and angiogenesis via upregulation of bFGF and VEGF, and suppressed inflammation and oxidative stress by reducing IL-1β, MPO, and MDA levels, while increasing GPx and SOD activities. This work introduces an innovative natural compound-loaded BNC platform that integrates mechanical support with molecular-level regulation of inflammation and redox balance, offering a promising, multifunctional biomaterial for advanced wound healing applications.

Keywords:  Bacterial nanocellulose; Cutaneous wound healing; Esculin; Growth factors expression; Inflammation modulation; Oxidative stress

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.148810
ACS Omega. 2025 Oct 28. 10(42): 50208-50217

Involvement of Integrated Stress Response in Drug-Induced Secondary Dystonia.

Tricia A Simon, Sanjana B Parise, Natalie E Jackson, Rekha C Patel.

A maladaptive integrated stress response (ISR) involving dysregulation of eukaryotic translation initiation factor α (eIF2α) signaling is observed in several types of inherited primary dystonia. In the case of secondary dystonia resulting as a side effect of various antipsychotic and antiemetic drugs, the involved molecular pathways have not been characterized. In this study, we investigated the contribution of the ISR pathway to drug-induced dystonia. Using murine neuroblastoma-derived Neuro-2a (N2a) cells, we investigated the ability of antipsychotic drugs to induce ISR. We tested eight drugs reported in the literature to cause dystonia as a side effect. After the N2a cells were treated with these drugs at their reported plasma concentrations, the cell extracts were analyzed for ISR induction by Western blot analyses. The involvement of PKR (protein kinase, RNA-activated) and PACT (PKR activator) was evaluated by coimmunoprecipitation analyses, and the ability of luteolin to disrupt the PACT-PKR interaction to suppress ISR induction was tested by coimmunoprecipitation and Western blot analyses. Our results indicate that the antipsychotic drugs induce ISR by activating PERK (PKR-like endoplasmic reticulum resident kinase) as well as PKR, resulting in eIF2α phosphorylation. PACT associates with PKR after exposure to antipsychotic drugs, causing PKR activation, and luteolin disrupts the PACT-PKR interaction to suppress ISR. Based on our studies, ISR induction is identified as a pathomechanism for secondary dystonia for the first time, and luteolin can be explored further for its ability to suppress ISR and avoid or alleviate secondary drug-induced dystonia.

DOI: https://doi.org/10.1021/acsomega.5c06867
Biochim Biophys Acta Rev Cancer. 2025 Oct 31. pii: S0304-419X(25)00233-1. [Epub ahead of print]1880(6): 189491

The mitochondrial nexus: Targeting metabolic vulnerabilities, oxidative stress, and immunomodulation to induce cancer cell death.

Woo Hyun Park.

  Mitochondria, far from being mere cellular powerhouses, act as central command hubs dictating cell fate by integrating metabolic cues with life-or-death decisions. In cancer, these organelles undergo profound functional and structural reprogramming to support relentless proliferation, survival, and adaptation to stress. This metabolic plasticity, however, creates unique vulnerabilities exploitable for therapeutic gain. This comprehensive review synthesizes recent insights into the multifaceted roles of mitochondria in cancer, focusing on how inhibiting their core functions can trigger diverse cell death pathways and modulate the tumor microenvironment. This paper delves into the central role of mitochondria in orchestrating various forms of regulated cell death (RCD), including apoptosis, ferroptosis, necroptosis, and the newly defined cuproptosis. A primary focus is placed on the dual nature of mitochondrial reactive oxygen species (ROS), which can promote tumorigenesis but can also be pharmacologically elevated to catastrophic levels, triggering oxidative stress-induced demise. This review systematically categorizes and discusses a burgeoning pharmacopeia of mitochondrial inhibitors-targeting the electron transport chain (ETC), metabolic enzymes like glutaminase, protein homeostasis, and ion channels-and analyzes their mechanisms of action, preclinical evidence, and clinical translation status. Furthermore, this paper examines how these agents can overcome chemoresistance and synergize with existing treatments, including the exciting interface with immunotherapy, where mitochondrial fitness is paramount for robust anti-tumor T-cell responses and the induction of immunogenic cell death (ICD). By dissecting the complex interplay between mitochondrial inhibition, metabolic disruption, oxidative stress, and cell death, this review highlights the immense promise of mitochondria-targeted therapies and charts the course for future innovations in oncology.

Keywords:  Cancer metabolism; Immunotherapy; Mitochondria; Oxidative stress; Regulated cell death; Targeted therapy

DOI:  https://doi.org/10.1016/j.bbcan.2025.189491
Cell Commun Signal. 2025 Nov 03. 23(1): 472

Cell-type-specific dysregulation of mitochondrial calcium signaling in Alzheimer's disease.

Shatakshi Shukla, Ashlesha A Kadam, Shanikumar Goyani, Natasha Jaiswal, Kunal Samantaray, Shiridhar Kashyap, Dhanendra Tomar, Pooja Jadiya.

   BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid plaques, tau tangles, and synaptic dysfunction. Despite decades of research, effective disease-modifying therapies remain elusive, highlighting the need for alternative therapeutic targets. While neurons have traditionally been the focus of AD studies, increasing evidence underscores critical roles for glial cells particularly microglia and astrocytes in disease progression. Mitochondrial calcium (mCa2+) dysregulation has emerged as a key contributor to neurodegeneration, yet how mCa2⁺ signaling varies across brain cell types and contributes to AD pathology remains poorly understood.
METHODS: We developed stable human SH-SY5Y (neuroblastoma-derived cells), HMC3 (microglial-like cells), and SVGp12 (astrocytic-like cells) immortalized cell lines expressing APP mutations (Swedish, Florida, and London; APPswe/F/L). We assessed mitochondrial calcium uniporter (mtCU) expression, mCa2+ flux using ratiometric calcium (Ca2+) indicators, and evaluated calcium retention capacity (mito-CRC) as a readout of mitochondrial permeability transition pore opening. Bioenergetic parameters including ATP, NADH, membrane potential, and oxygen consumption rate (OCR) were measured alongside structural mitochondrial changes, ROS levels, and cell death using imaging and biochemical assays.
RESULTS: APPswe/F/L expression induced mitochondrial dysfunction across all brain immortalized cell types, with neuroblastoma-derived cells exhibiting the highest susceptibility to mCa2+ overload, energy failure, and cell death. Compared to neuroblastoma-derived cells, glial-like cells (astrocytic-like and microglial-like cells) showed higher expression of mtCU components, elevated mCa2+ uptake at high Ca²⁺ concentrations, and greater mito-CRC. Conversely, neuroblastoma-derived cells displayed faster mCa2+ uptake at low Ca2+ levels, indicating distinct regulatory thresholds. Glial-like cells exhibited more elaborate mitochondrial networks and enhanced metabolic capacity, yet all cell types showed impaired mitochondrial structure, reduced membrane potential and respiration, and increased ROS under mutant APP expression.
CONCLUSIONS: This study reveals cell-type-specific differences in mCa2+ signaling and mitochondrial function in AD, uncovering unique vulnerabilities in neuroblastoma-derived and glial-like cells. These findings highlight the need for cell-targeted strategies to restore mCa2+ homeostasis and mitochondrial function in AD.

Keywords:  Alzheimer’s disease; Cell death; Cell-type specificity; Glial-like cells; Mitochondrial bioenergetics; Mitochondrial calcium; Neuroblastoma-derived cells; Oxidative stress

DOI:  https://doi.org/10.1186/s12964-025-02460-0
Exp Lung Res. 2025 ;51(1): 123-137

Extracellular matrix and immune dysfunction: An overlooked relationship in idiopathic pulmonary fibrosis.

Upama Nyaupane, Kerri A Johannson, Margaret M Kelly, FuiBoon Kai.

  Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease. Current clinically approved treatments slow disease progression but are not curative. Thus, there is a critical need to better define the pathogenic mechanisms of IPF and develop novel approaches to treat this devastating lung condition. Immune dysregulation of both the innate and adaptive immune systems, accompanied by fibrosis, constitutes a key hallmark of IPF. IPF is generally considered to be a fibroproliferative disorder rather than an immune condition because, historically, immunomodulatory therapies have failed to produce significant clinical effect. This lack of response is frustrating given that there is evidence of immune dysfunction in IPF and highlights the need to clarify the role of immune cells and inflammatory pathways in IPF. There is increasing evidence that the extracellular matrix (ECM) directs cell fate and function, and we propose that ECM remodeling and immune dysfunction in IPF generate a self-perpetuating fibrotic circuit that is refractory to classical anti-inflammatory agents. Understanding the relationship between ECM and immune dysfunction in IPF pathogenesis could help identify novel therapeutic approaches for this devastating disease.

Keywords:  Pulmonary fibrosis; extracellular matrix; inflammation; tissue regeneration

DOI:  https://doi.org/10.1080/01902148.2025.2582970
Syst Biol Reprod Med. 2025 Dec;71(1): 549-573

Mitochondrial quality control disorder: a potential mechanism of male infertility.

Shanshan Qin, Ziming Zhu, Shenmin Lv, Zhipeng Guo, Linhui Xia, Xiaoyu Gong, Xiangyu Wang, Jinxiang Yuan, Kai Meng, Jianping Zhu.

  In recent years, the incidence of male infertility has increased to approximately 10%, with a continued upward trend. Therefore, understanding the mechanisms underlying male infertility and developing effective treatment strategies have become essential areas of focus. Mitochondria are regulated by a complex quality control system including mitochondrial dynamics, mitophagy and biogenesis, which not only maintains mitochondrial structural and functional integrity, but also supports the stability of testicular tissue and the intracellular environment necessary for male fertility. Several studies have demonstrated that dysfunction in mitochondrial dynamics and mitophagy is closely associated with a decline in male fertility. Disruptions caused by excessive external stimuli or gene mutations can impair these processes, resulting in oxidative damage, apoptosis, inflammation, and ferroptosis. These pathological changes ultimately damage testicular cells and tissues. Consequently, this review will focus on the two key mechanisms: mitochondrial dynamics and mitophagy. Furthermore, mitochondrial biogenesis-responsible for producing new mitochondria and regulating the number of mitochondria-also plays an important role in maintaining male fertility. Related studies have shown that mitochondrial biogenesis dysfunction can trigger a cascade of pathological events that lead to testicular tissue damage. In summary, this review systematically examines the roles of mitochondrial dynamics and mitophagy in regulating male fertility. It provides an in-depth analysis of the pathological mechanisms by which dysfunction in these processes leads to male infertility. Additionally, this review summarizes current therapeutic agents targeting mitochondrial dynamics and mitophagy, aiming to identify potential strategies for the clinical treatment of male infertility.

Keywords:  infertility treatments; male fertility; mitochondrial dynamics; mitophagy

DOI:  https://doi.org/10.1080/19396368.2025.2574003
Biol Pharm Bull. 2025 ;48(11): 1652-1666

Mitochondrial Activation and Therapeutics: Innovations in Cell- and Organelle-Specific Medicine.

Itsumi Sato, Masahiro Shiraishi, Kaede Norota, Kaoru Shiraki, Yuma Yamada.

  Mitochondria are essential for cellular functions, including ATP production, calcium homeostasis, oxidative stress regulation, and apoptosis. Mitochondrial dysfunction is associated with a variety of diseases, including neurodegenerative disorders, skeletal muscle diseases, and mitochondrial diseases. This review explores the latest mitochondrial-targeted therapeutic approaches across the following key perspectives: (1) technological innovations in mitochondrial transplantation, focusing on tunnel nanotubes and extracellular vesicles; (2) the role of mitochondria in skeletal muscle diseases and therapeutic activation strategies; (3) advances in mitochondrial enhancement techniques within cell therapy, particularly in pediatric applications; and (4) the latest treatment modalities for mitochondrial diseases, such as gene and cell therapies. Taken together, these strategies demonstrate the transformative potential of mitochondrial targeting in cell- and organelle-specific medicine. Additionally, the MITO-Porter system is highlighted as an innovative drug delivery platform contributing to these advances.

Keywords:  cell therapy; drug delivery system; mitochondria; mitochondrial disease; organelle medicine; skeletal muscle disease

DOI:  https://doi.org/10.1248/bpb.b25-00218
Aging Med (Milton). 2025 Oct;8(5): 475-492

The Mechanism and Potential Therapeutic Strategies of Vascular Aging.

Wan-Zhou Wu, Xuan Wang, Fang-Fang Wu, Xiao-Tian Yan, Yong-Ping Bai.

  As we approach the mid-21st century, more developing countries are progressing towards becoming developed nations. Advances in medical technology have resulted in the prolonged human lifespan and a sustained decline in birth rates, leading to a growing proportion of the population being aged 65 and above. The aging process is associated with organ function deterioration, increased risks of age-related diseases, and a decrease in the quality of life for older adults. While there is ongoing debate about whether aging should be considered a disease or a natural physiological process, understanding the reasons for aging, identifying and measuring aging, and intervening in the aging process have become key topics in current medical research. Recent studies indicate that the rate of organ aging varies among individuals, with blood vessels being one of the organs that age first. Vascular aging increases the risk of cardiovascular diseases, overall mortality, and shortens lifespan. Therefore, in-depth research on vascular aging is crucial for understanding its impact on vascular and multi-organ function. In this review, we discuss the phenotypes caused by vascular aging, mechanisms of aging in various vascular cells, and potential therapeutic strategies for vascular aging.

Keywords:  endothelial dysfunction; therapy; vascular aging; vascular stiffness

DOI:  https://doi.org/10.1002/agm2.70043
Exp Physiol. 2025 Nov 04.

Distinct profiles of mitochondrial bioenergetics and redox balance in left atrial and ventricular myocardium in the healthy rat heart.

Tingting Fang, Alex Chan, Janice Chew-Harris, Toan Pham.

  The left ventricle (LV) is the primary pumping chamber of the heart, generating high systolic pressure to sustain systemic circulation. LV contractile dysfunction is a hallmark of various cardiovascular diseases and is associated with mitochondrial dysfunction, characterised by decreased oxidative phosphorylation (OXPHOS) capacity and increased oxidative stress. While our understanding of cardiac mitochondrial physiology has been gained from studies on LV tissues in animal models or atrial tissues in human studies, findings are often generalised across cardiac regions. Given that fundamental differences in anatomical structure, physiological function and metabolic demands exist between the LV and left atrium (LA), this study aimed to compare mitochondrial bioenergetics between LV and LA tissues from healthy rat hearts. Using high-resolution respirometry coupled with fluorimetry, we assessed mitochondrial respiration, ATP production and hydrolysis, and reactive oxygen species (ROS) production rates. Protein expression of mitochondrial respiratory complexes and antioxidant enzymes was quantified using western blotting. Our results showed that per tissue mass, LV tissues exhibited greater mitochondrial OXPHOS respiration, ATP production and hydrolysis rates, ROS production rate, and higher protein levels of mitochondrial complexes and antioxidant enzymes, consistent with higher citrate synthase activity as a marker of mitochondrial content. However, when normalised to mitochondrial content, LV tissues exhibited lower OXPHOS respiration and ATP production, expression of mitochondrial complexes and antioxidant proteins compared to LA. This study provides new insights into chamber-specific differences in mitochondrial function under physiological conditions, suggesting the importance of considering regional mitochondrial profiles in studies of cardiac mitochondrial function in health and disease.

Keywords:  ATP; ROS; SOD; catalase; left atrium; left ventricle; mitochondrial function

DOI:  https://doi.org/10.1113/EP093102
Hum Cell. 2025 Nov 04. 39(1): 1

Srpx2 exerts multifaceted cardio-protection in septic cardiomyopathy: PI3K/AKT-dependent attenuation of mitochondrial oxidative stress, apoptotic signaling, and inflammatory response.

Yan Guo, Ying Liu, Mingkai Zhou, Yulan Zhao.

  Mitochondrial dysfunction is a key contributor to septic cardiomyopathy, driving myocardial inflammation and apoptosis. This study found that Sushi-repeat containing protein X-linked 2 (Srpx2) is associated with mitochondrial damage and is downregulated in the myocytes of lipopolysaccharide (LPS)-treated rats. Sprague Dawley rats were intraperitoneally injected with LPS (10 mg/kg) to establish a septic cardiomyopathy model. Adeno-associated viruses (8.5 × 1011 vg/mL) containing Srpx2-overexpressing plasmids were injected into rats through their tail vein. Srpx2 overexpression improved hemodynamics and decreased myocardial damage in LPS-treated rats. H9C2 cells were treated with LPS (10 μg/mL) to establish an in vitro septic model. The cells were then transfected with Srpx2-overexpressing plasmids. Srpx2 overexpression ameliorated mitochondrial damage, which was evidenced by restoring mitochondrial morphology, enhancing the complex activities, and elevating ATP and mitochondrial membrane potential levels in cardiomyocytes. Srpx2 overexpression reduced mitochondrial reactive oxygen species levels and superoxide generation in cardiomyocytes. Srpx2 overexpression decreased cleaved caspase-3 and 9 protein levels. Tumor necrosis factor-α and interleukin-1 beta levels were also reduced in cardiomyocytes with Srpx2 overexpression, suggesting reversal of inflammation. The RNA-sequencing data indicated that Srpx2 might regulate the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway to protect cardiomyocytes. Srpx2 overexpression increased the p-PI3K and p-AKT protein levels. The treatment of H9C2 cells with 10 μM LY294002, a PI3K/AKT pathway inhibitor, reversed the protective effects of Srpx2 against mitochondrial damage and apoptosis. In conclusion, Srpx2 alleviates mitochondrial damage by activating the PI3K/AKT pathway, thereby reducing apoptosis and inflammation in septic cardiomyopathy.

Keywords:  Apoptosis; Mitochondrial damage; PI3K/AKT pathway; Septic cardiomyopathy; Sushi-repeat containing protein X-linked 2

DOI:  https://doi.org/10.1007/s13577-025-01306-8
J Inflamm Res. 2025 ;18 15207-15235

The Role of Mitochondrial Dysfunction and Inflammatory Response in the Pathogenesis of Sepsis-Induced Myocardial Injury: A Mechanistic Study.

An-Bu Liu, Sheng Wang, Yue Shen, Lei Ma, Jun-Fei Zhang.

  Sepsis, a severe systemic infection triggered by the invasion of bacterial, viral, fungal, and other pathogens into human tissues, frequently results in substantial damage to the heart, which is one of the primary organs affected. This myocardial injury is strongly linked to poor patient outcomes in sepsis. Recent research has identified key factors such as mitochondrial dysfunction, metabolic disturbances, cell death, and dysregulated inflammatory responses as critical contributors to the pathogenesis of sepsis-induced myocardial injury (SIMI). These mechanisms not only enhance our understanding of SIMI but also offer potential therapeutic targets. The review aims to investigate the pathophysiological mechanisms driving myocardial injury in sepsis, particularly from the perspective of mitochondrial dysfunction. It will examine the complex interactions between inflammatory dysregulation, calcium homeostasis disruption, metabolic reprogramming, and mitochondrial dysfunction in the onset and progression of SIMI. By exploring therapeutic approaches focused on restoring mitochondrial function, this research aims to establish a theoretical framework for interventions targeting SIMI, thereby providing a robust foundation for the development of targeted therapies for SIMI.

Keywords:  RCD; SIMI; inflammatory responses; metabolic reprogramming; mitochondrial dysfunction; sepsis-induced myocardial injury

DOI:  https://doi.org/10.2147/JIR.S552730
Pharmacol Rep. 2025 Nov 05.

Cell-free strategies for cardiomyocyte proliferation and heart repair.

Agnieszka Łoboda, Tomasz Zieliński, Józef Dulak.

  Heart regeneration, or the replacement or restoration of damaged myocardium, remains one of the most challenging areas in regenerative medicine, primarily due to the limited regenerative capacity of the adult human heart. Unlike the embryonic heart, which exhibits robust cardiomyocyte proliferation, postnatal cardiac muscle cells permanently exit the cell cycle, resulting in minimal regenerative potential following injury such as myocardial infarction. This limitation contributes significantly to the progression of heart failure, a leading cause of morbidity and mortality worldwide. Recent breakthroughs in understanding the molecular and cellular mechanisms that govern cardiomyocyte proliferation have revealed that targeting signaling pathways (e.g., Hippo-YAP), cell cycle regulators, epigenetic modulators, and extracellular components may be a promising strategy for stimulating heart repair. Despite these advances, cardiac regeneration still faces significant obstacles in replacing damaged tissue and ensuring the regenerated muscle functions effectively within the complex heart system. This review aims to provide a comprehensive analysis of emerging regulatory mechanisms involved in cardiomyocyte proliferation and myocardial regeneration. It critically evaluates current strategies for promoting heart regeneration, with particular emphasis on the most promising molecular pathways and therapeutic approaches with translational potential. Ongoing research, as summarized in this review, continues to expand the potential of regenerative medicine to repair heart damage, offering hope for more effective treatments for heart disease.

Keywords:  Cardiomyocytes; Heart failure; Heart regeneration; Myocardial infarction

DOI:  https://doi.org/10.1007/s43440-025-00805-7