bims-mecosi 2025-03-16 papers

bims-mecosi

Biomed News

on Membrane contact sites

Issue of 2025–03–16
twelve papers selected by
Verena Kohler, Umeå University

Lipid Dynamics at Membrane Contact Sites.
Electron Microscopy to Visualize and Quantify Mitochondrial Structure and Organellar Interactions in Cultured Cells During Senescence.
Disruption of ER-mitochondria contact sites induces autophagy-dependent loss of P-bodies through the Ca2+-CaMKK2-AMPK pathway.
Mechanisms and functions of lysosomal lipid homeostasis.
The inter-organelle cross-talk finely orchestrated in the amyloidogenic processing of amyloid precursor protein in dendritic arborization neurons of Drosophila.
Role of Pink1 in Regulating Osteoclast Differentiation during Periodontitis.
Shape Matters: The Utility and Analysis of Altered Yeast Mitochondrial Morphology in Health, Disease, and Biotechnology.
Zhizichi decoction alleviates depressive-like behaviors through modulating mitochondria-associated membrane via the IP3R3-GRP75-VDAC1 complex.
The endoplasmic reticulum-mitochondrial crosstalk involved in nanoplastics and di(2-ethylhexyl) phthalate co-exposure induced the damage to mouse mammary epithelial cells.
Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy.
Thiram-induced ER stress promotes mitochondrial calcium signaling and NLRP3 inflammasome activation in a tissue specific manner.
Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.

Annu Rev Biochem. 2025 Mar 11.

Lipid Dynamics at Membrane Contact Sites.

Karin M Reinisch, Pietro De Camilli, Thomas J Melia.

In eukaryotes, lipid building blocks for cellular membranes are made largely in the endoplasmic reticulum and then redistributed to other organelles. Lipids are transported between organelles by vesicular trafficking or else by proteins located primarily at sites where different organelles are closely apposed. Here we discuss transport at organelle contact sites mediated by shuttle-like proteins that carry single lipids between membranes to fine-tune their composition and by the more recently discovered bridge-like proteins that tether two organelles and provide a path for bulk lipid movement. Protein-mediated lipid transport is assisted by integral membrane proteins that have roles in (a) lowering the energy barrier for lipid transfer between the membrane and the lipid transfer protein, a key parameter determining the transfer rate, and (b) scrambling lipids to counteract the bilayer asymmetry that would result from such transfer. Advances in this field are shedding new light on a variety of physiological mechanisms.

DOI: https://doi.org/10.1146/annurev-biochem-083024-122821
Methods Mol Biol. 2025 ;2906 229-242

Electron Microscopy to Visualize and Quantify Mitochondrial Structure and Organellar Interactions in Cultured Cells During Senescence.

Christina Glytsou.

  Mitochondria are multifunctional organelles that play a crucial role in numerous cellular processes, including oncogene-induced senescence. Recent studies have demonstrated that mitochondria undergo notable morphological and functional changes during senescence, with mitochondria dysregulation being a critical factor contributing to the induction of this state. To elucidate the intricate and dynamic structure of these organelles, high-resolution visualization techniques are imperative. Electron microscopy offers nanometer-scale resolution images, enabling the comprehensive study of organelles' architecture. This chapter provides a detailed guide for preparing fixed samples from cultured cells for electron microscopy imaging. It also describes various quantification methods to accurately assess organellar parameters, including morphometric measurements of mitochondrial shape, cristae structure, and mitochondria-endoplasmic reticulum contact sites. These analyses yield valuable insights into the status of subcellular organelles, advancing our understanding of their involvement in cellular senescence and disease.

Keywords:  EM sample preparation; Electron microscopy; MERCs; Mitochondria visualization; Mitochondrial structure

DOI:  https://doi.org/10.1007/978-1-0716-4426-3_13
J Cell Sci. 2025 Mar 01. pii: JCS263652. [Epub ahead of print]138(5):

Disruption of ER-mitochondria contact sites induces autophagy-dependent loss of P-bodies through the Ca2+-CaMKK2-AMPK pathway.

Nikhil More, Jomon Joseph.

  P-bodies (PBs) and stress granules (SGs) are conserved, non-membranous cytoplasmic condensates of RNA-protein complexes. PBs are implicated in post-transcriptional regulation of gene expression through mRNA decay, translational repression and/or storage. Although much is known about the de novo formation of PBs and SGs involving liquid-liquid phase separation through multiple protein-protein and protein-RNA interactions, their subcellular localization and turnover mechanisms are less understood. Here, we report the presence of a subpopulation of PBs and SGs that are in proximity to ER-mitochondria contact sites (ERMCSs) in mammalian cells. Disruption of ERMCSs, achieved through depletion of ER-mitochondria tethering proteins, leads to the disappearance of PBs but not SGs. This effect can be reversed by inhibiting autophagy through both genetic and pharmacological means. Additionally, we find that the disruption of ERMCSs leads to cytosolic Ca2+-induced activation of CaMKK2 and AMP-activated protein kinase (AMPK), ultimately resulting in an autophagy-dependent decrease in PB abundance. Collectively, our findings unveil a mechanism wherein disturbances in ERMCSs induce autophagy-dependent loss of PBs via activation of the Ca2+-CaMKK2-AMPK pathway, thus potentially linking the dynamics and functions of ERMCS with post-transcriptional gene regulation.

Keywords:  Autophagy; CaMKK2; ER–mitochondria contact sites; P-bodies; Stress granules

DOI:  https://doi.org/10.1242/jcs.263652
Cell Chem Biol. 2025 Feb 28. pii: S2451-9456(25)00035-2. [Epub ahead of print]

Mechanisms and functions of lysosomal lipid homeostasis.

Michael Ebner, Florian Fröhlich, Volker Haucke.

  Lysosomes are the central degradative organelle of mammalian cells and have emerged as major intersections of cellular metabolite flux. Macromolecules derived from dietary and intracellular sources are delivered to the acidic lysosomal lumen where they are subjected to degradation by acid hydrolases. Lipids derived from lipoproteins, autophagy cargo, or autophagosomal membranes themselves constitute major lysosomal substrates. Dysregulation of lysosomal lipid processing, defective export of lipid catabolites, and lysosomal membrane permeabilization underly diseases ranging from neurodegeneration to metabolic syndromes and lysosomal storage disorders. Mammalian cells are equipped with sophisticated homeostatic control mechanisms that protect the lysosomal limiting membrane from excessive damage, prevent the spillage of luminal hydrolases into the cytoplasm, and preserve the lysosomal membrane composition in the face of constant fusion with heterotypic organelles such as endosomes and autophagosomes. In this review we discuss the molecular mechanisms that govern lysosomal lipid homeostasis and, thereby, lysosome function in health and disease.

Keywords:  contact sites; lipids; lysosomes; membrane homeostasis; phosphoinositides; signalling

DOI:  https://doi.org/10.1016/j.chembiol.2025.02.003
Theranostics. 2025 ;15(7): 2951-2966

The inter-organelle cross-talk finely orchestrated in the amyloidogenic processing of amyloid precursor protein in dendritic arborization neurons of Drosophila.

Guo Cheng, Jin Chang, Shanshan Ke, Zimin Dai, Deyong Gong, Hui Gong, Wei Zhou.

  Background: Organelles in neuronal dendrites facilitate local metabolic processes and energy supply, crucial for dendrite development and neurodegenerative diseases. The distinct functions of dendritic organelles have been well studied, however, their crosstalk under physiological and pathological contexts remains elusive. We aimed to establish an in vivo model system of contacts between multi-organelles for investigating the modulation of inter-organelle crosstalk in Alzheimer's disease (AD). Methods: A dendrite model of organelle contacts was developed in Drosophila neurons using a set of proximity-driven probes and four-color Airyscan super-resolution imaging. The systematic modulations among multiple contact sites (CSs) between organelles were examined by manipulating CS tethers and vesicular transporters. Finally, perturbations of these CSs and the dendrite structure in the amyloidogenic processing of amyloid precursor protein (APP) were evaluated by introducing three stages of the processing in this model system. Results: A dynamic network, interconnected via CSs and organized with multi-organelle contacts, was presented among Golgi outposts, the endoplasmic reticulum, lysosomes, and mitochondria (GELM). The CS modulations were found to encompass both their density and motility. Notably, multi-CSs participated in complementary modulations spanning across different cellular pathways. Furthermore, the CS network was revealed to be progressively disturbed in APP amyloidogenic processing, with upregulations in density and motility extending from single- to multi-CSs. These CS perturbations, along with defects in dendrite structural plasticity, could be partially rescued by knocking down Miro. Conclusion: The elucidation of CS modulation modes in the GELM network model reveals a cascaded dysregulation of organelle crosstalk during APP amyloidogenic processing. It expands the mechanisms of inter-organelle communication and provides novel insights into neurodegeneration in AD pathology.

Keywords:  Alzheimer's disease; Drosophila; amyloidogenic processing of APP; complementary modulation; dendritic arborization neurons; inter-organelle communication; organelle contact sites

DOI:  https://doi.org/10.7150/thno.104345
J Dent Res. 2025 Mar 12. 220345251315723

Role of Pink1 in Regulating Osteoclast Differentiation during Periodontitis.

H Gou, T Wang, Y Chen, Y Zhou, J Li, Y Xu.

  Periodontitis has recently been recognized as an inflammatory disease caused by oxidative stress, with mitochondrial dysfunction being a key factor leading to oxidative stress. PTEN-induced kinase 1 (PINK1) is an essential protein for mitochondrial quality control, which protects cells from oxidative stress by inducing mitophagy to degrade damaged mitochondria, but its role in periodontitis has not been elucidated. This study aimed to explore the contribution and underlying mechanisms of Pink1 in regulating the differentiation and function of osteoclasts during periodontitis. Here we observed a significant downregulation of PINK1 expression in periodontitis-affected tissues. Then we constructed a periodontitis model in mice with fluorescently labeled mononuclear/macrophages, and the results showed that as the modeling time extended, the alveolar bone destruction gradually worsened and was accompanied by gradually decreased Pink1 expression in osteoclasts and a significantly increased osteoclast number. In vitro experiments further demonstrated a negative correlation between Pink1 and osteoclast differentiation. In addition, alveolar bone destruction in the Pink1 knockout mice was significantly more advanced than that in the littermate wild type mice after ligature-induced periodontitis and enhanced osteoclastogenesis and bone-resorptive capacity in vitro. RNA-sequencing analysis and in vitro validation revealed that the absence of Pink1 led to a decrease in oxidative phosphorylation levels and an enhancement of calcium-mediated signaling, specifically the calcineurin-NFATc1 pathway, via an intracellular calcium source. Further mechanistic studies found that the deficiency of Pink1 inhibited mitophagy but strengthened mitochondrial-endoplasmic reticulum coupling, which, by promoting the interaction of Mfn2-IP3R-VDAC1 proteins, increased the concentration of mitochondrial calcium ions, thereby triggering more active osteoclast differentiation. The aforementioned process can be reversed by the IP3R channel inhibitor Bcl-XL. These findings unveiled that Pink1 was involved in osteoclast differentiation by regulating mitochondrial calcium transport mediated by mitochondria-associated endoplasmic reticulum membranes, providing a new theoretical basis for the pathogenesis and treatment of periodontitis.

Keywords:  alveolar bone loss; calcium signaling; mitochondria-associated endoplasmic reticulum membranes; mitophagy; osteoclastogenesis

DOI:  https://doi.org/10.1177/00220345251315723
Int J Mol Sci. 2025 Feb 27. pii: 2152. [Epub ahead of print]26(5):

Shape Matters: The Utility and Analysis of Altered Yeast Mitochondrial Morphology in Health, Disease, and Biotechnology.

Therese Kichuk, José L Avalos.

  Mitochondria are involved in a wide array of critical cellular processes from energy production to cell death. The morphology (size and shape) of mitochondrial compartments is highly responsive to both intracellular and extracellular conditions, making these organelles highly dynamic. Nutrient levels and stressors both inside and outside the cell inform the balance of mitochondrial fission and fusion and the recycling of mitochondrial components known as mitophagy. The study of mitochondrial morphology and its implications in human disease and microbial engineering have gained significant attention over the past decade. The yeast Saccharomyces cerevisiae offers a valuable model system for studying mitochondria due to its ability to survive without respiring, its genetic tractability, and the high degree of mitochondrial similarity across eukaryotic species. Here, we review how the interplay between mitochondrial fission, fusion, biogenesis, and mitophagy regulates the dynamic nature of mitochondrial networks in both yeast and mammalian systems with an emphasis on yeast as a model organism. Additionally, we examine the crucial role of inter-organelle interactions, particularly between mitochondria and the endoplasmic reticulum, in regulating mitochondrial dynamics. The dysregulation of any of these processes gives rise to abnormal mitochondrial morphologies, which serve as the distinguishing features of numerous diseases, including Parkinson's disease, Alzheimer's disease, and cancer. Notably, yeast models have contributed to revealing the underlying mechanisms driving these human disease states. In addition to furthering our understanding of pathologic processes, aberrant yeast mitochondrial morphologies are of increasing interest to the seemingly distant field of metabolic engineering, following the discovery that compartmentalization of certain biosynthetic pathways within mitochondria can significantly improve chemical production. In this review, we examine the utility of yeast as a model organism to study mitochondrial morphology in both healthy and pathologic states, explore the nascent field of mitochondrial morphology engineering, and discuss the methods available for the quantification and classification of these key mitochondrial morphologies.

Keywords:  analysis; biofuel; cancer; contact sites; engineering; fission; fusion; imaging; mitochondria; morphology; neurodegenerative; pathology

DOI:  https://doi.org/10.3390/ijms26052152
J Ethnopharmacol. 2025 Mar 10. pii: S0378-8741(25)00312-5. [Epub ahead of print] 119628

Zhizichi decoction alleviates depressive-like behaviors through modulating mitochondria-associated membrane via the IP3R3-GRP75-VDAC1 complex.

Ye Liu, Zicheng Zhang, Yimeng Zhao, Ruoyu Jiang, Zhihua Geng, Yujie Tao, Jiarui Zhang, Weiwei Tao.

   ETHNOPHARMACOLOGICAL RELEVANCE: Zhizichi Decoction (ZZCD), a traditional Chinese medicine (TCM), is derived from the combination of Gardenia jasminoides J.Ellis [Rubiaceae] and Semen Sojae Praeparatum, a fermented derivative of Glycine max (L.) Merr. [Leguminosae]. ZZCD has demonstrated anti-inflammatory properties and the potential to promote neural plasticity. Neuroinflammation is believed to contribute to the development of depressive symptoms.
AIM OF THE STUDY: This study investigates the potential antidepressant effects of ZZCD, focusing on its role in regulating neuroinflammatory responses and mitochondria-associated membrane (MAM) structure.
MATERIALS AND METHODS: Using high-performance liquid chromatography (HPLC), we identified five active ingredients in ZZCD. We then evaluated its effect in a chronic social defeat stress (CSDS) mouse model. A combination of Network pharmacology analysis, Western-blot, immunostaining, enzyme-linked immunosorbent assay (ELISA), co-immunoprecipitation (CO-IP), mitochondrial transmembrane potential (ΔΨm), and transmission electron microscopy (TEM) was adopted to elucidate the mechanisms by which ZZCD improves MAM structure, inhibits neuroinflammation, and exerts antidepressant effects. Finally, according to the molecular docking results, a GRP75 overexpression viral vector was constructed to manipulate the MAM-related protein GRP75, further validating the mechanism of ZZCD's antidepressant effect.
RESULTS: ZZCD treatment significantly ameliorated depressive-like behaviors induced by CSDS in mice and reversed adverse changes in endoplasmic reticulum (ER) stress, MAM structure, and mitochondria injury. In addition, ZZCD effectively reduced microglial inflammatory activation and suppressed the increased expression of pro-inflammatory cytokines. Finally, the antidepressant effects of ZZCD were primarily mediated through the IP3R3-GRP75-VDAC1 complex, as demonstrated by the overexpression of the GRP75 protein.
CONCLUSION: In summary, ZZCD exerts antidepressant effects in the CSDS model by improving the MAM structure, alleviating neuroinflammation, and enhancing mitochondrial function.

Keywords:  Anti-depressant; MAMs; Mitochondrial; Network pharmacology; Neuroinflammation; Zhizichi decoction

DOI:  https://doi.org/10.1016/j.jep.2025.119628
Environ Pollut. 2025 Mar 06. pii: S0269-7491(25)00387-2. [Epub ahead of print]372 126014

The endoplasmic reticulum-mitochondrial crosstalk involved in nanoplastics and di(2-ethylhexyl) phthalate co-exposure induced the damage to mouse mammary epithelial cells.

Caihong Wang, Xiang Ji, Xiaoya Wang, Yunmeng Song, Chunqiang Pan, Mingrong Qian, Yuanxiang Jin.

  With the extensive use of plastic products, significant amounts of microplastics, nanoplastic particles (NPs), and plasticizers such as Di(2-ethylhexyl) phthalate (DEHP) are continuously released into the environment. However, the toxic effects of NPs alone or in combination with DEHP on mammary glands remain unreported. This study investigates the impacts of NPs and DEHP on the structure and function of mouse mammary epithelial cells and elucidates the underlying molecular mechanisms. We found that co-exposure to NPs and DEHP induced severe pyroptosis, inflammation and oxidative stress in HC11 cells. Co-exposure also caused mitochondrial damage, as evidenced by changes in mitochondrial membrane potential, increase in mitochondrial ROS and inhibition of ATP production. Moreover, NPs and DEHP co-exposure increased the transcriptional levels of endoplasmic reticulum (ER) stress-related genes, activated the inflammation-related NLRP3 signaling pathway, and damaged the cell membrane integrity. Notably, Co-exposure enhanced the ER-mitochondria crosstalk in HC11 cells, as evidenced by the upregulated transcriptional levels of ER Ca2+ channel proteins (Ip3r1, Grp75 and Vdac1), increased mitochondrial Ca2+ levels, and expanded mitochondrial-ER contact areas. In summary, this study revealed that NPs and DEHP co-exposure had the potential to induce pyroptosis and inflammation by enhancing the ER-mitochondria crosstalk, ultimately resulting in injury to mammary glands. These findings would provide some new insights into the molecular mechanisms underlying the toxic effects of NPs and DEHP to mammary glands.

Keywords:  DEHP; Endoplasmic reticulum stress; Mammary gland; Mitochondrial dysfunction; Nanoplastics; Pyroptosis

DOI:  https://doi.org/10.1016/j.envpol.2025.126014
Circ Heart Fail. 2025 Mar 11. e011867

Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy.

Kyohei Fujita, Patrick Desmond, Jordan Blondelle, Matúš Soták, Meenu Rohini Rajan, Madison Clark, Éric Estève, Yunghang Chan, Yusu Gu, Virginia Actis Dato, Valeria Marrocco, Nancy D Dalton, Majid Ghassemian, Aryanne Do, Matthew Klos, Kirk L Peterson, Farah Sheikh, Yoshitake Cho, Emma Börgeson, Stephan Lange.

   BACKGROUND: Muscle proteins of the obscurin protein family play important roles in sarcomere organization and sarcoplasmic reticulum and T-tubule architecture and function. However, their precise molecular functions and redundancies between protein family members as well as their involvement in cardiac diseases remain to be fully understood.
METHODS: To investigate the functional roles of Obsc (obscurin) and its close homolog Obsl1 (obscurin-like 1) in the heart, we generated and analyzed knockout mice for Obsc, Obsl1, as well as Obsc/Obsl1 double knockouts.
RESULTS: We show that double-knockout mice are viable but show postnatal deficits in cardiac muscle sarcoplasmic reticulum and mitochondrial architecture and function at the microscopic, biochemical, and cellular levels. Altered sarcoplasmic reticulum structure resulted in perturbed calcium cycling, whereas mitochondrial ultrastructure deficits were linked to decreased levels of Chchd3 (coiled-coil-helix-coiled-coil-helix domain containing 3), a Micos (mitochondrial contact site and cristae organizing system) complex protein. Hearts of double-knockout mice also show altered levels of Atg4 proteins, novel Obsl1 interactors, resulting in abnormal mitophagy, and increased unfolded protein response. At the physiological level, loss of obscurin and Obsl1 resulted in a profound delay of cardiac relaxation, associated with metabolic signs of heart failure.
CONCLUSIONS: Taken together, our data suggest that Obsc and Obsl1 play crucial roles in cardiac sarcoplasmic reticulum structure, calcium cycling, mitochondrial function, turnover, and metabolism.

Keywords:  autophagy; heart failure; mice; mitophagy; muscle proteins

DOI:  https://doi.org/10.1161/CIRCHEARTFAILURE.124.011867
Ecotoxicol Environ Saf. 2025 Mar 12. pii: S0147-6513(25)00362-8. [Epub ahead of print]293 118026

Thiram-induced ER stress promotes mitochondrial calcium signaling and NLRP3 inflammasome activation in a tissue specific manner.

Shah Nawaz, Md F Kulyar, Quan Mo, Zhao Zhang, Chuxian Quan, Mudassar Iqbal, El Fatihi Imad, Jiakui Li.

  Thiram, a broadly used dithiocarbamate fungicide, exaggerates endoplasmic reticulum (ER) stress and interferes with mitochondrial function, thus disrupting cellular homeostasis. Here, we intend to identify the molecular actions of thiram at the mitochondrial-associated ER membranes (MAMs) that lead to the induction of ER stress and mitochondrial calcium overload in both liver and bone tissues. Taken together, we show that thiram-induced remodelling of MAMs leads to huge ER stress and calcium dysregulation. Histological and immunohistochemical examinations revealed that thiram-induced hyperactivation of IP3R1 mediated the release of endoplasmic reticulum calcium, but mitochondrial calcium uptake was mediated by voltage-dependent anion channels VDAC1. This stress response was characterized by increased glucose regulated protein 78 (GRP78) expression in the liver and tibial growth plates (GP). In this respect, a new liver-bone axis was delineated for thiram-induced ER stress. More interestingly, the activation of NLRP3 inflammasome was very striking in tibial growth plates but not in liver tissues. Hence, the results highlight the systemic effects of thiram by identifying a critical metabolic junction that might play a role in metabolic disorders such as tibial dyschondroplasia and related bone disorders, e.g., osteoarthritis and osteoporosis.

Keywords:  Calcium signaling; Endoplasmic reticulum; Inflammasome; Liver-bone axis; NLRP3; Thiram

DOI:  https://doi.org/10.1016/j.ecoenv.2025.118026
Phytomedicine. 2025 Mar 07. pii: S0944-7113(25)00260-0. [Epub ahead of print]140 156620

Mitochondrial dynamics and metabolism in macrophages for cardiovascular disease: A review.

Yi-Lang Zhong, Chen-Qin Xu, Ji Li, Zhi-Qiang Liang, Miao-Miao Wang, Chao Ma, Cheng-Lin Jia, Yong-Bing Cao, Jian Chen.

   BACKGROUND: Mitochondria regulate macrophage function, affecting cardiovascular diseases like atherosclerosis and heart failure. Their dynamics interact with macrophage cell death mechanisms, including apoptosis and necroptosis.
PURPOSE: This review explores how mitochondrial dynamics and metabolism influence macrophage inflammation and cell death in CVDs, highlighting therapeutic targets for enhancing macrophage resilience and reducing CVD pathology, while examining molecular pathways and pharmacological agents involved.
STUDY DESIGN: This is a narrative review that integrates findings from various studies on mitochondrial dynamics and metabolism in macrophages, their interactions with the endoplasmic reticulum (ER) and Golgi apparatus, and their implications for CVDs. The review also considers the potential therapeutic effects of pharmacological agents on these pathways.
METHODS: The review utilizes a comprehensive literature search to identify relevant studies on mitochondrial dynamics and metabolism in macrophages, their role in CVDs, and the effects of pharmacological agents on these pathways. The selected studies are analyzed and synthesized to provide insights into the complex relationships between mitochondria, the ER, and Golgi apparatus, and their implications for macrophage function and fate.
RESULTS: The review reveals that mitochondrial metabolism intertwines with cellular architecture and function, particularly through its intricate interactions with the ER and Golgi apparatus. Mitochondrial-associated membranes (MAMs) facilitate Ca2+ transfer from the ER to mitochondria, maintaining mitochondrial homeostasis during ER stress. The Golgi apparatus transports proteins crucial for inflammatory signaling, contributing to immune responses. Inflammation-induced metabolic reprogramming in macrophages, characterized by a shift from oxidative phosphorylation to glycolysis, underscores the multifaceted role of mitochondrial metabolism in regulating immune cell polarization and inflammatory outcomes. Notably, mitochondrial dysfunction, marked by heightened reactive oxygen species generation, fuels inflammatory cascades and promotes cell death, exacerbating CVD pathology. However, pharmacological agents such as Metformin, Nitazoxanide, and Galanin emerge as potential therapeutic modulators of these pathways, offering avenues for mitigating CVD progression.
CONCLUSION: This review highlights mitochondrial dynamics and metabolism in macrophage inflammation and cell death in CVDs, suggesting therapeutic targets to improve macrophage resilience and reduce pathology, with new pharmacological agents offering treatment opportunities.

Keywords:  Cardiovascular diseases; Durgs; Macrophages; Mitochondria

DOI:  https://doi.org/10.1016/j.phymed.2025.156620