bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–01–26
fifty-five papers selected by
Gavin McStay, Liverpool John Moores University
  1. Notoginsenoside R1 Attenuates H/R Injury in H9c2 Cells by Maintaining Mitochondrial Homeostasis.
  2. Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
  3. Bayesian-optimized deep learning for identifying essential genes of mitophagy and fostering therapies to combat drug resistance in human cancers.
  4. Naotaifang formula regulates Drp1-induced remodeling of mitochondrial dynamics following cerebral ischemia-reperfusion injury.
  5. Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer's disease pathologic process via GPR41 and GPR43.
  6. Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis.
  7. Mitochondria mechanosensing: The powerhouse fueling cellular force signaling.
  8. Metformin-induced mitophagy suppresses auditory hair cell apoptosis via AMPK pathway.
  9. A potential therapeutic approach for ulcerative colitis: targeted regulation of mitochondrial dynamics and mitophagy through phytochemicals.
  10. Single-cell atlas reveals multi-faced responses of losartan on tubular mitochondria in diabetic kidney disease.
  11. Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies.
  12. Drp1-associated genes implicated in sepsis survival.
  13. Betulinic acid mitigates lipopolysaccharide-induced intestinal injury of weaned piglets through modulation of the mitochondrial quality control.
  14. Effects of photobiomodulation in mitochondrial quantity, biogenesis and mitophagy-associated genes in breast cancer cells.
  15. Lycium barbarum glycopeptide ameliorates aging phenotypes and enhances cardiac metabolism by activating the PINK1/Parkin-mediated mitophagy pathway in D-galactose-induced mice.
  16. Penehyclidine hydrochloride activates PARK2 and modulates ubiquitination of AIFM1 to rescue renal tubular injury in diabetic kidney disease.
  17. ApoM maintains cellular homeostasis between mitophagy and apoptosis by affecting the stability of Nnt mRNA through the Zic3-ApoM-Elavl2-Nnt axis during neural tube closure.
  18. Mitochondrial quality control: Biochemical mechanism of cardiovascular disease.
  19. Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.
  20. Derivation and Characterization of Isogenic OPA1 Mutant and Control Human Pluripotent Stem Cell Lines.
  21. MitoStores: stress-induced aggregation of mitochondrial proteins.
  22. Single-cell mitophagy patterns within the tumor microenvironment modulate intercellular communication, impacting the progression and prognosis of hepatocellular carcinoma.
  23. Mitochondrial regulation of obesity by POMC neurons.
  24. Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons.
  25. Hypoxia-Inducible Factor-1α Regulates BNIP3-Dependent Mitophagy and Mediates Metabolic Reprogramming Through Histone Lysine Lactylation Modification to Affect Glioma Proliferation and Invasion.
  26. Revealing the Complex Interaction of Noncoding RNAs, Sirtuin Family, and Mitochondrial Function.
  27. Daphnetin-mediated mitophagy alleviates intervertebral disc degeneration via the Nrf2/PINK1 pathway.
  28. Optogenetic control of mitochondrial aggregation and function.
  29. SQYC formula improves the efficacy of PD-1 monoclonal antibodies in MSS colorectal cancer by regulating dendritic cell mitophagy via the PINK1-Parkin pathway.
  30. Sleep fragmentation impairs cognitive function and exacerbates Alzheimer's disease-related pathology in a mouse model by disrupting mitochondrial biogenesis.
  31. Duck Tembusu virus induced mitophagy in vacuolate spermatogenic cells is mediated by PINK1-Parkin pathway.
  32. Improved Black Phosphorus Nanocomposite Hydrogel for Bone Defect Repairing: Mechanisms for Advancing Osteogenesis.
  33. Mitochondrial protein import stress.
  34. New triterpenoid saponins isolated from the leaves of Astragalus membranaceus (Fisch.) Bge. and their neuroprotective effects.
  35. Urolithin A alleviates NLRP3 inflammasome activation and pyroptosis by promoting microglial mitophagy following spinal cord injury.
  36. Improved Efficacy of Triple-Negative Breast Cancer Immunotherapy via Hydrogel-Based Co-Delivery of CAR-T Cells and Mitophagy Agonist.
  37. Salidroside enhances 5-fluorouracil sensitivity against hepatocellular carcinoma via YIPF5-induced mitophagy.
  38. Aberrant fumarate metabolism links interferon release in diffuse systemic sclerosis.
  39. Oxymatrine alleviates ALD-induced cardiac hypertrophy by regulating autophagy via activation Nrf2/SIRT3 signaling pathway.
  40. Mitochondrial Calcium Homeostasis and Atrial Fibrillation: Mechanisms and Therapeutic Strategies Review.
  41. In vitro stretch modulates mitochondrial dynamics and energy metabolism to induce smooth muscle differentiation in mesenchymal stem cells.
  42. GCTransNet: 3D mitochondrial instance segmentation based on Global Context Vision Transformers.
  43. Parthenolide improves sepsis-induced coagulopathy by inhibiting mitochondrial-mediated apoptosis in vascular endothelial cells through BRD4/BCL-xL pathway.
  44. Disruption of the Pum2 axis Aggravates neuronal damage following cerebral Ischemia-Reperfusion in mice.
  45. Discovering and targeting mitochondrial loss in NOTCH1-related aortic aneurysm.
  46. TMAO accelerates cellular aging by disrupting endoplasmic reticulum integrity and mitochondrial unfolded protein response.
  47. Nuclear Condensates of WW Domain-Containing Adaptor With Coiled-Coil Regulate Mitophagy via Alternative Splicing.
  48. Molecular mechanism of mitochondrial autophagy mediating impaired energy metabolism leading to osteoporosis.
  49. The Interplay between Metabolic Reprogramming, Mitochondrial Impairment, and Steroid Response in Proliferative Vitreoretinopathy.
  50. Correction: Linolenic acid ameliorates sarcopenia in C. elegans by promoting mitophagy and fighting oxidative stress.
  51. Harnessing natural saponins: Advancements in mitochondrial dysfunction and therapeutic applications.
  52. Epigallocatechin 3-gallate-induced neuroprotection in neurodegenerative diseases: molecular mechanisms and clinical insights.
  53. Tetrandrine targeting SIRT5 exerts anti-melanoma properties via inducing ROS, ER stress, and blocked autophagy.
  54. Mitochondrial swap from cancer to immune cells thwarts anti-tumour defences.
  55. Emamectin Benzoate and Microplastics Led to Skeletal Muscle Atrophy in Common Carp via Induced Oxidative Stress, Mitochondrial Dysfunction, and Protein Synthesis and Degradation Imbalance.
  1. Curr Issues Mol Biol. 2025 Jan 10. pii: 44. [Epub ahead of print]47(1):
    Notoginsenoside R1 Attenuates H/R Injury in H9c2 Cells by Maintaining Mitochondrial Homeostasis.
    Yuanbo Xu, Piao Wang, Ting Hu, Ke Ning, Yimin Bao.
      Mitochondrial homeostasis is crucial for maintaining cellular energy production and preventing oxidative stress, which is essential for overall cellular function and longevity. Mitochondrial damage and dysfunction often occur concomitantly in myocardial ischemia-reperfusion injury (MIRI). Notoginsenoside R1 (NGR1), a unique saponin from the traditional Chinese medicine Panax notoginseng, has been shown to alleviate MIRI in previous studies, though its precise mechanism remains unclear. This study aimed to elucidate the mechanisms of NGR1 in maintaining mitochondrial homeostasis in hypoxia/reoxygenation (H/R) H9c2 cells. The results showed that NGR1 pretreatment effectively increased cell survival rates post-H/R, reduced lactate dehydrogenase (LDH) leakage, and mitigated cell damage. Further investigation into mitochondria revealed that NGR1 alleviated mitochondrial structural damage, improved mitochondrial membrane permeability transition pore (mPTP) persistence, and prevented mitochondrial membrane potential (Δψm) depolarization. Additionally, NGR1 pretreatment enhanced ATP levels, increased the activity of mitochondrial respiratory chain complexes I-V after H/R, and reduced excessive mitochondrial reactive oxygen species (mitoROS) production, thereby protecting mitochondrial function. Further analysis indicated that NGR1 upregulated the expression of mitochondrial biogenesis-related proteins (PGC-1α, Nrf1, Nrf2) and mitochondrial fusion proteins (Opa1, Mfn1, Mfn2), while downregulating mitochondrial fission proteins (Fis1, Drp1) and reducing mitochondrial autophagy (mitophagy) levels, as well as the expression of mitophagy-related proteins (Pink1, Parkin, BNIP3) post-H/R. Therefore, this study showed that NGR1 can maintain mitochondrial homeostasis by regulating mitophagy, mitochondrial fission-fusion dynamics, and mitochondrial biogenesis, thereby alleviating H9c2 cell H/R injury and protecting cardiomyocytes.
    Keywords:  Notoginsenoside R1; hypoxia/reoxygenation; mitochondrial homeostasis; mitophagy
    DOI:  https://doi.org/10.3390/cimb47010044
  2. Front Pharmacol. 2024 ;15 1474310
    Mitochondrial quality control: a pathophysiological mechanism and potential therapeutic target for chronic obstructive pulmonary disease.
    Mengjiao Xu, Peng Feng, Jun Yan, Lei Li.
      Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disease worldwide. Mitochondrial quality control mechanisms encompass processes such as mitochondrial biogenesis, fusion, fission, and autophagy, which collectively maintain the quantity, morphology, and function of mitochondria, ensuring cellular energy supply and the progression of normal physiological activities. However, in COPD, due to the persistent stimulation of harmful factors such as smoking and air pollution, mitochondrial quality control mechanisms often become deregulated, leading to mitochondrial dysfunction. Mitochondrial dysfunction plays a pivotal role in the pathogenesis of COPD, contributing toinflammatory response, oxidative stress, cellular senescence. However, therapeutic strategies targeting mitochondria remain underexplored. This review highlights recent advances in mitochondrial dysfunction in COPD, focusing on the role of mitochondrial quality control mechanisms and their dysregulation in disease progression. We emphasize the significance of mitochondria in the pathophysiological processes of COPD and explore potential strategies to regulate mitochondrial quality and improve mitochondrial function through mitochondrial interventions, aiming to treat COPD effectively. Additionally, we analyze the limitations and challenges of existing therapeutic strategies, aiming to provide new insights and methods for COPD treatment.
    Keywords:  chronic obstructive pulmonary disease; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial quality control; mitophagy; therapeutic strategies
    DOI:  https://doi.org/10.3389/fphar.2024.1474310
  3. J Cell Mol Med. 2025 Jan;29(2): e18254
    Bayesian-optimized deep learning for identifying essential genes of mitophagy and fostering therapies to combat drug resistance in human cancers.
    Wenyi Jin, Junwen Chen, Zhongyi Li, Zhang Yubiao, Hao Peng.
      Dysregulated mitophagy is essential for mitochondrial quality control within human cancers. However, identifying hub genes regulating mitophagy and developing mitophagy-based treatments to combat drug resistance remains challenging. Herein, BayeDEM (Bayesian-optimized Deep learning for identifying Essential genes of Mitophagy) was proposed for such a task. After Bayesian optimization, BayeDEM demonstrated its excellent performance in identifying critical genes regulating mitophagy of osteosarcoma (area under curve [AUC] of ROC: 98.96%; AUC of PR curve: 100%). CERS1 was identified as the most essential gene regulating mitophagy (mean (|SHAP value|): 4.14). Inhibition of CERS1 sensitized cisplatin-resistant osteosarcoma cells to cisplatin, restricting their growth, proliferation, invasion, migration and colony formation and inducing apoptosis. Mechanistically, inhibition of CERS1 restricted mitophagy to destroy the mitochondrial quality control in cisplatin-resistant osteosarcoma cells, including mitochondrial membrane potential loss and unfavourable mitochondrial dynamics, rendering them susceptible to cisplatin-induced apoptosis. More importantly, mitophagy facilitated the immunosuppressive microenvironment formation by significantly modulating T-cell differentiation, adhesion and antigen presentation, and mitophagy mainly affects malignant osteoblasts in the early-mid developmental stage. Immunologically, mitophagy potentially modulated the MIF signalling transmission between malignant osteoblasts and B cells, DCs, CD8+ T cells, NK cells and monocytes through the MIF-(CD74 + CXCR4) receptor-ligand interaction, thereby modulating the biological functions of these immune cells. Collectively, BayeDEM emerged as a promising tool for oncologists to identify pivotal genes governing mitophagy, thereby enabling mitophagy-centric therapeutic strategies to counteract drug resistance.
    Keywords:  Bayesian optimization; CERS1; deep learning; mitophagy
    DOI:  https://doi.org/10.1111/jcmm.18254
  4. Free Radic Biol Med. 2025 Jan 18. pii: S0891-5849(25)00037-1. [Epub ahead of print]229 139-153
    Naotaifang formula regulates Drp1-induced remodeling of mitochondrial dynamics following cerebral ischemia-reperfusion injury.
    Ruining She, Heyan Tian, Feiyue Sun, Jinwen Ge, Zhigang Mei.
      Cerebral ischemia-reperfusion injury (CIRI) has emerged as a hindrance for rehabilitation of ischemic stroke patients. Naotaifang (NTF) exhibits beneficial efficacy in alleviating inflammation and ferroptosis in vitro during CIRI. While the potential role of NTF in regulating mitochondrial dynamics in CIRI are not elucidated. This study aimed to explore the mechanism of NTF against CIRI by regulating the dynamin-related protein 1 (Drp1)-dependent mitochondrial fission/fusion. Modeling middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo to evaluate the effects of NTF on the MCAO/R-damaged neurons and the structure, dynamics and function of mitochondria. An oxygen-glucose deprivation/reperfusion (OGD/R) cell model was established to evaluate the role of NTF in OGD/R-damaged cells. Function of Drp1 in CIRI and the neuroprotection of NTF through the mitochondrial fission/fusion pathway were investigated in vivo and in vitro. The results revealed that in vivo, NTF alleviated neuron injury in a dose-dependent manner, down-regulated Drp1 and fission protein 1 (Fis1) levels, upregulated optic atrophy 1 (Opa1), mitofusin 1/2 (Mfn1 and Mfn2), facilitated mitochondrial fusion and inhibited mitochondrial fission to rescue cells from CIRI. In vitro, Drp1 overexpression inhibited mitochondrial fusion and activated mitochondrial fission, while silencing of Drp1 exhibited the opposite result. NTF rebalanced mitochondrial dynamic in the OGD/R cell model. NTF could alleviate neuron injury following CIRI by regulating the balance of mitochondrial fission and fusion. Targeting Drp1-dependent mitochondrial dynamics may represent a viable treatment strategy for addressing the issues of CIRI post ischemic stroke.
    Keywords:  Cerebral ischemia-reperfusion injury; Drp1; Ischemic stroke; Mitochondrial fission/fusion; Naotaifang
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.031
  5. Microbiome. 2025 Jan 20. 13(1): 16
    Akkermansia muciniphila and its metabolite propionic acid maintains neuronal mitochondrial division and autophagy homeostasis during Alzheimer's disease pathologic process via GPR41 and GPR43.
    Zifan Wang, Cai Wang, Boyu Yuan, Li Liu, Haoming Zhang, Mingqiang Zhu, Hongxia Chai, Jie Peng, Yanhua Huang, Shuo Zhou, Juxiong Liu, Liyong Wu, Wei Wang.
       BACKGROUND: Alzheimer's disease (AD) is a prevalent neurodegenerative disease (ND). In recent years, multiple clinical and animal studies have shown that mitochondrial dysfunction may be involved in the pathogenesis of AD. In addition, short-chain fatty acids (SCFA) produced by intestinal microbiota metabolism have been considered to be important factors affecting central nervous system (CNS) homeostasis. Among the main mediators of host-microbe interactions, volatile fatty acids play a crucial role. Nevertheless, the influence and pathways of microorganisms and their metabolites on Alzheimer's disease (AD) remain uncertain.
    RESULTS: In this study, we present distinctions in blood and fecal SCFA levels and microbiota composition between healthy individuals and those diagnosed with AD. We found that AD patients showed a decrease in the abundance of Akkermansia muciniphila and a decrease in propionic acid both in fecal and in blood. In order to further reveal the effects and the mechanisms of propionic acid on AD prevention, we systematically explored the effects of propionic acid administration on AD model mice and cultured hippocampal neuronal cells. Results showed that oral propionate supplementation ameliorated cognitive impairment in AD mice. Propionate downregulated mitochondrial fission protein (DRP1) via G-protein coupled receptor 41 (GPR41) and enhanced PINK1/PARKIN-mediated mitophagy via G-protein coupled receptor 43 (GPR43) in AD pathophysiology which contribute to maintaining mitochondrial homeostasis both in vivo and in vitro. Administered A. muciniphila to AD mice before disease onset showed improved cognition, mitochondrial division and mitophagy in AD mice.
    CONCLUSIONS: Taken together, our results demonstrate that A. muciniphila and its metabolite propionate protect against AD-like pathological events in AD mouse models by targeting mitochondrial homeostasis, making them promising therapeutic candidates for the prevention and treatment of AD. Video Abstract.
    Keywords:   Akkermansia muciniphila ; Alzheimer’s disease; Mitochondrial division and mitophagy; Propionic acid
    DOI:  https://doi.org/10.1186/s40168-024-02001-w
  6. Metabolites. 2025 Jan 16. pii: 59. [Epub ahead of print]15(1):
    Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis.
    Jiayin Wang, Dandan Jia, Zhiwang Zhang, Dan Wang.
      Background/Objectives: Sarcopenia, characterized by the progressive loss of muscle mass and strength, is linked to physical disability, metabolic dysfunction, and an increased risk of mortality. Exercise therapy is currently acknowledged as a viable approach for addressing sarcopenia. Nevertheless, the molecular mechanisms behind exercise training or physical activity remain poorly understood. The disruption of mitochondrial homeostasis is implicated in the pathogenesis of sarcopenia. Exercise training effectively delays the onset of sarcopenia by significantly maintaining mitochondrial homeostasis, including promoting mitophagy, improving mitochondrial biogenesis, balancing mitochondrial dynamics, and maintaining mitochondrial redox. Exerkines (e.g., adipokines, myokines, hepatokines, and osteokines), signaling molecules released in response to exercise training, may potentially contribute to skeletal muscle metabolism through ameliorating mitochondrial homeostasis, reducing inflammation, and regulating protein synthesis as a defense against sarcopenia. Methods: In this review, we provide a detailed summary of exercise-induced exerkines and confer their benefit, with particular focus on their impact on mitochondrial homeostasis in the context of sarcopenia. Results: Exercise induces substantial adaptations in skeletal muscle, including increased muscle mass, improved muscle regeneration and hypertrophy, elevated hormone release, and enhanced mitochondrial function. An expanding body of research highlights that exerkines have the potential to regulate processes such as mitophagy, mitochondrial biogenesis, dynamics, autophagy, and redox balance. These mechanisms contribute to the maintenance of mitochondrial homeostasis, thereby supporting skeletal muscle metabolism and mitochondrial health. Conclusions: Through a comprehensive investigation of the molecular mechanisms within mitochondria, the context reveals new insights into the potential of exerkines as key exercise-protective sensors for combating sarcopenia.
    Keywords:  exercise; exerkines; mitochondrial homeostasis; sarcopenia
    DOI:  https://doi.org/10.3390/metabo15010059
  7. Curr Biol. 2025 Jan 20. pii: S0960-9822(24)01646-4. [Epub ahead of print]35(2): R76-R79
    Mitochondria mechanosensing: The powerhouse fueling cellular force signaling.
    Jorge Oliver-De La Cruz, Pere Roca-Cusachs.
      Mechanical forces influence mitochondrial dynamics through previously unexplored mechanisms. A new study demonstrates that actomyosin tension inhibits mitochondrial fission by phosphorylating a key component of the fission complex and that this event regulates the nuclear accumulation of critical transcription factors.
    DOI:  https://doi.org/10.1016/j.cub.2024.12.006
  8. Brain Res Bull. 2025 Jan 16. pii: S0361-9230(25)00026-7. [Epub ahead of print] 111214
    Metformin-induced mitophagy suppresses auditory hair cell apoptosis via AMPK pathway.
    Yifan Lai, Jiawei Qiu, Kuang Zheng, Xiang Li, Yinuo Lin, Zhengzheng Li, Haiqiu Sun.
      Hearing loss is a pervasive issue affecting numerous individuals, and its etiology and categorization are multifaceted. Among these, sensorineural hearing loss (SNHL) emerges as the most prevalent variant among these. The primary causative factor underlying SNHL resides in the depletion of auditory hair cells within the cochlea, yet the pursuit of efficacious therapeutic interventions remains an ongoing challenge. Previous investigations have illuminated the role of mitochondrial dysfunction in precipitating cellular apoptosis, and mitophagy has emerged as a promising mechanism to ameliorate such dysfunction. Additionally, it has been noted that metformin possesses the specific ability to induce mitophagy. Herein, our objective is to explore the protective effects of metformin-induced mitophagy against apoptosis in auditory hair cells (HEI-OC1 cells) and explore its potential mechanisms. Our results revealed that metformin effectively triggered mitophagy in HEI-OC1 cells. Moreover, metformin treatment showed the ability to prevent tert-butyl hydroperoxide (TBHP) induced mitochondrial dysfunction and intrinsic apoptotic pathways. Mechanistically, we discovered that metformin activates AMP-activated protein kinase (AMPK) signaling in HEI-OC1 cells stimulated by TBHP, thereby triggering mitophagy. Overall, our results suggest that metformin may represent a promising and innovative therapeutic strategy for mitigating the onset of hearing loss.
    Keywords:  Metformin; apoptosis; autophagy; hearing loss; mitophagy
    DOI:  https://doi.org/10.1016/j.brainresbull.2025.111214
  9. Front Immunol. 2024 ;15 1506292
    A potential therapeutic approach for ulcerative colitis: targeted regulation of mitochondrial dynamics and mitophagy through phytochemicals.
    Jianping Zhou, Yuting Xi, Ting Wu, Xiaoyu Zeng, Jun Yuan, Lei Peng, Hao Fu, Ce Zhou.
      Mitochondria are important organelles that regulate cellular energy and biosynthesis, as well as maintain the body's response to environmental stress. Their dynamics and autophagy influence occurrence of cellular function, particularly under stressful conditions. They can generate reactive oxygen species (ROS) which is a major contributor to inflammatory diseases such as ulcerative colitis (UC). In this review, we discuss the key effects of mitochondrial dynamics and mitophagy on the pathogenesis of UC, with a particular focus on the cellular energy metabolism, oxidative stress, apoptosis, and immunoinflammatory activities. The therapeutic efficacy of existing drugs and phytochemicals targeting the mitochondrial pathway are discussed to reveal important insights for developing therapeutic strategies for treating UC. In addition, new molecular checkpoints with therapeutic potential are identified. We show that the integration of mitochondrial biology with the clinical aspects of UC may generate ideas for enhancing the clinical management of UC.
    Keywords:  UC; mitochondrial dynamics; mitophagy; nature products; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2024.1506292
  10. J Transl Med. 2025 Jan 21. 23(1): 90
    Single-cell atlas reveals multi-faced responses of losartan on tubular mitochondria in diabetic kidney disease.
    Zhen Zhu, Guangxin Luan, Song Wu, Yiyi Song, Shuang Shen, Kaiyue Wu, Shengnan Qian, Weiping Jia, Jun Yin, Tao Ren, Jianping Ye, Li Wei.
       BACKGROUND AND OBJECTIVE: Mitochondria are crucial to the function of renal tubular cells, and their dynamic perturbation in many aspects is an important mechanism of diabetic kidney disease (DKD). Single-nucleus RNA sequencing (snRNA-seq) technology is a high-throughput sequencing analysis technique for RNA at the level of a single cell nucleus. Here, our DKD mouse kidney single-cell RNA sequencing conveys a more comprehensive mitochondrial profile, which helps us further understand the therapeutic response of this unique organelle family to drugs.
    METHODS: After high fat diet (HFD), mice were intraperitoneally injected with streptozotocin (STZ) to induce DKD, and then divided into three subsets: CON (healthy) subset, DKD (vehicle) subset, and LST (losartan; 25 mg/kg/day) subset. Divide HK-2 cell into LG (low glucose; 5 mM) and HG (high glucose; 30 mM) and HG + LST (losartan; 1 µ M) subsets. snRNA-seq was performed on the renal tissues of LST and DKD subset mice. To reveal the effects of losartan on gene function and pathway changes in renal tubular mitochondria, Gene Ontology (GO) enrichment analysis and GSEA/GSVA scoring were performed to analyze the specific response of proximal tubular (PT) cell mitochondria to losartan treatment, including key events in mitochondrial homeostasis such as mitochondrial morphology, dynamics, mitophagy, autophagic flux, mitochondrial respiratory chain, apoptosis, and ROS generation. Preliminary validation through in vitro and in vivo experiments, including observation of changes in mitochondrial morphology and dynamics using probes such as Mitotracker Red, and evaluation of the effect of losartan on key events of mitochondrial homeostasis perturbation using electron microscopy, laser confocal microscopy, immunofluorescence, and Western blotting. Detection of autophagic flux in cells by transfecting Ad-mCherry-GFP-LC3B dual fluorescence labeled adenovirus. Various fluorescent probes and energy detector are used to detect mitochondrial apoptosis, ROS, and respiration of mitochondrion.
    RESULTS: Through the single-cell atlas of DKD mouse kidneys, it was found that losartan treatment significantly increased the percentage of PT cells. Gene Ontology (GO) enrichment analysis of differentially expressed genes showed enrichment of autophagy of mitochondrion pathway. Further GSEA analysis and GSVA scoring revealed that mitophagy and other key mitochondrial perturbation events, such as ROS production, apoptosis, membrane potential, adenosine triphosphate (ATP) synthesis, and mitochondrial dynamics, were involved in the protective mechanism of losartan on PT cells, thereby improving mitochondrial homeostasis. Consistent results were also obtained in mice and cellular experiments. In addition, we highlighted a specific renal tubular subpopulation with mitophagy phenotype found in single-cell data, and preliminarily validated it with co-localization and increased expression of Pink1 and Gclc in kidney specimens of DKD patients treated with losartan.
    CONCLUSIONS: Our research suggests that scRNA-seq can reflect the multifaceted mitochondrial landscape of DKD renal tubular cells after drug treatment, and these findings may provide new targets for DKD therapy at the organelle level.
    Keywords:  Diabetic kidney disease; Losartan; Mitochondrial homeostasis perturbation; Mitophagy; snRNA-seq
    DOI:  https://doi.org/10.1186/s12967-025-06074-5
  11. Neurotherapeutics. 2025 Jan 17. pii: S1878-7479(25)00003-0. [Epub ahead of print] e00525
    Mitochondrial dysfunction in Alzheimer's disease: Guiding the path to targeted therapies.
    Kyle C McGill Percy, Zhunren Liu, Xin Qi.
      Alzheimer's disease (AD) is characterized by progressive neurodegeneration, marked by the accumulation of amyloid-β (Aβ) plaques and tau tangles. Emerging evidence suggests that mitochondrial dysfunction plays a pivotal role in AD pathogenesis, driven by impairments in mitochondrial quality control (MQC) mechanisms. MQC is crucial for maintaining mitochondrial integrity through processes such as proteostasis, mitochondrial dynamics, mitophagy, and precise communication with other subcellular organelles. In AD, disruptions in these processes lead to bioenergetic failure, gene dysregulation, the accumulation of damaged mitochondria, neuroinflammation, and lipid homeostasis impairment, further exacerbating neurodegeneration. This review elucidates the molecular pathways involved in MQC and their pathological relevance in AD, highlighting recent discoveries related to mitochondrial mechanisms underlying neurodegeneration. Furthermore, we explore potential therapeutic strategies targeting mitochondrial dysfunction, including gene therapy and pharmacological interventions, offering new avenues for slowing AD progression. The complex interplay between mitochondrial health and neurodegeneration underscores the need for innovative approaches to restore mitochondrial function and mitigate the onset and progression of AD.
    Keywords:  Alzheimer's disease; Amyloid beta; Gene therapy; Mitochondrial quality control; Pharmacotherapy; Tauopathy
    DOI:  https://doi.org/10.1016/j.neurot.2025.e00525
  12. Front Immunol. 2024 ;15 1516145
    Drp1-associated genes implicated in sepsis survival.
    Marissa D Pokharel, Anlin Feng, Ying Liang, Wenli Ma, Saurabh Aggarwal, Hoshang Unwalla, Stephen M Black, Ting Wang.
      Sepsis is a severe and life-threatening medical syndrome that can lead to organ failure and death. Despite advances in medical treatment, current therapies are often inadequate, with high septic mortality rates. Therefore, there is a critical need for reliable prognostic markers to be used in clinical settings to improve the management and outcomes of patients with sepsis. Recent studies have suggested that mitochondrial dynamics, including the processes of mitochondrial fission and fusion, are closely related to the severity of sepsis and the status of inflammation. By monitoring transcriptomic signals related to mitochondrial dynamics, new and reliable biomarkers can be engineered to more accurately predict sepsis survival risk. Such biomarkers would be invaluable in clinical settings, aiding healthcare providers in the early identification of high-risk patients and improving treatment strategies. To achieve this goal, we utilized the major mitochondrial fission regulatory protein dynamin-related protein 1 (Drp1, gene code DNM1L) and identified Drp1-associated genes that are enriched with sepsis survival genes. A 12-gene signature (GS) was established as a differentially expressed gene (DEG)-based GS. Next, we compared genes of proteins that interact with Drp1 to sepsis survival genes and identified 7 common genes, establishing a GS we term as protein-protein interaction (PPI)-based GS. To evaluate if these GSs can predict sepsis survival, we used publicly available human blood transcriptomic datasets from sepsis patients. We confirmed that both GSs can successfully predict sepsis survival in both discovery and validation cohorts with high sensitivity and specificity, with the PPI-based GS showing enhanced prognostic performance. Together, this study successfully engineers a new and validated blood-borne biomarker (PPI-based 7-gene GS) for sepsis survival risk prediction. This biomarker holds the potential for improving the early identification of high-risk sepsis patients and optimizing personalized treatment strategies to reduce sepsis mortality.
    Keywords:  DRP1; fission; inflammation; mitochondria; sepsis survival
    DOI:  https://doi.org/10.3389/fimmu.2024.1516145
  13. Int Immunopharmacol. 2025 Jan 18. pii: S1567-5769(25)00086-4. [Epub ahead of print]148 114097
    Betulinic acid mitigates lipopolysaccharide-induced intestinal injury of weaned piglets through modulation of the mitochondrial quality control.
    Jiayu He, Chunlin Huang, Li Kong, You Huang, Zhaoping Ou, Mingqi Yang, Jiao Wu, Yu Yang, Huan Yao, Jine Yi, Shuiping Liu.
      Intestinal injury of weaned piglets often leads to reduced immunity, diarrhea and growth retardation, resulting in significant economic losses to agriculture. Betulinic acid (BA) is a natural plant-derived active ingredient with multiple pharmacological activities including immune modulation and anti-inflammatory. This study was aimed to investigate the potential mechanism that BA as a feed additive mitigated lipopolysaccharide (LPS)-induced intestinal injury in piglets. The results indicated that BA pretreatment improved the morphology and structure of the intestine, enhanced intestinal mucosal barrier function, and activated the PPAR signaling pathway to reduce the mRNA levels of intestinal CD40 and CXCL13. Meanwhile, BA pretreatment improved the LPS-induced disruption of intestinal microbiota by increasing the abundance of the Firmicutes and decreasing the abundance of the Bacteroidota and Proteobacteria. Furthermore, BA pretreatment activated the AMPK/SIRT1/PGC-1α signaling pathway to enhance mitochondrial biogenesis, restored a balance to mitochondrial dynamics, and modulated the PINK1/Parkin, BNIP3 and FUNDC1 signaling pathways to activate mitophagy, thereby alleviating LPS-induced intestinal injury. Overall, the present study elucidated that dietary supplementation with BA could alleviate LPS-induced intestinal injury in weaned piglets by regulating mitochondrial quality control, which provided a novel approach for alleviating intestinal stress in weaned piglets.
    Keywords:  Betulinic acid; Intestinal injury; Intestinal microbiota; Mitochondrial quality control; Weaned piglets
    DOI:  https://doi.org/10.1016/j.intimp.2025.114097
  14. Lasers Med Sci. 2025 Jan 24. 40(1): 38
    Effects of photobiomodulation in mitochondrial quantity, biogenesis and mitophagy-associated genes in breast cancer cells.
    Larissa Alexsandra da Silva Neto Trajano, Priscyanne Barreto Siqueira, Daphne Pinheiro, Thayssa Gomes Farias, Márcia Soares Dos Santos, Bruno Ricardo Barreto Pires, Adenilson de Souza da Fonseca, Andre Luiz Mencalha.
      In this article, we aim to evaluate the effects of photobiomodulation on mitochondria quantity, biogenesis, and mitophagy-associated genes in breast cancer (BC) cells. Both models were irradiated with a low-power infrared laser (880 nm, 150 mW) and amber LED (617 nm, 1500 mW), alone or simultaneously. We evaluated the mRNA expression of PINK1 and PGC-1α genes, and the mitochondrial number was assessed based on the ratio of mitochondrial DNA/genomic DNA (mtDNA/gDNA). No significant difference was observed in the mtDNA/gDNA ratio comparing the low-power infrared laser (LPIL) and LED-irradiated groups to their control counterparts. Similarly, no difference was observed in the mRNA levels of PINK1 and PGC-1α of the irradiated group with an LPIL and LED alone or in combination. In conclusion, PBM with LPIL and LED did not alter the mtDNA/gDNA ratio nor modulate the mRNA levels of the genes related to mitophagy and biogenesis in BC cells.
    Keywords:  LED; Low-power infrared laser; Mitochondrial biogenesis; Mitophagy; Photobiomodulation; mtDNA
    DOI:  https://doi.org/10.1007/s10103-025-04287-0
  15. Exp Gerontol. 2025 Jan 18. pii: S0531-5565(25)00014-2. [Epub ahead of print]200 112686
    Lycium barbarum glycopeptide ameliorates aging phenotypes and enhances cardiac metabolism by activating the PINK1/Parkin-mediated mitophagy pathway in D-galactose-induced mice.
    Tianchan Peng, Jian Xiang, Yun Tian, Xiaogen Tang, Lina Wang, Lijuan Gao, Oscar Junhong Luo, Li'an Huang, Guobing Chen.
       BACKGROUND: Aging is a complex biological process that disrupts tissue structure and impairs physiological function, which contributes to the development of age-related diseases such as cardiovascular disorders. However, effective treatment strategies are lacking.
    OBJECTIVE: To investigate the geroprotective effects of Lycium barbarum glycopeptide (LbGp) and its potential mechanisms in a D-galactose-induced accelerated aging mouse model.
    METHODS: Mice were subcutaneously injected with D-galactose (500 mg/kg/day) for 12 weeks to induce aging, while LbGp was orally administered (100 mg/kg/day) throughout the study. The geroprotective effects of LbGp were assessed by behavioral tests, cardiac echocardiography, pathohistological and transcriptomic analyses. Transmission electron microscopy was used to observe the ultrastructure of mitochondria. Mitochondrial stress assays and JC-1 fluorescent probe were conducted to evaluate mitochondrial function. Flow cytometer and western blot were performed to assess mitophagy flux.
    RESULTS: LbGp treatment improved the aging phenotypes of D-galactose-induced mice, with a pronounced enhancement in cardiac function compared to neurocognitive and skeletal muscle functions. Transcriptome analysis indicated that LbGp ameliorated energy metabolism in the heart. Mitochondrial assays revealed LbGp improved mitochondrial function and preserved structural integrity of the mitochondrial inner membrane. LbGp attenuated mitochondrial fission and restored impaired PINK1/Parkin-mediated mitophagy pathway caused by D-galactose in cardiomyocytes.
    CONCLUSION: LbGp can ameliorate aging phenotypes and enhance cardiac metabolism by activating the PINK1/Parkin-mediated mitophagy pathway in D-galactose-induced mice. These findings underscore its potential as a therapeutic agent for aging and aging-related cardiovascular diseases.
    Keywords:  Aging; Cardiac metabolism; D-galactose; Lycium barbarum glycopeptide; Mitophagy
    DOI:  https://doi.org/10.1016/j.exger.2025.112686
  16. J Pharmacol Sci. 2025 Feb;pii: S1347-8613(24)00077-X. [Epub ahead of print]157(2): 45-56
    Penehyclidine hydrochloride activates PARK2 and modulates ubiquitination of AIFM1 to rescue renal tubular injury in diabetic kidney disease.
    Li Chen, Jing Tang, HongBao Tan.
       BACKGROUND: Renal tubular injury (RTI) is one of the key characteristics of diabetic nephropathy (DN). Penehyclidine hydrochloride (PHC) was an anticholinergic drug with renoprotective effects, but its specific mechanism in the treatment of DN was still unclear.
    METHODS: We treated different diabetic mouse models and high glucose-induced RTI models by PHC. Histological analyses were performed using flow cytometry and staining, and ELISA evaluated the ROS, apoptosis, and related markers under different treatments. The molecular interactions were analyzed by ChIP, dual-luciferase reporter, and CoIP.
    RESULTS: PHC alleviated RTI by activating mitophagy and inhibiting apoptosis, and the protective effect could be rescued by PARK2 knockdown. Nrf2 bound to the promoter region of PARK2 and promoted its expression. PHC reduced the level of apoptosis by reducing the degree of nuclear translocation of AIFM1, which was rescued by PARK2 knockdown. PARK2 knockdown reduced the non-degradative ubiquitination of AIFM1, thus promoting its nuclear translocation and ultimately facilitating renal tubular cells (RTCs) apoptosis. The over-expression of AIFM1 rescued the RTCs apoptosis antagonized by PHC.
    CONCLUSIONS: PHC activated Nrf2 to up-regulate PARK2 transcription to induce mitophagy and inhibit apoptosis mediated by nuclear translocation of AIFM1 through promoting non-degradative ubiquitination of AIFM1, ultimately rescuing RTI in DN.
    Keywords:  AIFM1; Diabetic nephropathy; Non-degradative ubiquitination; PARK2; Penehyclidine hydrochloride
    DOI:  https://doi.org/10.1016/j.jphs.2024.12.001
  17. Cell Death Dis. 2025 Jan 19. 16(1): 29
    ApoM maintains cellular homeostasis between mitophagy and apoptosis by affecting the stability of Nnt mRNA through the Zic3-ApoM-Elavl2-Nnt axis during neural tube closure.
    Qing Liu, Dan Liu, Yuejiao Wang, Xiaowei Wei, Wei Ma, Hui Gu, Shanshan Jia, Yiwen He, Wenting Luo, Songying Cao, Zhonghua Yang, Anhua Wu, Zhengwei Yuan.
      Research on the aetiology of neural tube defects (NTDs) has made progress in recent years. However, the molecular mechanism of apolipoproteins underlying NTDs development remains unclear. This study aimed to investigate the function of apolipoprotein M (ApoM) in the pathogenesis of NTDs and its underlying mechanisms. We demonstrated that ApoM expression was reduced in the spinal cord samples of rat models and human fetuses with NTDs respectively. Specifically, lack of ApoM resulted in reduced cytosolic localization of Elavl2 and caused Nnt mRNA degradation, which further led to impaired cell homeostasis by suppressing PINK1-PRKN-mediated mitophagy and promoting apoptosis and subsequent NTDs formation. Moreover, Zic3 directly interacted with the promoter of ApoM and activated its transcription. Lastly, intra-amniotic delivery of adenoviral recombinant Zic3 or ApoM could promote mitophagy and alleviate apoptosis in spinal cords of NTDs. Collectively, these findings highlight the important role of the Zic3-ApoM-Elavl2-Nnt axis in cellular homeostasis during neural tube development, thereby revealing an intracellular molecular regulatory mechanism of ApoM, providing a mechanistic basis for understanding embryonic neural development, and offering experimental evidence for potential therapeutic targets for NTDs.
    DOI:  https://doi.org/10.1038/s41419-025-07343-3
  18. Biochim Biophys Acta Mol Cell Res. 2025 Jan 19. pii: S0167-4889(25)00011-4. [Epub ahead of print]1872(3): 119906
    Mitochondrial quality control: Biochemical mechanism of cardiovascular disease.
    Francesca Inferrera, Ylenia Marino, Tiziana Genovese, Salvatore Cuzzocrea, Roberta Fusco, Rosanna Di Paola.
      Mitochondria play a key role in the regulation of energy homeostasis and ATP production in cardiac cells. Mitochondrial dysfunction can trigger several pathological events that contribute to the development and progression of cardiovascular diseases. These mechanisms include the induction of oxidative stress, dysregulation of intracellular calcium cycling, activation of the apoptotic pathway, and alteration of lipid metabolism. This review focuses on the role of mitochondria in intracellular signaling associated with cardiovascular diseases, emphasizing the contributions of reactive oxygen species production and mitochondrial dynamics. Indeed, mitochondrial dysfunction has been implicated in every aspect of cardiovascular disease and is currently being evaluated as a potential target for therapeutic interventions. To treat cardiovascular diseases and improve overall heart health, it is important to better understand these biochemical systems. These findings allow the achievement of targeted therapies and preventive measures. Therefore, this review investigates different studies that demonstrate how changes in mitochondrial dynamics like fusion, fission, and mitophagy contribute to the development or worsening of disorders related to heart diseases by summarizing current research on their role.
    Keywords:  Cardiovascular diseases; Intracellular signaling; Mitochondrial dysfunction; Oxidative stress; Therapeutic interventions
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.119906
  19. Funct Integr Genomics. 2025 Jan 23. 25(1): 26
    Mitochondria and its epigenetic dynamics: Insight into synaptic regulation and synaptopathies.
    Shiwangi Gupta, Abhinoy Kishore, Vikas Rishi, Aanchal Aggarwal.
      Mitochondria, the cellular powerhouses, are pivotal to neuronal function and health, particularly through their role in regulating synaptic structure and function. Spine reprogramming, which underlies synapse development, depends heavily on mitochondrial dynamics-such as biogenesis, fission, fusion, and mitophagy as well as functions including ATP production, calcium (Ca2+) regulation, and retrograde signaling. Mitochondria supply the energy necessary for assisting synapse development and plasticity, while also regulating intracellular Ca2+ homeostasis to prevent excitotoxicity and support synaptic neurotransmission. Additionally, the dynamic processes of mitochondria ensure mitochondrial quality and adaptability, which are essential for maintaining effective synaptic activity. Emerging evidence highlights the significant role of epigenetic modifications in regulating mitochondrial dynamics and function. Epigenetic changes influence gene expression, which in turn affects mitochondrial activity, ensuring coordinated responses necessary for synapse development. Furthermore, metabolic changes within mitochondria can impact the epigenetic machinery, thereby modulating gene expression patterns that support synaptic integrity. Altered epigenetic regulation affecting mitochondrial dynamics and functions is linked to several neurological disorders, including Amyotrophic Lateral Sclerosis, Huntington's, Alzheimer's, and Parkinson's diseases, emphasizing its crucial function. The review delves into the molecular machinery involved in mitochondrial dynamics, ATP and Ca2+ regulation, highlighting the role of key proteins that facilitate the processes. Additionally, it also shed light on the emerging epigenetic factors influencing these regulations. It provides a thorough summary on the current understanding of the role of mitochondria in synapse development and emphasizes the importance of both molecular and epigenetic mechanisms in maintaining synaptic integrity.
    DOI:  https://doi.org/10.1007/s10142-025-01530-3
  20. Cells. 2025 Jan 17. pii: 137. [Epub ahead of print]14(2):
    Derivation and Characterization of Isogenic OPA1 Mutant and Control Human Pluripotent Stem Cell Lines.
    Katherine A Pohl, Xiangmei Zhang, Johnny Jeonghyun Ji, Linsey Stiles, Alfredo A Sadun, Xian-Jie Yang.
      Dominant optic atrophy (DOA) is the most commonly inherited optic neuropathy. The majority of DOA is caused by mutations in the OPA1 gene, which encodes a dynamin-related GTPase located to the mitochondrion. OPA1 has been shown to regulate mitochondrial dynamics and promote fusion. Within the mitochondrion, proteolytically processed OPA1 proteins form complexes to maintain membrane integrity and the respiratory chain complexity. Although OPA1 is broadly expressed, human OPA1 mutations predominantly affect retinal ganglion cells (RGCs) that are responsible for transmitting visual information from the retina to the brain. Due to the scarcity of human RGCs, DOA has not been studied in depth using the disease affected neurons. To enable studies of DOA using stem-cell-derived human RGCs, we performed CRISPR-Cas9 gene editing to generate OPA1 mutant pluripotent stem cell (PSC) lines with corresponding isogenic controls. CRISPR-Cas9 gene editing yielded both OPA1 homozygous and heterozygous mutant ESC lines from a parental control ESC line. In addition, CRISPR-mediated homology-directed repair (HDR) successfully corrected the OPA1 mutation in a DOA patient's iPSCs. In comparison to the isogenic controls, the heterozygous mutant PSCs expressed the same OPA1 protein isoforms but at reduced levels; whereas the homozygous mutant PSCs showed a loss of OPA1 protein and altered mitochondrial morphology. Furthermore, OPA1 mutant PSCs exhibited reduced rates of oxygen consumption and ATP production associated with mitochondria. These isogenic PSC lines will be valuable tools for establishing OPA1-DOA disease models in vitro and developing treatments for mitochondrial deficiency associated neurodegeneration.
    Keywords:  CRISPR-Cas9 editing; OPA1 gene; dominant optic atrophy; isogenic human pluripotent stem cell lines; mitochondria
    DOI:  https://doi.org/10.3390/cells14020137
  21. Biol Chem. 2025 Jan 21.
    MitoStores: stress-induced aggregation of mitochondrial proteins.
    Pragya Kaushik, Johannes M Herrmann, Katja G Hansen.
      Most mitochondrial proteins are synthesized in the cytosol and post-translationally imported into mitochondria. If the rate of protein synthesis exceeds the capacity of the mitochondrial import machinery, precursor proteins can transiently accumulate in the cytosol. The cytosolic accumulation of mitochondrial precursors jeopardizes cellular protein homeostasis (proteostasis) and can be the cause of diseases. In order to prevent these toxic effects, most non-imported precursors are rapidly degraded by the ubiquitin-proteasome system. However, cells employ a second layer of defense which is the facilitated sequestration of mitochondrial precursor proteins in transient protein aggregates. The formation of such structures is triggered by nucleation factors such as small heat shock proteins. Disaggregases and chaperones can liberate precursors from cytosolic aggregates to pass them on to the mitochondrial import machinery or, under persistent stress conditions, to the proteasome for degradation. Owing to their role as transient buffering systems, these aggregates were referred to as MitoStores. This review articles provides a general overview about the MitoStore concept and the early stages in mitochondrial protein biogenesis in yeast and, in cases where aspects differ, in mammalian cells.
    Keywords:  aggregates; mitochondria; mitostores; proteasome; protein targeting; quality control
    DOI:  https://doi.org/10.1515/hsz-2024-0148
  22. Front Immunol. 2024 ;15 1448878
    Single-cell mitophagy patterns within the tumor microenvironment modulate intercellular communication, impacting the progression and prognosis of hepatocellular carcinoma.
    Zhengyan Li, Wei Chen, Shu Yao, Zuxiang Peng, Hongming Liu, Yongliang Tang, Yi Feng.
       Background: Hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive system with a high incidence that seriously threatens patients' lives and health. However, with the rise and application of new treatments, such as immunotherapy, there are still some restrictions in the treatment and diagnosis of HCC, and the therapeutic effects on patients are not ideal.
    Methods: Two single-cell RNA sequencing (scRNA-seq) datasets from HCC patients, encompassing 25,189 cells, were analyzed in the study. We utilized non-negative matrix factorization (NMF) clustering to identify mitophagy patterns in HCC TME cells, including cancer-associated fibroblasts (CAFs), T cells, B cells, and tumor-associated macrophages (TAMs). Cell-to-cell communication was analyzed using the CellChat package, and pseudotime trajectory analysis was performed using the Monocle package. Gene regulatory networks were investigated with the SCENIC package, and survival analyses were conducted with mitophagy-related signatures.
    Results: HCC samples analysis identified 22 clusters, including 7 principal cell types. Complex cell communications were observed among these cell types. Mitophagy-related CAFs, TAMs, CD8+ T cells, and B cells were identified. These subtypes had different biological states, cell-cell communications, and metabolic pathways. Mitophagy levels were elevated in tumor samples. Changes in mitophagy-related genes within specific cell subtypes were associated with different overall survival rates. However, mitophagy did not seem to affect the effectiveness of immunotherapy.
    Conclusion: This study provides evidence that mitophagy within the HCC TME modulates intercellular communication, influencing tumor progression and patient prognosis. Targeting mitophagy may offer a promising approach to improve the long-term prognosis of HCC patients.
    Keywords:  bioinformatics; hepatocellular carcinoma; mitophagy; prognosis; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1448878
  23. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 19. pii: S0925-4439(25)00027-4. [Epub ahead of print] 167682
    Mitochondrial regulation of obesity by POMC neurons.
    Xing-Dan Luo, Si Tang, Xiang-Yun Luo, Luosang Quzhen, Ruo-Han Xia, Xian-Wang Wang.
      Pro-opiomelanocortin (POMC) neurons, nestled in the hypothalamus, play a pivotal role in the intricate coordination of energy homeostasis and metabolic pathways. These neurons' mitochondria, often hailed as the cell's powerhouses, are crucial for maintaining cellular energy equilibrium and metabolic functionality. Recent research has illuminated the complex interplay between mitochondrial dynamics and POMC neuronal activity, underscoring their critical involvement in the pathogenesis of a spectrum of metabolic disorders, notably obesity and diabetes. This comprehensive review delves into the molecular mechanisms that underlie how mitochondrial function within POMC neurons modulates metabolic regulation. We dissect the impact of mitochondrial dynamics, encompassing fusion, fission, mitophagy, and biogenesis, on the regulation of POMC neuronal activity. Furthermore, we scrutinize the role of mitochondrial dysfunction in POMC neurons in the etiology of obesity, identifying key therapeutic targets within these pathways. We offer an in-depth perspective on the indispensable role of POMC neuronal mitochondria in metabolic regulation and chart future research directions to bridge the existing knowledge gaps in this field.
    Keywords:  Metabolic regulation; Mitochondrion; Obesity; POMC
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167682
  24. bioRxiv. 2025 Jan 07. pii: 2025.01.07.631801. [Epub ahead of print]
    Fis1 is required for the development of the dendritic mitochondrial network in pyramidal cortical neurons.
    Klaudia Strucinska, Parker Kneis, Travis Pennington, Katarzyna Cizio, Patrycja Szybowska, Abigail Morgan, Joshua Weertman, Tommy L Lewis.
      Mitochondrial ATP production and calcium buffering are critical for metabolic regulation and neurotransmission making the formation and maintenance of the mitochondrial network a critical component of neuronal health. Cortical pyramidal neurons contain compartment-specific mitochondrial morphologies that result from distinct axonal and dendritic mitochondrial fission and fusion profiles. We previously showed that axonal mitochondria are maintained at a small size as a result of high axonal mitochondrial fission factor (Mff) activity. However, loss of Mff activity had little effect on cortical dendritic mitochondria, raising the question of how fission/fusion balance is controlled in the dendrites. Thus, we sought to investigate the role of another fission factor, fission 1 (Fis1), on mitochondrial morphology, dynamics and function in cortical neurons. We knocked down Fis1 in cortical neurons both in primary culture and in vivo , and unexpectedly found that Fis1 depletion decreased mitochondrial length in the dendrites, without affecting mitochondrial size in the axon. Further, loss of Fis1 activity resulted in both increased mitochondrial motility and dynamics in the dendrites. These results argue Fis1 exhibits dendrite selectivity and plays a more complex role in neuronal mitochondrial dynamics than previously reported. Functionally, Fis1 loss resulted in reduced mitochondrial membrane potential, increased sensitivity to complex III blockade, and decreased mitochondrial calcium uptake during neuronal activity. The altered mitochondrial network culminated in elevated resting calcium levels that increased dendritic branching but reduced spine density. We conclude that Fis1 regulates morphological and functional mitochondrial characteristics that influence dendritic tree arborization and connectivity.
    DOI:  https://doi.org/10.1101/2025.01.07.631801
  25. J Biochem Mol Toxicol. 2025 Feb;39(2): e70069
    Hypoxia-Inducible Factor-1α Regulates BNIP3-Dependent Mitophagy and Mediates Metabolic Reprogramming Through Histone Lysine Lactylation Modification to Affect Glioma Proliferation and Invasion.
    Feng Dong, Haichang Yin, Zhixing Zheng.
       OBJECTIVE: Gliomas are the predominant form of malignant brain tumors. We investigated the mechanism of hypoxia-inducible factor-1α (HIF-1α) affecting glioma metabolic reprogramming, proliferation and invasion.
    METHODS: Human glioma cell U87 was cultured under hypoxia and treated with small interfering (si)HIF-1α, si-B cell lymphoma-2/adenovirus E1B 19-kDa interacting protein 3 (siBNIP3), si-YT521-B homology domain 2 (siYTHDF2), 3-methyladenine and 2-deoxyglucose, with exogenous sodium lactate-treated normally-cultured cells as a lactate-positive control. Cellular hexokinase 2, lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 enzyme activities, glucose uptake, and levels of lactic acid and adenosine triphosphate (ATP), and HIF-1α, glycolysis-related proteins, mitophagy-related proteins, histone H3 lysine 18 lactylation (H3K18la) and YTHDF2 were determined by ELISA, 2-NBDG, kits, and Western blot. Extracellular acidification rate (ECAR), and cell proliferation, invasion, apoptosis and mitophagy were evaluated by extracellular flux analysis, CCK-8, Transwell, flow cytometry, and immunofluorescence staining. H3K18la-YTHDF2 relationship and YTHDF2-BNIP3 interaction were assessed by ChIP and Co-IP assays.
    RESULTS: Hypoxia-induced highly-expressed HIF-1α in glioma cells increased glycolysis-related protein levels, glycolytic enzyme activities, glucose uptake, lactic acid production, ATP level and ECAR, thereby promoting metabolic reprogramming, invasion and proliferation. HIF-1α mediated metabolic reprogramming, proliferation and invasion through BNIP3-dependent mitophagy, which were partly negated by mitophagy inhibition. HIF-1α induced histone Kla modification to upregulate YTHDF2. YTHDF2 downregulation impeded YTHDF2-BNIP3 interaction and inhibited HIF-1α-induced BNIP3-dependent mitophagy, curbing glioma cell metabolic reprogramming, proliferation and invasion.
    CONCLUSIONS: Hypoxia-induced high HIF-1α expression upregulated YTHDF2 through hH3K18la modification, enhanced YTHDF2-BNIP3 interaction, and regulated BNIP3-dependent mitophagy-mediated metabolic reprogramming to affect glioma proliferation and invasion.
    Keywords:  B cell lymphoma‐2/adenovirus E1B 19‐kDa interacting protein 3; histone lysine lactylation modification; hypoxia‐inducible factor‐1α; metabolic reprogramming; mitophagy
    DOI:  https://doi.org/10.1002/jbt.70069
  26. J Gene Med. 2025 Jan;27(1): e70007
    Revealing the Complex Interaction of Noncoding RNAs, Sirtuin Family, and Mitochondrial Function.
    Ludong Yuan, Leijing Yin, Xiaofang Lin, Jing Li, Pengfei Liang, Bimei Jiang.
      Mitochondria are key organelles that perform and coordinate various metabolic processes in the cell, and their homeostasis is essential for the maintenance of eukaryotic life. To maintain mitochondrial homeostasis and cellular health, close communication between noncoding RNAs (ncRNAs) and proteins is required. For example, there are numerous crosstalk between ncRNAs and the sirtuin (SIRT1-7) family, which is a group of nicotinamide adenine dinucleotides (NAD(+))-dependent Type III deacetylases. NcRNAs are involved in the regulation of gene expression of sirtuin family members, and deacetylation of sirtuin family members can also influence the generation of ncRNAs. This review focuses on the relationship between the two mentioned above and summarizes the impact of their interactions on mitochondrial metabolism, oxidative stress, mitochondrial apoptotic pathways, mitochondrial biogenesis, mitochondrial dynamics, and other mitochondria-related pathophysiological processes. Finally, the review also describes targeted and appropriate treatment strategies. In conclusion, we provide an overview of the ncRNA-sirtuins/mitochondria relationship that could provide a reference for related research in the mitochondrial field and help the future development of new biomedical applications in this area.
    Keywords:  apoptosis; metabolism; mitochondria; noncoding RNAs; oxidative stress; sirtuins
    DOI:  https://doi.org/10.1002/jgm.70007
  27. Acta Biochim Biophys Sin (Shanghai). 2025 Jan 22.
    Daphnetin-mediated mitophagy alleviates intervertebral disc degeneration via the Nrf2/PINK1 pathway.
    Yiting Tu, Jiaping Ren, Weiyuan Fang, Chencheng Zhou, Binli Zhao, Tianyong Hua, Yiqi Chen, Zhenya Chen, Yongzeng Feng, Haiming Jin, Xiangyang Wang.
      Intervertebral disc degeneration (IDD) is a major cause of low back pain (LBP), and effective therapies are still lacking. Reactive oxygen species (ROS) stress induces NLRP3 inflammasome activation, and this, along with extracellular matrix metabolism (ECM) degradation in nucleus pulposus cells (NPCs), plays a crucial role in the progression of IDD. Daphnetin (DAP) is a biologically active phytochemical extracted from plants of the Genus Daphne, which possesses various bioactivities, including antioxidant properties. In the present study, we demonstrate that DAP significantly attenuates tert-butyl hydroperoxide (TBHP)-induced ECM degradation, oxidative stress and NLRP3 inflammasome activation in NPCs. Furthermore, DAP could facilitate mitophagy to increase the removal of damaged mitochondria, consequently reducing mitochondrial ROS accumulation and alleviating NLRP3 inflammasome activation. Mechanistically, we unveil that DAP activates mitophagy by stimulating the Nrf2/PINK1 signaling pathway in TBHP-induced NPCs. In vivo experiments further corroborate the protective effect of DAP against IDD progression in a rat model induced by disc puncture. Accordingly, our findings reveal that DAP could be a promising therapeutic candidate for the treatment of IDD.
    Keywords:  IDD; NLRP3 inflammasome; Nrf2/PINK1; daphnetin; extracellular matrix; mitophagy
    DOI:  https://doi.org/10.3724/abbs.2025002
  28. Front Bioeng Biotechnol. 2024 ;12 1500343
    Optogenetic control of mitochondrial aggregation and function.
    Luhao Zhang, Xuechun Liu, Min Zhu, Yuanfa Yao, Zhichao Liu, Xianming Zhang, Xin Deng, Yi Wang, Liting Duan, Xiaogang Guo, Junfen Fu, Yingke Xu.
      The balance of mitochondrial fission and fusion plays an important role in maintaining the stability of cellular homeostasis. Abnormal mitochondrial fission and fragmentation have been shown to be associated with oxidative stress, which causes a variety of human diseases from neurodegeneration disease to cancer. Therefore, the induction of mitochondrial aggregation and fusion may provide an alternative approach to alleviate these conditions. Here, an optogenetic-based mitochondrial aggregation system (Opto-MitoA) developed, which is based on the CRY2clust/CIBN light-sensitive module. Upon blue light illumination, CRY2clust relocates from the cytosol to mitochondria where it induces mitochondrial aggregation by CRY2clust homo-oligomerization and CRY2clust-CIBN hetero-dimerization. Our functional experiments demonstrate that Opto-MitoA-induced mitochondrial aggregation potently alleviates niclosamide-caused cell dysfunction in ATP production. This study establishes a novel optogenetic-based strategy to regulate mitochondrial dynamics in cells, which may provide a potential therapy for treating mitochondrial-related diseases.
    Keywords:  ATP; aggregation; imaging; mitochondria; optogenetics
    DOI:  https://doi.org/10.3389/fbioe.2024.1500343
  29. Phytomedicine. 2025 Jan 11. pii: S0944-7113(25)00027-3. [Epub ahead of print]138 156388
    SQYC formula improves the efficacy of PD-1 monoclonal antibodies in MSS colorectal cancer by regulating dendritic cell mitophagy via the PINK1-Parkin pathway.
    Hong Wang, Yi Ji, Shan Deng, Xiao Ying Qin, Xie Tao Ye, Ye Yang Sun, Xiao Yu Che, Lin Yang, Chu Yue Huang, Yan Chen, Yu Ping Liu.
       BACKGROUND: Microsatellite stable (MSS) colorectal carcinomas (CRCs) exhibit poor responsiveness to immunotherapy such as immune checkpoint inhibitors (ICIs). In the realm of clinical cancer treatment, traditional Chinese medicines (TCMs) are extensively utilized for their immunomodulatory properties. Shen Qi Yi Chang (SQYC), a clinical prescription for CRC treatment, improve the life quality of CRC patients and enhance their immune function.
    PURPOSE: This study was to reveal the effect and mechanism of SQYC in improving the effect of PD-1 inhibitors in the treatment of MSS-type CRC.
    METHODS: CT26-luc in situ CRC tumor model and human CRC organoid model was established to evaluate the anti-tumor efficacy of SQYC combined with PD-1 inhibitor. Flow cytometry analysis was utilized to investigate the effect of SQYC on the infiltration and immune function of TILs and DCs in the immune microenvironment. Following this, RNA sequencing analysis, seahorse, TEM and immunofluorescence were performed to regulation of SQYC on mitophagy in DCs cells. UPLC-Q-TOF/MS and molecular docking were used to reveal the key blood-entering components of SQYC-regulated PINK1-parkin pathway.
    RESULTS: The SQYC-containing serum improved the efficacy of sintilimab in MSS CRC organoid model. After combined administration of 11.4 g/kg/day SQYC extract and 5 mg/kg α-PD-1, it was observed that SQYC enhanced the efficacy of PD-1 inhibitor against MSS CRC. Flow cytometry and immunofluorescence analysis revealed an augmented infiltration of tumor-infiltrating lymphocytes (TILs) and an improved antigen presentation function of dendritic cells (DCs). Notably, RNA sequencing analysis demonstrated an evident correlation with mitochondrial function related pathways following SQYC treatment. Mechanistically, SQYC promoted mitophagy in DCs via the PINK1-Parkin pathway, thereby improving mitochondrial quality, energy metabolism, and mitochondrial dynamics. Evaluation of the blood components of SQYC coupled with molecular docking, demonstrated good binding affinity with PINK1/PARKIN/LC3.
    CONCLUSION: Our findings highlight SQYC as a promising candidate for improving immunotherapy in MSS CRC, suggesting that targeting PINK1-Parkin in DCs could represent a novel strategy for improving the efficacy of ICIs. Furthermore, it provides new theoretical and scientific underpinnings to enhance the clinical efficacy of immunosuppressants.
    Keywords:  DCs; MSS CRC; Mitophagy; PD-1 inhibitor; PINK1-Parkin; SQYC
    DOI:  https://doi.org/10.1016/j.phymed.2025.156388
  30. Exp Neurol. 2025 Jan 18. pii: S0014-4886(25)00017-2. [Epub ahead of print]386 115153
    Sleep fragmentation impairs cognitive function and exacerbates Alzheimer's disease-related pathology in a mouse model by disrupting mitochondrial biogenesis.
    Shunjie Liu, Xingyi Liu, Man Ke, Jinliang Wang.
      A large proportion of Alzheimer's disease (AD) patients suffer from various types of chronic sleep disturbances, including sleep fragmentation (SF). In addition, impaired mitochondrial biogenesis is an important feature of AD, but whether it is altered in sleep disorders has not been fully elucidated. Hence, we aimed to investigate the relationship between SF and mitochondrial biogenesis and the possible impact of SF on AD-related pathology. In this study, thirty-six 9-month-old 3xTgAD model mice and thirty-six 9-month-old wild-type (WT) C57BL/6 J mice were divided into a control group (6 weeks of normal sleep), a SF group (6 weeks of SF) and a SF + recovery sleep group (6 weeks of SF followed by 2 weeks of recovery sleep). Cognitive functions were assessed by behavioural experiments. Mitochondrial structure and function and the activity of a classic mitochondrial biogenesis signalling pathway were investigated using transmission electron microscopy (TEM), reverse transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence and Western blotting. Markers of AD-related pathology, including the levels of amyloid β (Aβ) and tau proteins, were assessed by immunofluorescence and Western blotting. The expression of insulin-degrading enzyme (IDE) was assessed by Western blotting. We found that long-term SF impaired the cognitive functions of the mice. In addition, chronic SF reduced the expression of mitochondrial respiratory chain components, the number of mitochondria, the fluorescence intensity of COX-IV, the level of mitochondrial DNA (mtDNA) and the expression of crucial regulators of the AMPK/SIRT-1/PGC-1α signalling pathway in the mouse prefrontal cortex and hippocampus, while recovery sleep could partly abrogate these effects. Moreover, SF reduced the protein level of IDE and increased the Aβ burden and tau hyperphosphorylation. This study demonstrates that chronic SF can negatively regulate the AMPK/SIRT-1/PGC-1α signalling pathway to disrupt mitochondrial biogenesis in the brains of mice, which may subsequently exacerbate AD-related pathology by decreasing the expression of IDE.
    Keywords:  Alzheimer's disease; Mitochondrial biogenesis; Pathology; Sleep fragmentation
    DOI:  https://doi.org/10.1016/j.expneurol.2025.115153
  31. Poult Sci. 2025 Jan 14. pii: S0032-5791(25)00032-X. [Epub ahead of print]104(2): 104795
    Duck Tembusu virus induced mitophagy in vacuolate spermatogenic cells is mediated by PINK1-Parkin pathway.
    Yufei Huang, Xiaoman Yan, Xiaoya Chu, Yonghong Shi, Jacob Xiang, Sheng Yang.
      As a significant emerging and re-emerging pathogen in China, the widely spread of Duck Tembusu virus (DTMUV) caused enormous economic losses to poultry industry. On account of DTMUV diseases' main symptoms on haemorrhagic oophoritis, intensive attentions were focused on female reproductive organ. Nevertheless, the DTMUV infection of sperm and testis manifested that testis was an important vector for vertical transmission of DTMUV. In the present study, histopathology, immunofluorescence and transmission electron microscopy (TEM) analysis of DTMUV-infected duck testis revealed that DTMUV infection induced seminiferous epithelium injury via spermatogenic cells vacuolization. After DTMUV infection, the expression of autophagy-related genes and proteins in testis were significantly up-regulated. Further TEM analysis discovered that different stages of autophagic and mitophagy structures were visible in cytoplasm of spermatogenic cells after DTMUV infection. And more notably, the testicular protein expression of PINK1 and Parkin were significantly increased after DTMUV infection. In summary, our study discovered that, after DTMUV infection, PINK1-Parkin pathway mediated mitophagy were activated and then induced spermatogenic cells vacuolization.
    Keywords:  Autophagy; Duck Tembusu virus; Mitochondria; Permatogenic cells; Testis
    DOI:  https://doi.org/10.1016/j.psj.2025.104795
  32. Adv Healthc Mater. 2025 Jan 23. e2404934
    Improved Black Phosphorus Nanocomposite Hydrogel for Bone Defect Repairing: Mechanisms for Advancing Osteogenesis.
    Ailin Wu, Gaoqiang Ma, Yanhua Chen, Houda Gui, Baiyu Sun, Bing Zhang, Yingxue Liu, Sen Zhang, Guixue Lian, Dawei Song, Dongjiao Zhang.
      Bone defects caused by fractures and diseases often do not heal spontaneously. They require external agents for repair and regeneration. Bone tissue engineering is emerging as a promising alternative to traditional therapies like autografts and allografts. Nanobiomaterials enhance osteoblast resistance to harsh environments by promoting cell differentiation. Black phosphorus (BP), a novel 2D material in biomedicine, displays unique osteogenic and antimicrobial properties. However, BP nanosheets still face clinical limitations like rapid degradation and high-dose cytotoxicity. To address these, the introduction of amino-silicon phthalocyanine (SiPc-NH2) is investigated to see if it can enhance BP dispersion, reduce BP oxidation, and improve stability and safety for better osteogenesis and antibacterial effects through noncovalent interactions (van der Waals, π-π stacking and electrostatic interactions). Here, the self-healing hydrogel is successfully designed using a step-by-step co-assembly of BP and SiPc-NH2. SiPc-NH2 as a "structural stabilizer" of BP nanosheets reconstructed well-dispersed BP-SiPc-NH2 nanosheets, which improves the biocompatibility of BP, reduces oxidation and enhances photothermal conversion, guaranteeing osteogenic and antimicrobial properties. Furthermore, findings show BP-SiPc-NH2-induced mitochondrial changes support osteogenesis by regulating the crosstalk between Hippo and Wnt signaling pathways-mediated mitochondrial homeostasis, and boosting cellular bioenergetics. Overall, this mitochondrial morphology-based BP-SiPc-NH2 strategy holds great promise for bone repair applications.
    Keywords:  amino siloxane phthalocyanines; antibacterial; black phosphorus; bone regeneration; mitochondrial dynamics; mitochondrial homeostasis; mitochondrial quality control
    DOI:  https://doi.org/10.1002/adhm.202404934
  33. Nat Cell Biol. 2025 Jan 22.
    Mitochondrial protein import stress.
    Nikolaus Pfanner, Fabian den Brave, Thomas Becker.
      Mitochondria have to import a large number of precursor proteins from the cytosol. Chaperones keep these proteins in a largely unfolded state and guide them to the mitochondrial import sites. Premature folding, mitochondrial stress and import defects can cause clogging of import sites and accumulation of non-imported precursors, representing a critical burden for cellular proteostasis. Here we discuss how cells respond to mitochondrial protein import stress by regenerating clogged import sites and inducing stress responses. The mitochondrial protein import machinery has a dual role by serving as sensor for detecting mitochondrial dysfunction and inducing stress-response pathways. The production of chaperones that fold or sequester precursor proteins in deposits is induced and the proteasomal activity is increased to remove the excess precursor proteins. Together, these pathways reveal how mitochondria are tightly integrated into a cellular proteostasis and stress response network to maintain cell viability.
    DOI:  https://doi.org/10.1038/s41556-024-01590-w
  34. Bioorg Chem. 2025 Jan 09. pii: S0045-2068(25)00029-X. [Epub ahead of print]156 108149
    New triterpenoid saponins isolated from the leaves of Astragalus membranaceus (Fisch.) Bge. and their neuroprotective effects.
    Wenxiang Xu, Xinyuan Li, Qian Zhang, Peng Jiang, Yiqiang Zhang, Yumeng Luo, Wei Guan, Mengmeng Li, Qingshan Chen, Lili Zhang, Haixue Kuang, Bingyou Yang, Yan Liu.
      Fifteen new triterpenoid saponins designated as huangqiyesaponin A-O (1-15), in addition to eleven previously identified compounds (16-26), were extracted from the leaves of Astragalus membranaceus (Fisch.) Bge. utilizing a 70% ethanol solution. The structural characterization of the isolated compounds was achieved through the application of 1D and 2D NMR spectroscopy, in combination with single crystal X-ray diffraction analysis. Additionally, d-galactose-stimulated HT22 mouse hippocampal neuronal cells were utilized to assess the potential neuroprotective effects of all isolated compounds. The findings indicated that compounds 5, 11, and 13-15 exhibited significant neuroprotective effects. To elucidate the signaling pathway associated with the neuroprotective effects of compounds 13 and 15, the protein expression levels of PINK1, parkin, P62, and LC3-II were evaluated through WB analysis. The results of the study indicated that the compounds 13 and 15 enhanced the proportion of LC3-II to LC3-I as well as the protein expressions of PINK1 and parkin while concurrently reducing the expression of P62 protein, suggesting that these compounds exert neuroprotective effects by promoting mitochondrial autophagy.
    Keywords:  HT22 cell; Neuroprotective effect; Promoting mitochondrial autophagy; The leaves of Astragalus membranaceus (Fisch.) Bge.; Triterpenoid saponin
    DOI:  https://doi.org/10.1016/j.bioorg.2025.108149
  35. Int Immunopharmacol. 2025 Jan 18. pii: S1567-5769(25)00046-3. [Epub ahead of print]148 114057
    Urolithin A alleviates NLRP3 inflammasome activation and pyroptosis by promoting microglial mitophagy following spinal cord injury.
    Kongbin Chen, Jiahao Ying, Jiangwei Zhu, Liang Chen, Rongjie Liu, Mengqi Jing, Yuchao Wang, Kailiang Zhou, Long Wu, Chenyu Wu, Jian Xiao, Wenfei Ni.
      Spinal cord injury (SCI) is a potentially fatal condition that often results in loss of motor and sensory functions, thereby significantly burdening global health initiatives. Urolithin A (UA), an intestinal microbial metabolite of ellagic acid, is known for its potent anti-inflammatory properties in chronic inflammation contexts. UA treatment in humans induces a molecular signature of improved mitochondrial and cellular health. Yet, its effects on acute inflammation following SCI remain unclear. In this study, we developed an impact-induced mouse model for SCI and treated the injured mice with UA (50 mg/kg/d, till 8 weeks) via intragastric administration. Furthermore, we subjected BV2 cells to lipopolysaccharide and adenosine 5'-triphosphate to simulate the post-injury inflammatory response. Our results demonstrated that pre-treatment with UA (10 μM) effectively inhibited NLRP3 inflammasome activation in LPS-primed BV2 cells. This inhibition was evidenced by reduced cleaved Caspase-1 and mature IL-1β release, diminished ASC speck formation, and decreased gasdermin D (GSDMD)-mediated pyroptosis. Additionally, UA treatment restored mitochondrial activity and ROS production attenuated by NLRP3 activation, increased LC3-II expression, and enhanced LC3 co-localization with mitochondria. 3-Methyladenine (3-MA), an autophagy inhibitor, can partially reverse the stimulatory effect of UA on mitophagy, as well as the inhibitory effect of UA on pyroptosis. This study highlighted the protective role of UA against SCI through its promotion of mitophagy, which in turn inhibits NLRP3 inflammasome activation and pyroptosis.
    Keywords:  Autophagy; Mitophagy; NLRP3 inflammasome; Pyroptosis; Spinal cord injury; Urolithin A
    DOI:  https://doi.org/10.1016/j.intimp.2025.114057
  36. Adv Sci (Weinh). 2025 Jan 22. e2409835
    Improved Efficacy of Triple-Negative Breast Cancer Immunotherapy via Hydrogel-Based Co-Delivery of CAR-T Cells and Mitophagy Agonist.
    Guodong Li, Ruoxin Du, Donghui Wang, Xiangmei Zhang, Lizhuo Wang, Shuangpeng Pu, Xiaoju Li, Shuning Wang, Juliang Zhang, Beichen Liu, Yuan Gao, Huadong Zhao.
      Leaky and structurally abnormal blood vessels and increased pressure in the tumor interstitium reduce the infiltration of CAR-T cells in solid tumors, including triple-negative breast cancer (TNBC). Furthermore, high burden of tumor cells may cause reduction of infiltrating CAR-T cells and their functional exhaustion. In this study, various effector-to-target (E:T) ratio experiments are established to model the treatment using CAR-T cells in leukemia (high E:T ratio) and solid tumor (low E:T ratio). It is found that the antitumor immune response is decreased in solid tumors with low E:T ratio. Furthermore, single cell sequencing is performed to investigate the functional exhaustion at a low ratio. It is revealed that the inhibition of mitophagy-mediated mitochondrial dysfunction diminished the antitumor efficacy of CAR-T-cell therapy. The mitophagy agonist BC1618 is screened via AI-deep learning and cytokine detection, in vivo and in vitro studies revealed that BC1618 significantly strengthened the antitumor response of CAR-T cells via improving mitophagy. Here, injection hydrogels are engineered for the controlled co-delivery of CAR-T cells and BC1618 that improves the treatment of TNBC. Local delivery of hydrogels creates an inflammatory and mitophagy-enhanced microenvironment at the tumor site, which stimulates the CAR-T cells proliferation, provides antitumor ability persistently, and improves the effect of treatment.
    Keywords:  CAR‐T‐cell therapy; TNBC; hydrogel co‐delivery; mitophagy agonist; single cell sequencing
    DOI:  https://doi.org/10.1002/advs.202409835
  37. Front Pharmacol. 2024 ;15 1503490
    Salidroside enhances 5-fluorouracil sensitivity against hepatocellular carcinoma via YIPF5-induced mitophagy.
    Sumin Sun, Haili Hu, Feiyu Li, Sheng Huan, Long Chen, Jiahui Chen, Peihua Sun, Xiaoqing Dong.
      Hepatocellular carcinoma (HCC) is a major medical challenge due to its high incidence and poor prognosis. 5-Fluorouracil (5-FU), although extensively studied in the treatment of HCC and other solid tumors, has limited application as a first-line therapy for HCC due to its resistance and significant inter-patient variability. To address these issues, researchers have explored drug repurposing. One of our key findings in this endeavour was the potent anti-HCC effect of the natural product Salidroside (Sal) when co-administered with 5-FU. Sal was found to inhibit mitosis and promote cellular senescence in HCC cells via a mechanism distinct from 5-FU, specifically by inducing excessive mitophagy that led to cellular mitochondrial dysfunction. Importantly, YIPF5 was confirmed as a potential molecular target of Sal. This natural product modulated YIPF5-induced mitophagy and influenced both mitosis and senescence in HCC cells. The combination of Sal and 5-FU demonstrated significant therapeutic effects in a mouse HCC model. In conclusion, our study was not only in line with the innovative strategy of drug repurposing, but also important for drug design and natural product screening targeting the relevant pathways.
    Keywords:  5-fluorouracil; hepatocellular carcinoma; mitophagy; mitosis; salidroside; senescence
    DOI:  https://doi.org/10.3389/fphar.2024.1503490
  38. J Dermatol Sci. 2025 Jan 09. pii: S0923-1811(25)00002-7. [Epub ahead of print]
    Aberrant fumarate metabolism links interferon release in diffuse systemic sclerosis.
    Thomas Steadman, Steven O'Reilly.
       BACKGROUND: Systemic Sclerosis (SSc) is an idiopathic rheumatic inflammatory disease that is characterised by inflammation and skin fibrosis. Type I interferon is significantly elevated in the disease.
    OBJECTIVE: The objective of this study is to determine the role of the TCA cycle metabolite fumarate in SSc.
    METHODS: CD14 + cells were isolated from 12 SSc patients and healthy controls. Fumarate hydratase and Interferon dependant genes were quantified by qPCR. In vitro inhibition of STING using a small molecule STING inhibitor and enforced mitophagy was induced in vitro and IFN-β release was quantified. VDAC1 inhibitor was used to determine the role of mt DNA release in IFN-β induction. In whole skin biopsies fumarate and succinate was quantified.
    RESULTS: Fumarate Hydratase is significantly reduced in SSc monocytes. Type I interferon is also elevated in monocytes from SSc donors compared to controls. The mitochondrial-specific stress marker GDF-15 was significantly elevated in SSc monocytes. Blockade of the cGAS-STING pathway chemically reduced interferon-β release and induced mitophagy also retarded release of the cytokine in response to LPS stimulation. Inhibition of VDAC1 mitigated IFN-β, as did the depletion of mitochondria in cells. Furthermore, the itaconate derivative 4-octyl itaconate reduced IFN-β induction in SSc monocytes, that was downstream of mitochondrial nucleic acid release. Fumarate, but not succinate was elevated in whole skin biopsies.
    CONCLUSION: Fumarate metabolism links interferon release in SSc and may underlie the aberrant expression of interferon in SSc via cytosolic DNA released from mitochondria.
    Keywords:  CGAS; DNA; Fibrosis; Fumarate hydratase; Interferon; STING; Systemic sclerosis
    DOI:  https://doi.org/10.1016/j.jdermsci.2025.01.002
  39. Phytomedicine. 2025 Jan 13. pii: S0944-7113(25)00028-5. [Epub ahead of print]138 156389
    Oxymatrine alleviates ALD-induced cardiac hypertrophy by regulating autophagy via activation Nrf2/SIRT3 signaling pathway.
    Dingchun Lu, Shun Wu, Xueting Wang, Jian Zhang, Yini Xu, Ling Tao, Xiangchun Shen.
       BACKGROUND: Cardiac hypertrophy is a prevalent early pathological manifestation in various cardiovascular diseases, lacking effective interventions to impede its progression. Although oxymatrine (OMT) has shown potential benefits for cardiac function, its therapeutic efficacy and mechanism in cardiac hypertrophy remain incompletely understood. Notably, mitochondrial damage and dysregulated autophagy are pivotal pathogenic mechanisms in cardiac hypertrophy.
    PURPOSE: We investigate the pharmacological characteristics and mechanism of OMT in mitochondrial function and autophagy in cardiac hypertrophy.
    STUDY DESIGN AND METHODS: A murine model of cardiac hypertrophy was induced by aldosterone in combination with high-salt drinking water, while primary cardiomyocyte hypertrophy was induced by aldosterone in vitro. Cardiac hypertrophy was assessed using echocardiography and histopathological staining. Autophagosomes and mitochondrial morphology were visualized by transmission electron microscopy. Levels of reactive oxygen species (ROS), malondialdehyde (MDA), and adenosine triphosphate (ATP) were quantified using commercial kits. The binding affinity of OMT with Nrf2 was assessed through molecular docking. Furthermore, adenovirus, agonists, and inhibitors were employed to modulate Nrf2, followed by quantitative real-time polymerase chain reaction (qRT-PCR), immunoblotting, co-immunoprecipitation, chromatin immunoprecipitation, immunohistochemistry, and cellular thermal shift assay.
    RESULTS: OMT effectively attenuated aldosterone-induced cardiac hypertrophy both in vivo and in vitro. OMT promoted the activation of Nrf2, leading to elevated SIRT3 expression and enhanced autophagolysosome fusion, thereby modulating mitophagy and improving mitochondrial function. Moreover, the cardioprotective effects of OMT were abolished upon silencing or inhibition of Nrf2. OMT binds to Nrf2, facilitating its dissociation and nuclear translocation.
    CONCLUSION: OMT activates Nrf2, consequently enhancing SIRT3 transcription, restoring autophagic flux, and preserving mitochondrial integrity, thereby mitigating aldosterone-induced cardiac hypertrophy. In summary, our study is the first to discover and confirm that OMT can stabilize Nrf2, promoting its activation and subsequently up-regulating SIRT3, which in turn facilitates mitochondrial autophagy. Additionally, PARKIN appears to play a key role in SIRT3-mediated regulation of mitophagy, warranting further investigation.
    Keywords:  Autophagy; Cardiac hypertrophy; Mitochondria; Nrf2; Oxymatrine
    DOI:  https://doi.org/10.1016/j.phymed.2025.156389
  40. Curr Probl Cardiol. 2025 Jan 17. pii: S0146-2806(25)00011-8. [Epub ahead of print] 102988
    Mitochondrial Calcium Homeostasis and Atrial Fibrillation: Mechanisms and Therapeutic Strategies Review.
    Yixuan Chang, Qi Zou.
      Atrial fibrillation (AF) is tightly linked to mitochondrial dysfunction, calcium (Ca²⁺) imbalance, and oxidative stress. Mitochondrial Ca²⁺ is essential for regulating metabolic enzymes, maintaining the tricarboxylic acid (TCA) cycle, supporting the electron transport chain (ETC), and producing ATP. Additionally, Ca²⁺ modulates oxidative balance by regulating antioxidant enzymes and reactive oxygen species (ROS) clearance. However, Ca²⁺ homeostasis disruptions, particularly overload, result in excessive ROS production, mitochondrial permeability transition pore (mPTP) opening, and oxidative stress-induced damage. These changes lead to mitochondrial dysfunction, Ca²⁺ leakage, and cardiomyocyte apoptosis, driving AF progression and atrial remodeling. Therapeutically, targeting mitochondrial Ca²⁺ homeostasis shows promise in mitigating AF. Moderate Ca²⁺ regulation enhances energy metabolism, stabilizes mitochondrial membrane potential, and bolsters antioxidant defenses by upregulating enzymes like superoxide dismutase and glutathione peroxidase. This reduces ROS generation and facilitates clearance. Proper Ca²⁺ levels also prevent electron leakage and promote mitophagy, aiding in damaged mitochondria removal and reducing ROS accumulation. Future strategies include modulating Ryanodine receptor 2 (RyR2), mitochondrial calcium uniporter (MCU), and sodium-calcium exchanger (NCLX) to control Ca²⁺ overload and oxidative damage. Addressing mitochondrial Ca²⁺ dynamics offers a compelling approach to breaking the cycle of Ca²⁺ overload, oxidative stress, and AF progression. Further research is needed to clarify the mechanisms of mitochondrial Ca²⁺ regulation and its role in AF pathogenesis. This knowledge will guide the development of innovative treatments to improve outcomes and quality of life for AF patients.
    DOI:  https://doi.org/10.1016/j.cpcardiol.2025.102988
  41. FASEB J. 2025 Jan 31. 39(2): e70354
    In vitro stretch modulates mitochondrial dynamics and energy metabolism to induce smooth muscle differentiation in mesenchymal stem cells.
    Yu Liu, Zhijie Yang, Jing Na, Xinyuan Chen, Ziyi Wang, Lisha Zheng, Yubo Fan.
      The smooth muscle cells (SMCs) located in the vascular media layer are continuously subjected to cyclic stretching perpendicular to the vessel wall and play a crucial role in vascular wall remodeling and blood pressure regulation. Mesenchymal stem cells (MSCs) are promising tools to differentiate into SMCs. Mechanical stretch loading offers an opportunity to guide the MSC-SMC differentiation and mechanical adaption for function regeneration of blood vessels. This study shows that cyclic stretch induces the expression of SMC markers α-SMA and SM22 in MSCs. These cells exhibit contractile ability in vitro and facilitate angiogenesis in the Matrigel plug assay in vivo. The contraction of SMCs requires remodeling of their energy metabolism. However, the underlying mechanism in the differentiation of MSCs into SMCs remains to be revealed. Cyclic stretch training promotes glycolysis, oxidative phosphorylation, and mitochondrial fusion and modulates mitochondrial dynamics-related proteins (MFN1, MFN2, DRP1) expression, thereby contributing to MSCs differentiation. Yes-associated protein (YAP) affects mitochondrial dynamics, oxidative phosphorylation, and glycolysis to regulate stretch-mediated differentiation into SMCs. Additionally, Piezo-type mechanosensitive ion channel component 1 (Piezo1) impacts energy metabolism and MSCs differentiation by regulating intracellular Ca2+ levels and YAP nuclear localization. It indicates that YAP can integrate stretch force and energy metabolism signals to regulate the differentiation of MSCs into SMCs.
    Keywords:  cyclic stretch; energy metabolism; mesenchymal stem cells; mitochondrial dynamics; smooth muscle cells
    DOI:  https://doi.org/10.1096/fj.202402944R
  42. J Struct Biol. 2025 Jan 20. pii: S1047-8477(25)00005-X. [Epub ahead of print] 108170
    GCTransNet: 3D mitochondrial instance segmentation based on Global Context Vision Transformers.
    Chaoyi Chen, Yidan Yan, Jingpeng Wu, Wen-Biao Gan.
      Mitochondria are double membrane-bound organelles essential for generating energy in eukaryotic cells. Mitochondria can be readily visualized in 3D using Volume Electron Microscopy (vEM), and accurate image segmentation is vital for quantitative analysis of mitochondrial morphology and function. To address the challenge of segmenting small mitochondrial compartments in vEM images, we propose an automated mitochondrial segmentation method called GCTransNet. This method employs grayscale migration technology to preprocess images, effectively reducing intensity distribution differences across EM images. By utilizing 3D Global Context Vision Transformers (GC-ViT) combined with global context self-attention modules and local self-attention modules, GCTransNet precisely models long-range and short-range spatial interactions. The long-range interactions enable the model to capture the global structural relationships within the mitochondrial segmentation network, while the short-range interactions refine local details and boundaries. In our approach, the encoder of the 3D U-Net network, a classical multi-scale learning architecture that retains high-resolution features through skip connections and combines multi-scale features for precise segmentation, is replaced by a 3D GC-ViT. The GC-ViT leverages shifted window-based self-attention, capturing long-range dependencies and offering improved segmentation accuracy compared to traditional U-Net encoders. In the MitoEM mitochondrial segmentation challenge, GCTransNet achieved state-of-the-art results, demonstrating its superiority in automated mitochondrial segmentation. The code and its documentation are publicly available at https://github.com/GanLab123/GCTransNet.
    Keywords:  3D instance segmentation; Electron microscopy image; Mitochondrial morphology; Vision Transformer
    DOI:  https://doi.org/10.1016/j.jsb.2025.108170
  43. J Transl Med. 2025 Jan 17. 23(1): 80
    Parthenolide improves sepsis-induced coagulopathy by inhibiting mitochondrial-mediated apoptosis in vascular endothelial cells through BRD4/BCL-xL pathway.
    Jun Zhang, Xing Zhu, Yong Li, Yinyu Wu, Yunxia Du, Hai Yang, Zhengchao Liu, Haoyu Pei, Rui Li, Huan Luo, Deyu Zuo, Han She, Qingxiang Mao.
       BACKGROUND: Sepsis is a systemic inflammatory syndrome that can cause coagulation abnormalities, leading to damage in multiple organs. Vascular endothelial cells (VECs) are crucial in the development of sepsis-induced coagulopathy (SIC). The role of Parthenolide (PTL) in regulating SIC by protecting VECs remains unclear.
    METHODS: The study utilized septic rats and lipopolysaccharide (LPS)-stimulated VECs to simulate a SIC model and observe the therapeutic effects of PTL. Additionally, nanotechnology was employed to produce Nano-PTL (N-PTL), to observe whether it has advantages over PTL in treating SIC.
    RESULTS: PTL has been shown to mitigate lung injury in septic rats, significantly reduce tumor necrosis factor-α (TNF-α) levels, and increase survival rates. PTL treatment also enhances coagulation function, augments vascular endothelial cell (VEC) function, reduces mitochondrial fragmentation, and increases both mitochondrial oxygen consumption rate (OCR) and mitochondrial membrane potential (MMP), while inhibiting reactive oxygen species (ROS) production. By increasing BRD4/BCL-xL levels, PTL can prevent mitochondrial-mediated apoptosis in VECs, improve VEC function, and consequently ameliorate SIC. Additionally, nanotechnology-synthesized N-PTL further enhances the protective effects on VECs and coagulation function.
    CONCLUSIONS: This study clarifies the therapeutic effects and mechanisms of PTL on SIC, offering new strategies and directions for the treatment of sepsis.
    Keywords:  Apoptosis; Mitochondria; Parthenolide; Sepsis-induced coagulopathy; Vascular endothelial cells
    DOI:  https://doi.org/10.1186/s12967-025-06114-0
  44. Brain Res. 2025 Jan 18. pii: S0006-8993(25)00013-7. [Epub ahead of print] 149455
    Disruption of the Pum2 axis Aggravates neuronal damage following cerebral Ischemia-Reperfusion in mice.
    Chang Cao, Jinxin Lu, Peng Lu, Lianxin Li, Feiyang Zhang, Xiang Li, Gang Chen, Lei Bai, Haiying Li.
      Stroke remains a leading cause of disability and mortality worldwide, with mitochondrial dysfunction closely linked to ischemic injury. This study explores the Norad-Pum2-Mff axis as a key regulator of mitochondrial function following ischemia-reperfusion (I/R) injury. Using an oxygen-glucose deprivation/reoxygenation (OGD/R) model, Mff protein levels were significantly elevated post-OGD/R, while mRNA levels remained unchanged, suggesting post-transcriptional regulation. Pumilio2 (Pum2), an RNA-binding protein, was shown to inhibit Mff translation, while Norad, a long non-coding RNA, sequestered Pum2, alleviating this inhibition. We observed decreased Pum2 levels and binding capacity to Mff mRNA, alongside increased Norad levels and binding to Pum2 in neurons after OGD/R. Overexpression of Pum2 in neurons reduced Mff levels, mitigated mitochondrial fragmentation, and alleviated neuronal injury. In a mouse model of middle cerebral artery occlusion/reperfusion (MCAO/R), Pum2 overexpression further improved mitochondrial morphology, reduced infarct volume, and enhanced neurobehavioral recovery. These findings suggest that targeting the Norad-Pum2-Mff axis could provide a promising therapeutic strategy for ischemic stroke by restoring mitochondrial function and reducing neuronal damage.
    Keywords:  Cerebral ischemia–reperfusion; Mff; Mice; Neuronal injury; Norad; Pum2
    DOI:  https://doi.org/10.1016/j.brainres.2025.149455
  45. Nat Cardiovasc Res. 2025 Jan 22.
    Discovering and targeting mitochondrial loss in NOTCH1-related aortic aneurysm.
      
    DOI:  https://doi.org/10.1038/s44161-025-00607-3
  46. Cell Mol Life Sci. 2025 Jan 21. 82(1): 53
    TMAO accelerates cellular aging by disrupting endoplasmic reticulum integrity and mitochondrial unfolded protein response.
    Fahimeh Varzideh, Emanuele Farroni, Urna Kaunsakar, Mahaba Eiwaz, Stanislovas S Jankauskas, Gaetano Santulli.
      
    DOI:  https://doi.org/10.1007/s00018-024-05546-z
  47. Adv Sci (Weinh). 2025 Jan 22. e2406759
    Nuclear Condensates of WW Domain-Containing Adaptor With Coiled-Coil Regulate Mitophagy via Alternative Splicing.
    Jiahe Wang, Yi Fan, Guowen Luo, Liang Xiong, Lijie Wang, Zhuoxuan Wu, Jiayi Wang, Zhengying Peng, Clifford J Rosen, Kefeng Lu, Junjun Jing, Quan Yuan, Zhenwei Zhang, Chenchen Zhou.
      Biomolecular condensates segregate nuclei into discrete regions, facilitating the execution of distinct biological functions. Here, it is identified that the WW domain containing adaptor with coiled-coil (WAC) is localized to nuclear speckles via its WW domain and plays a pivotal role in regulating alternative splicing through the formation of biomolecular condensates via its C-terminal coiled-coil (CC) domain. WAC acts as a scaffold protein and facilitates the integration of RNA-binding motif 12 (RBM12) into nuclear speckles, where RBM12 potentially interacts with the spliceosomal U5 small nuclear ribonucleoprotein (snRNP). Importantly, knockdown of RBM12, or deletion of the WAC CC domain led to altered splicing outcomes, resulting in an elevated level of BECN1-S, the short splice variant of BECN1 that is shown to upregulate mitophagy. Thus, the findings reveal a previously unrecognized mechanism for the nuclear regulation of mitochondrial function through liquid-liquid phase separation (LLPS) and provide insights into the pathogenesis of WAC-related disorders.
    Keywords:  WAC; mitophagy; nuclear speckles; phase‐separated biomolecular condensates; pre‐mRNA splicing; snRNP
    DOI:  https://doi.org/10.1002/advs.202406759
  48. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 20. pii: S0925-4439(25)00030-4. [Epub ahead of print] 167685
    Molecular mechanism of mitochondrial autophagy mediating impaired energy metabolism leading to osteoporosis.
    Yuheng He, Tao Liu, Xin Peng, Chaorui Yao, Daqian Zhou, Chao Song, Zhangchao Wei, Jinwen Chen, Zongchao Liu, Feng Jiang.
      Osteoporosis (OP) is a bone metabolic disease caused by decreased bone mass leading to destruction of bone microstructure. Treatment of OP is characterized by a lifelong nature, causing extreme financial and psychological burdens to patients. Hormonal abnormalities, cellular autophagy, Ferroptosis, and oxidative stress are all part of the intricate and varied pathophysiology of OP. Recent research has revealed that mitochondrial dysfunction is a significant factor in the onset and progression of OP. By regulating bone marrow mesenchymal stem cell differentiation through various signaling pathways and cytokines, abnormal mitochondrial energy metabolism brought on by oxidative stress processes impacts osteoblast and osteoclast proliferation and differentiation, causing an imbalance in bone metabolism that ultimately results in OP. Therefore, one possible method to prevent and manage OP may be to use mitochondria as a carrier to trigger osteogenic differentiation of bone marrow mesenchymal stem cells from mitochondrial energy consumption, oxidative stress, autophagy, and osteoclast death. In order to offer some theoretical references and therapeutic approaches for the clinical prevention and treatment of OP, we will examine the pathophysiology of OP from mitochondrial dysfunction in this work.
    Keywords:  Bone metabolism; Mitochondrial energy metabolism; Osteoporosis; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167685
  49. Free Radic Biol Med. 2025 Jan 16. pii: S0891-5849(25)00039-5. [Epub ahead of print]
    The Interplay between Metabolic Reprogramming, Mitochondrial Impairment, and Steroid Response in Proliferative Vitreoretinopathy.
    Xinyuan Huang, Qingbo Li, Manhong Xu, Shuo Sun, Yi Gong, Rong Luan, Manqiao Wang, Yan Shao, Xiaorong Li.
      Proliferative vitreoretinopathy (PVR) is a major cause of rhegmatogenous retinal detachment repair failure. Despite many attempts to find therapeutics for PVR, no pharmacotherapy has been proven effective. Steroids, as the epitome, show uncertain clinical effectiveness, which lacks an explanation and hints at unappreciated mechanisms of PVR. In this study, we investigated the involvement of metabolic reprogramming, mitochondrial impairment, and their association with steroid effectiveness in PVR using dexamethasone (Dex) as an example. Proteomics of vitreous samples from PVR patients demonstrated an upregulation in the glycolysis pathway. Transcriptomics of PVR tissues (dataset GSE179603) revealed downregulations in oxidative phosphorylation (OXPHOS), mitochondrial respiration, and mitochondrial quality control-related pathways. Transcriptomics of TGFβ and TNFα (TNT)-induced retinal pigment epithelial (RPE) cell model (GSE176513) confirmed the changes in glycolysis, OXPHOS, and mitochondria and also revealed downregulation of Dex response pathway with increased duration of TNT exposure. Transcriptomics of mouse RPE/choroid following Dex intravitreal injections (GSE49872) showed that glycolysis decreased at 1-week postinjection but increased at 1-month postinjection; OXPHOS increased but gradually decreased with treatment duration. The dispase-induced mouse PVR model revealed that a simultaneous Dex injection could alleviate PVR severity rather than an injection 5 days after the PVR induction. The TGFβ2-induced RPE cell model demonstrated the enhancement of EMT, oxidative stress, and mitochondrial impairment, which could be alleviated by Dex: Cellular ROS were accumulated; the mRNA expressions of antioxidases (GPX, SOD1 and TXN2) were decreased; mitochondrial morphology and dynamics were impaired, exhibiting decreases in mitochondrial heterogeneity, mitochondrial length and MFN2 expression; Mitochondrial membrane potential showed an elevation; and mitophagy was decreased, related to reduced Parkin recruitment. These results demonstrate the essential roles of metabolic reprogramming and mitochondrial dysfunction in PVR pathology, which is associated with the therapeutic effect of steroids. Steroid intervention might benefit the treatment of PVR in the early rather than late stages.
    Keywords:  metabolic reprogramming; mitochondria; proliferative vitreoretinopathy; retinal pigment epithelium; steroid
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.033
  50. Food Funct. 2025 Jan 21.
    Correction: Linolenic acid ameliorates sarcopenia in C. elegans by promoting mitophagy and fighting oxidative stress.
    Lu Zhang, Xueyi Zhang, Tao Zhang, Yiwen Guo, Wenjun Pei, Ruijie Liu, Ming Chang, Xingguo Wang.
      Correction for 'Linolenic acid ameliorates sarcopenia in C. elegans by promoting mitophagy and fighting oxidative stress' by Lu Zhang et al., Food Funct., 2023, 14, 1498-1509, https://doi.org/10.1039/D2FO02974J.
    DOI:  https://doi.org/10.1039/d5fo90010g
  51. Phytomedicine. 2025 Jan 10. pii: S0944-7113(25)00022-4. [Epub ahead of print]138 156383
    Harnessing natural saponins: Advancements in mitochondrial dysfunction and therapeutic applications.
    Hongmei Liu, Huan Wang, Xinyu Lin, Min Xu, Wenying Lan, Jinlian Wang.
       BACKGROUND: Mitochondrial dysfunction plays a crucial role in the development of a variety of diseases, notably neurodegenerative disorders, cardiovascular diseases, metabolic syndrome, and cancer. Natural saponins, which are intricate glycosides characterized by steroidal or triterpenoid structures, have attracted interest due to their diverse pharmacological benefits, including anti-inflammatory, antiviral, and anti-aging effects.
    PURPOSE: This review synthesizes recent advancements in understanding mitochondrial dysfunction and explores how saponins can modulate mitochondrial function. It focuses on their potential applications in neuroprotection, cardiovascular health, and oncology.
    STUDY DESIGN: The review incorporates a comprehensive literature analysis, highlighting the interplay between saponins and mitochondrial signaling pathways. Specific attention is given to the effects of saponins like ginsenoside Rg2 and 20(S)-protopanaxatriol on mitophagy and their neuroprotective, anti-aging, and synergistic therapeutic effects when combined.
    METHODS: We conducted a comprehensive review of current research and clinical trials using PubMed, Google Scholar, and SciFinder databases. The search focused on saponins' role in mitochondrial function and their therapeutic effects, including "saponins", "mitochondria" and "mitochondrial function". The analysis primarily focused on articles published between 2011 and 2024.
    RESULTS: The findings indicate that certain saponins can enhance mitophagy and modulate mitochondrial signaling pathways, showing promise in neuroprotection and anti-aging. Additionally, combinations of saponins have demonstrated synergistic effects in myocardial protection and cancer therapy, potentially improving therapeutic outcomes.
    CONCLUSION: Although saponins exhibit significant potential in modulating mitochondrial functions and developing innovative therapeutic strategies, their clinical applications are constrained by low bioavailability. Rigorous clinical trials are essential to translate these findings into effective clinical therapies, ultimately improving patient outcomes through a deeper understanding of saponins' impact on mitochondrial function.
    Keywords:  Bioavailability; Mitochondrial dysfunction; Natural product; Saponins; Therapeutic potential
    DOI:  https://doi.org/10.1016/j.phymed.2025.156383
  52. Mol Cell Biochem. 2025 Jan 20.
    Epigallocatechin 3-gallate-induced neuroprotection in neurodegenerative diseases: molecular mechanisms and clinical insights.
    Md Rezaul Islam, Abdur Rauf, Sumiya Akter, Happy Akter, Md Ibrahim Khalil Al-Imran, Samiul Islam, Meherun Nessa, Chaity Jahan Shompa, Md Nabil Rihan Shuvo, Imtiaz Khan, Waleed Al Abdulmonem, Abdullah S M Aljohani, Muhammad Imran, Marcello Iriti.
      Neurodegenerative diseases (NDs) are caused by progressive neuronal death and cognitive decline. Epigallocatechin 3-gallate (EGCG) is a polyphenolic molecule in green tea as a neuroprotective agent. This review evaluates the therapeutic effects of EGCG and explores the molecular mechanisms that show its neuroprotective properties. EGCG protects neurons in several ways, such as by lowering oxidative stress, stopping Aβ from aggregation together, changing cell signaling pathways, and decreasing inflammation. Furthermore, it promotes autophagy and improves mitochondrial activity, supporting neuronal survival. Clinical studies have demonstrated that EGCG supplementation can reduce neurodegenerative biomarkers and enhance cognitive function. This review provides insights into the molecular mechanisms and therapeutic potential of EGCG in treating various NDs. EGCG reduces oxidative stress by scavenging free radicals and enhancing antioxidant enzyme activity, aiding neuronal defense. It also protects neurons and improves cognitive abilities by inhibiting the toxicity and aggregation of Aβ peptides. It changes important cell signaling pathways like Nrf2, PI3K/Akt, and MAPK, which are necessary for cell survival, cell death, and inflammation. Additionally, it has strong anti-inflammatory properties because it inhibits microglial activation and downregulates pro-inflammatory cytokines. It improves mitochondrial function by reducing oxidative stress, increasing ATP synthesis, and promoting mitochondrial biogenesis, which promotes neurons' survival and energy metabolism. In addition, it also triggers autophagy, a cellular process that breaks down and recycles damaged proteins and organelles, eliminating neurotoxic aggregates and maintaining cellular homeostasis. Moreover, it holds significant promise as an ND treatment, but future research should focus on increasing bioavailability and understanding its long-term clinical effects. Future studies should focus on improving EGCG delivery and understanding its long-term effects in therapeutic settings. It can potentially be a therapeutic agent for managing NDs, indicating a need for further research.
    Keywords:  Clinical insights; Epigallocatechin 3-gallate; Molecular mechanisms; Neurodegeneration; Neuroprotection
    DOI:  https://doi.org/10.1007/s11010-025-05211-4
  53. J Pharm Anal. 2024 Oct;14(10): 101036
    Tetrandrine targeting SIRT5 exerts anti-melanoma properties via inducing ROS, ER stress, and blocked autophagy.
    Yacong Ji, Chongyang Li, Sicheng Wan, Zhen Dong, Chaolong Liu, Leiyang Guo, Shaomin Shi, Mingxin Ci, Minghao Xu, Qian Li, Huanrong Hu, Hongjuan Cui, Yaling Liu.
      Tetrandrine (TET), a natural bisbenzyl isoquinoline alkaloid extracted from Stephania tetrandra S. Moore, has diverse pharmacological effects. However, its effects on melanoma remain unclear. Cellular proliferation assays, multi-omics analyses, and xenograft models were used to determine the effect of TET on melanoma. The direct target of TET was identified using biotin-TET pull-down liquid chromatograph-mass spectrometry (LC-MS), cellular thermal shift assays, and isothermal titration calorimetry (ITC) analysis. Our findings revealed that TET treatment induced robust cellular autophagy depending on activating transcription factor 6 (ATF6)-mediated endoplasmic reticulum (ER) stress. Simultaneously, it hindered autophagic flux by inducing cytoskeletal protein depolymerization in melanoma cells. TET treatment resulted in excessive accumulation of reactive oxygen species (ROS) and simultaneously triggered mitophagy. Sirtuin 5 (SIRT5) was ultimately found to be a direct target of TET. Mechanistically, TET led to the degradation of SIRT5 via the ubiquitin (Ub)-26S proteasome system. SIRT5 knockdown induced ROS accumulation, whereas SIRT5 overexpression attenuated the TET-induced ROS accumulation and autophagy. Importantly, TET exhibited anti-cancer effects in xenograft models depending on SIRT5 expression. This study highlights the potential of TET as an antimelanoma agent that targets SIRT5. These findings provide a promising avenue for the use of TET in melanoma treatment and underscore its potential as a therapeutic candidate.
    Keywords:  Cytoskeletal protein depolymerization; Melanoma; Mitophagy; Reactive oxygen species (ROS); Sirtuin 5 (SIRT5); Tetrandrine
    DOI:  https://doi.org/10.1016/j.jpha.2024.101036
  54. Nature. 2025 Jan 22.
    Mitochondrial swap from cancer to immune cells thwarts anti-tumour defences.
    Jonathan R Brestoff.
      
    Keywords:  Cancer; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00077-4
  55. J Agric Food Chem. 2025 Jan 22.
    Emamectin Benzoate and Microplastics Led to Skeletal Muscle Atrophy in Common Carp via Induced Oxidative Stress, Mitochondrial Dysfunction, and Protein Synthesis and Degradation Imbalance.
    Wenying Sun, Jing Liu, Xu Shi, Yanju Bi, Huanyi Liu, Tong Xu.
      Pesticides and plastics have brought convenience to agricultural production and daily life, but they have also led to environmental pollution through residual chemicals. Emamectin benzoate (EMB) is among the most widely used insecticides, which can cause environmental pollution and harm the health of organisms. Additionally, microplastics (MPs), a relatively new type of pollutant, not only are increasing in residual amounts within water bodies and aquatic organisms but also exacerbate pollution by adsorbing other pollutants, leading to a mixed pollution scenario. Nevertheless, the toxicity and mechanism of EMB and MPs on common carp skeletal muscle have not been elucidated. Therefore, we established exposure models for EMB and MPs, and methods such as hematoxylin and eosin staining, immunofluorescence staining, JC-1 staining, and western blotting were employed to investigate the underlying mechanisms of skeletal muscle damage. The results of in vivo and in vitro experiments indicated that exposure to EMB or MPs led to oxidative stress, which in turn caused mitochondrial fusion/fission imbalance (with decreased Mfn1, Mfn2, and OPA1 and increased DRP1), reduced mitochondrial membrane potential, decreased ATP content, reduced protein synthesis, and increased degradation, ultimately resulting in skeletal muscle atrophy. Joint exposure caused more severe damage than single exposure, and the addition of NAC can effectively alleviate skeletal muscle atrophy. In summary, exposure to EMB and/or MPs induced excessive reactive oxygen species (ROS) production, giving rise to mitochondrial dysfunction and an imbalance in skeletal muscle protein synthesis and degradation, ultimately resulting in skeletal muscle atrophy in common carp.
    Keywords:  EMB; MPs; oxidative stress; protein synthesis and degradation; skeletal muscle atrophy
    DOI:  https://doi.org/10.1021/acs.jafc.4c10479
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