bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2025–01–19
fifty papers selected by
Gavin McStay, Liverpool John Moores University
  1. Targeting mitophagy in neurodegenerative diseases.
  2. The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria.
  3. FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production.
  4. Mitochondrial Electron Flow Dynamics Imaging for Assessing Mitochondrial Quality and Drug Screening.
  5. A Small-Molecule Drug for the Self-Checking of Mitophagy.
  6. Reacting to reductive stress at the mitochondrial import gate.
  7. Calycosin‑7‑O‑β‑D‑glucoside downregulates mitophagy by mitigating mitochondrial fission to protect HT22 cells from oxygen‑glucose deprivation/reperfusion‑induced injury.
  8. SIRT1/PGC-1α-mediated mitophagy participates the improvement roles of BMAL1 in podocytes injury in diabetic nephropathy: evidences from in vitro experiments.
  9. ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
  10. Fasting activates optineurin-mediated mitophagy in chondrocytes to protect against osteoarthritis.
  11. Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.
  12. TREM1 interferes with macrophage mitophagy via the E2F1-mediated TOMM40 transcription axis in rheumatoid arthritis.
  13. 4-hydroxybenzoic acid induces browning of white adipose tissue through the AMPK-DRP1 pathway in HFD-induced obese mice.
  14. Administration of AICAR, an AMPK Activator, Prevents and Reverses Diabetic Polyneuropathy (DPN) by Regulating Mitophagy.
  15. Compound K promotes thermogenic signature and mitochondrial biogenesis via the UCP1-SIRT3-PGC1α signaling pathway.
  16. Alcohol dehydrogenase 1 acts as a scaffold protein in mitophagy essential for fungal pathogen adaptation to hypoxic niches within hosts.
  17. Insufficient MIRO1 contributes to declined oocyte quality during reproductive aging.
  18. The role of mitophagy-related genes in prognosis and immunotherapy of cutaneous melanoma: a comprehensive analysis based on single-cell RNA sequencing and machine learning.
  19. APOC1 inhibit NKTCL doxorubicin sensitivity by promoting mitophagy.
  20. Aminoguanidine hemisulfate improves mitochondrial autophagy, oxidative stress, and muscle force in Duchenne muscular dystrophy via the AKT/FOXO1 pathway in mdx mice.
  21. ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function.
  22. Erratum: SIRT3-mediated mitochondrial autophagy in refeeding syndrome-related myocardial injury in sepsis rats.
  23. Plant Secondary Metabolites as Modulators of Mitochondrial Health: An Overview of Their Anti-Oxidant, Anti-Apoptotic, and Mitophagic Mechanisms.
  24. Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.
  25. 17β-estradiol promotes osteogenic differentiation of BMSCs by regulating mitophagy through ARC.
  26. Effects of Exercise Training on Cardiac Mitochondrial Functions in Diabetic Heart: A Systematic Review.
  27. Deapioplatycodin D inhibits glioblastoma cell proliferation by inducing BNIP3L-mediated incomplete mitophagy.
  28. Pym-18a, a novel pyrimidine derivative ameliorates glucocorticoid induced osteoblast apoptosis and promotes osteogenesis via autophagy and PINK 1/Parkin mediated mitophagy induction.
  29. Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.
  30. Continuity of Mitochondrial Budding: Insights from BS-C-1 Cells by In Situ Cryo-electron Tomography.
  31. OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.
  32. Targeting Endothelial Cell Mitochondrial Quality Control in PAH.
  33. Buyang Huanwu Decoction reduces mitochondrial autophagy in rheumatoid arthritis synovial fibroblasts in hypoxic culture by inhibiting the BNIP3-PI3K/Akt pathway.
  34. TFEB activator protects against ethanol toxicity-induced cardiac injury by restoring mitophagy and autophagic flux.
  35. Cardiac-targeted delivery of a novel Drp1 inhibitor for acute cardioprotection.
  36. Cordycepin alleviates metabolic dysfunction-associated liver disease by restoring mitochondrial homeostasis and reducing oxidative stress via Parkin-mediated mitophagy.
  37. PIM1 enhances insulin secretion and inhibits ferroptosis of high glucose-induced pancreatic β-cells through strengthening PINK1/Parkin-mediated mitophagy via inactivating JNK/p38 signaling pathway.
  38. PSMA2 promotes chemo- and radioresistance of oral squamous cell carcinoma by modulating mitophagy pathway.
  39. Yiqi Yangyin Huazhuo Tongluo Formula alleviates diabetic podocyte injury by regulating miR-21a-5p/FoxO1/PINK1-mediated mitochondrial autophagy.
  40. NR1D1 Inhibition Enhances Autophagy and Mitophagy in Alzheimer's Disease Models.
  41. Effects of Astragalus polysaccharide on the structure and function of skeletal muscle in D-galactose-induced C57BL/6J mice.
  42. Modulation of copper-induced neurotoxicity by monoisoamyl 2,3-dimercaptosuccinic acid loaded nanoparticles through inhibition of mitophagy and reduction of oxidative stress in SH-SY5Y cells.
  43. Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor.
  44. The role of mitochondrial remodeling in neurodegenerative diseases.
  45. Recombinant Follicle-Stimulating Hormone and Luteinizing Hormone Enhance Mitochondrial Function and Metabolism in Aging Female Reproductive Cells.
  46. Youthful Stem Cell Microenvironments: Rejuvenating Aged Bone Repair Through Mitochondrial Homeostasis Remodeling.
  47. Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
  48. Stress signaling caused by mitochondrial import malfunction can be terminated by SIFI: importance of stress response silencing.
  49. Disrupted mitochondrial morphology and function exacerbate inflammation in elderly-onset ulcerative colitis.
  50. Effect of introducing somatic mitochondria into an early embryo on zygotic gene activation†.
  1. Nat Rev Drug Discov. 2025 Jan 14.
    Targeting mitophagy in neurodegenerative diseases.
    Odetta Antico, Paul W Thompson, Nicholas T Hertz, Miratul M K Muqit, Laura E Parton.
      Mitochondrial dysfunction is a hallmark of idiopathic neurodegenerative diseases, including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer disease and Huntington disease. Familial forms of Parkinson disease and amyotrophic lateral sclerosis are often characterized by mutations in genes associated with mitophagy deficits. Therefore, enhancing the mitophagy pathway may represent a novel therapeutic approach to targeting an underlying pathogenic cause of neurodegenerative diseases, with the potential to deliver neuroprotection and disease modification, which is an important unmet need. Accumulating genetic, molecular and preclinical model-based evidence now supports targeting mitophagy in neurodegenerative diseases. Despite clinical development challenges, small-molecule-based approaches for selective mitophagy enhancement - namely, USP30 inhibitors and PINK1 activators - are entering phase I clinical trials for the first time.
    DOI:  https://doi.org/10.1038/s41573-024-01105-0
  2. Cell Mol Life Sci. 2025 Jan 12. 82(1): 42
    The interconnective role of the UPS and autophagy in the quality control of cancer mitochondria.
    Wanting Xu, Lei Dong, Ji Dai, Lu Zhong, Xiao Ouyang, Jiaqian Li, Gaoqing Feng, Huahua Wang, Xuan Liu, Liying Zhou, Qin Xia.
      Uncontrollable cancer cell growth is characterized by the maintenance of cellular homeostasis through the continuous accumulation of misfolded proteins and damaged organelles. This review delineates the roles of two complementary and synergistic degradation systems, the ubiquitin-proteasome system (UPS) and the autophagy-lysosome system, in the degradation of misfolded proteins and damaged organelles for intracellular recycling. We emphasize the interconnected decision-making processes of degradation systems in maintaining cellular homeostasis, such as the biophysical state of substrates, receptor oligomerization potentials (e.g., p62), and compartmentalization capacities (e.g., membrane structures). Mitochondria, the cellular hubs for respiration and metabolism, are implicated in tumorigenesis. In the subsequent sections, we thoroughly examine the mechanisms of mitochondrial quality control (MQC) in preserving mitochondrial homeostasis in human cells. Notably, we explored the relationships between mitochondrial dynamics (fusion and fission) and various MQC processes-including the UPS, mitochondrial proteases, and mitophagy-in the context of mitochondrial repair and degradation pathways. Finally, we assessed the potential of targeting MQC (including UPS, mitochondrial molecular chaperones, mitochondrial proteases, mitochondrial dynamics, mitophagy and mitochondrial biogenesis) as cancer therapeutic strategies. Understanding the mechanisms underlying mitochondrial homeostasis may offer novel insights for future cancer therapies.
    Keywords:  Autophagy-lysosome; Cancer therapy; Mitochondrial chaperones; Mitochondrial proteases; Mitophagy; Protein quality control; UPS
    DOI:  https://doi.org/10.1007/s00018-024-05556-x
  3. FEBS Open Bio. 2025 Jan 16.
    FAM136A depletion induces mitochondrial stress and reduces mitochondrial membrane potential and ATP production.
    Yushi Otsuka, Masato Yano.
      FAM136A deficiency has been associated with Ménière's disease. However, the underlying mechanism of action of this protein remains unclear. We hypothesized that FAM136A functions in maintaining mitochondria, even in HepG2 cells. To better characterize FAM136A function, we analyzed the cellular response caused by its depletion. FAM136A depletion induced reactive oxygen species (ROS) and reduced both mitochondrial membrane potential and ATP production. However, cleaved caspase-9 levels did not increase significantly. We next investigated why the depletion of FAM136A reduced the mitochondrial membrane potential and ATP production but did not lead to apoptosis. Depletion of FAM136A induced the mitochondrial unfolded protein response (UPRmt) and the expression levels of gluconeogenic phosphoenolpyruvate carboxykinases (PCK1 and PCK2) and ketogenic 3-hydroxy-3-methylglutaryl-CoA synthases (HMGCS1 and HMGCS2) were upregulated. Furthermore, depletion of FAM136A reduced accumulation of holocytochrome c synthase (HCCS), a FAM136A interacting enzyme that combines heme to apocytochrome c to produce holocytochrome c. Notably, the amount of heme in cytochrome c did not change significantly with FAM136A depletion, although the amount of total cytochrome c protein increased significantly. This observation suggests that greater amounts of cytochrome c remain unbound to heme in FAM136A-depleted cells.
    Keywords:  ATP; FAM136A; holocytochrome c synthetase; mitochondrial membrane potential; mitochondrial stress
    DOI:  https://doi.org/10.1002/2211-5463.13967
  4. Adv Sci (Weinh). 2025 Jan 13. e2410561
    Mitochondrial Electron Flow Dynamics Imaging for Assessing Mitochondrial Quality and Drug Screening.
    Youxiao Ren, Ling-Ling Wu, Wenjing Song, Yanan Gao, Litao Shao, Zhiyuan Lu, Songsong Wang, Xintian Shao, Zhenjie Yu, Mengrui Zhang, Jing Wu, Liwen Han, Kewu Zeng, Qixin Chen.
      Mitochondrial quality control is paramount for cellular development, with mitochondrial electron flow (Mito-EF) playing a central role in maintaining mitochondrial homeostasis. However, unlike visible protein entities, which can be monitored through chemical biotechnology, regulating mitochondrial quality control by invisible entities such as Mito-EF has remained elusive. Here, a Mito-EF tracker (Mito-EFT) with a four-pronged probe design is presented to elucidate the dynamic mechanisms of Mito-EF's involvement in mitochondrial quality control. Heightened aggregation of Mito-EF in fiber-like healthy mitochondria compared to round-like damaged mitochondria is demonstrated, revealed Mito-EF aggregation correlated with mitochondrial morphological remodeling, particularly in regions undergoing mitochondrial fission and fusion, and show the Mito-EF signal associated with mitochondrial cristae maintained by Dynamin-Related Protein 1 (DRP1). This underscores the importance of considering Mito-EF in assessing mitochondrial quality control parameters. A novel drug screening evaluation parameter, Mito-EF is also introduced to screen and discover mitochondrial-targeted therapeutic modulators. This tracker provides new avenues for investigating the role of Mito-EF in maintaining mitochondrial homeostasis and quality control, offering a potent tool for assessing mitochondrial quality and drug screening.
    Keywords:  drug screening; imaging; mitochondria; mitochondrial electron flow; morphology
    DOI:  https://doi.org/10.1002/advs.202410561
  5. Angew Chem Int Ed Engl. 2025 Jan 12. e202421269
    A Small-Molecule Drug for the Self-Checking of Mitophagy.
    Yanan Gao, Qingjie Bai, Youxiao Ren, Xintian Shao, Mengrui Zhang, Luling Wu, Simon Lewis, Tony James, Xiaoyuan Chen, Qixin Chen.
      Mitophagy that disrupt mitochondrial membrane potential (MMP), represents a critical focus in pharmacology. However, the discovery and evaluation of MMP-disrupting drugs are often hampered using commercially available marker molecules that target similar or identical zones. These markers can significantly interfere with, obscure, or amplify the functional effects of MMP-targeting drugs, frequently leading to clinical failures. In response to this challenge, we propose a "one-two punch" drug design strategy that integrates both target-zone drug functionality and non-target zone biological reporting within a single small-molecule drug. We have developed a novel mitophagy self-check drug (MitoSC) that exhibits dual-color and dual-localization properties. The functional component of this system is a variable MitoSC that disrupts MMP homeostasis, thereby inducing mitophagy. Upon activation, this component transforms into a blue-fluorescent monomer (MitoSC-fun) specifically within the mitochondrial target zone. The biological reporting component is represented by a red-fluorescent monomer (MitoSC-rep) that localizes to lysosomes, the non-target zone. As mitophagy progresses, the fluorescent signals from MitoSC-rep (lysosomes) and MitoSC-fun (mitochondria) converge, enabling real-time monitoring of the mitophagy process. Our findings underscore the potential of a single-molecule drug to exert target-zone specific actions while simultaneously providing non-target zone self-checking, offering a new perspective for drug design.
    Keywords:  Dual localization; Lysosomes; Mitochondria; Self-checking; Subcelluar
    DOI:  https://doi.org/10.1002/anie.202421269
  6. Trends Cell Biol. 2025 Jan 13. pii: S0962-8924(24)00281-2. [Epub ahead of print]
    Reacting to reductive stress at the mitochondrial import gate.
    Sylvie Callegari.
      A byproduct of mitochondrial energy production is the generation of reactive oxygen species (ROS). Too much ROS is toxic, but ROS deficiency is equally deleterious (reductive stress). In a recent study, McMinimy et al. uncovered a ubiquitin proteasome-mediated mechanism at the translocase of the outer membrane (TOM) complex, which senses ROS depletion and adjusts mitochondrial protein import accordingly.
    Keywords:  TOM complex; mitochondrial import; proteasome; reactive oxygen species; reductive stress; ubiquitin
    DOI:  https://doi.org/10.1016/j.tcb.2024.12.013
  7. Mol Med Rep. 2025 Mar;pii: 71. [Epub ahead of print]31(3):
    Calycosin‑7‑O‑β‑D‑glucoside downregulates mitophagy by mitigating mitochondrial fission to protect HT22 cells from oxygen‑glucose deprivation/reperfusion‑induced injury.
    Xiangli Yan, Siqi Quan, Roujia Guo, Zibo Li, Ming Bai, Baoying Wang, Pan Su, Erping Xu, Yucheng Li.
      Calycosin‑7‑O‑β‑D‑glucoside (CG), a major active ingredient of Astragali Radix, exerts neuroprotective effects against cerebral ischemia; however, whether the effects of CG are associated with mitochondrial protection remains unclear. The present study explored the role of CG in improving mitochondrial function in a HT22 cell model of oxygen‑glucose deprivation/reperfusion (OGD/R). The Cell Counting Kit‑8 assay, flow cytometry, immunofluorescence and western blotting were performed to investigate the effects of CG on mitochondrial function. The results demonstrated that mitochondrial function was restored after treatment with CG, as indicated by reduced mitochondrial reactive oxygen species levels, increased mitochondrial membrane potential and improved mitochondrial morphology. Overactivated mitophagy was revealed to be inhibited by the regulation of proteins involved in fission [phosphorylated‑dynamin‑related protein 1 (Drp1) and Drp1] and mitophagy (LC3, p62 and translocase of outer mitochondrial membrane 20), and mitochondrial biogenesis was demonstrated to be enhanced by increased levels of sirtuin 1 (SIRT1) and peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α). In addition, neuronal apoptosis was ameliorated by CG, as determined by a decreased rate of apoptosis, and levels of caspase‑3 and Bcl‑2/Bax. In conclusion, the present study demonstrated that CG may alleviate OGD/R‑induced injury by upregulating SIRT1 and PGC‑1α protein expression, and reducing excessive mitochondrial fission and overactivation of mitophagy.
    Keywords:  CG; HT22 cells; OGD/R; mitochondrial fission; mitophagy
    DOI:  https://doi.org/10.3892/mmr.2025.13436
  8. Eur J Med Res. 2025 Jan 15. 30(1): 29
    SIRT1/PGC-1α-mediated mitophagy participates the improvement roles of BMAL1 in podocytes injury in diabetic nephropathy: evidences from in vitro experiments.
    Yanxia Rui, Yinfeng Guo, Linying He, Min-Er Wang, Henglan Wu.
       BACKGROUND: Dysfunction in podocyte mitophagy has been identified as a contributing factor to the onset and progression of diabetic nephropathy (DN), and BMAL1 plays an important role in the regulation of mitophagy. Thus, this study intended to examine the impact of BMAL1 on podocyte mitophagy in DN and elucidate its underlying mechanisms.
    MATERIALS AND METHODS: High D-glucose (HG)-treated MPC5 cells was used as a podocyte injury model for investigating the potential roles of BMAL1 in DN. Mitophagy was examined by detecting autophagosomes using transmission electron microscopy, and detecting the colocalization of LC3 and Tom20 using immunofluorescence staining. The interaction between BMAL1 and SIRT1 was conducted by immunoprecipitation (Co-IP) assay.
    RESULTS: In HG-induced podocyte injury model, we found that BMAL1 and SIRT1 mRNA level was significantly decreased, and positively correlated with mitophagy dysfunction. BMAL1 overexpression could ameliorate HG-induced podocyte injury, evidenced by improved cell viability, decreased cell apoptosis and inflammatory cytokines expression (TNF-α, IL-1β, and IL-6). BMAL1 overexpression could promote podocyte mitophagy coupled with increased expression of mitophagy markers PINK1 and Parkin. In terms of mechanism, Co-IP suggested that BMAL1 could interact with SIRT1. SIRT1 inhibitor Ex-527 addition obviously inhibit the effect of BMAL1 overexpression on the mitophagy, demonstrating that BMAL1 may act on mitophagy by SIRT1//PGC-1α axis.
    CONCLUSIONS: Our in vitro experiments demonstrate that BMAL1/SIRT1/PGC-1α pathway may protect podocytes against HG-induced DN through promoting mitophagy.
    Keywords:  BMAL1; Diabetic nephropathy; Mitophagy; Podocyte injury; SIRT1/PGC-1α
    DOI:  https://doi.org/10.1186/s40001-025-02280-5
  9. iScience. 2025 Jan 17. 28(1): 111544
    ZFAND6 promotes TRAF2-dependent mitophagy to restrain cGAS-STING signaling.
    Kashif Shaikh, Melissa Bowman, Sarah M McCormick, Linlin Gao, Jiawen Zhang, Jesse White, John Tawil, Arun Kapoor, Ravit Arav-Boger, Christopher C Norbury, Edward W Harhaj.
      ZFAND6 is a zinc finger protein that interacts with TNF receptor-associated factor 2 (TRAF2) and polyubiquitin chains and has been linked to tumor necrosis factor (TNF) signaling. Here, we report a previously undescribed function of ZFAND6 in maintaining mitochondrial homeostasis by promoting mitophagy. Deletion of ZFAND6 in bone marrow-derived macrophages (BMDMs) upregulates reactive oxygen species (ROS) and the accumulation of damaged mitochondria due to impaired mitophagy. Consequently, mitochondrial DNA (mtDNA) is released into the cytoplasm, triggering the spontaneous expression of interferon-stimulated genes (ISGs) in a stimulator of interferon genes (STING) dependent manner, which leads to enhanced viral resistance. Mechanistically, ZFAND6 bridges a TRAF2-cIAP1 interaction and mediates the recruitment of TRAF2 to damaged mitochondria, which is required for the initiation of ubiquitin-dependent mitophagy. Our results suggest that ZFAND6 promotes the interactions of TRAF2 and cIAP1 and the clearance of damaged mitochondria by mitophagy to maintain mitochondrial homeostasis.
    Keywords:  Cell biology; Omics; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.111544
  10. Commun Biol. 2025 Jan 16. 8(1): 68
    Fasting activates optineurin-mediated mitophagy in chondrocytes to protect against osteoarthritis.
    Min-Na Zhang, Ran Duan, Gui-Hong Chen, Mei-Jun Chen, Chun-Gu Hong, Xin Wang, Zhi-Lin Pang, Chun-Yuan Chen, Hua-Feng Liu, Da Zhong, Hui Xie, Wen-Bao Hu, Zheng-Zhao Liu.
      Mitochondrial homeostasis plays a crucial role in the pathogenesis of osteoarthritis (OA), a chronic musculoskeletal disorder characterized by articular cartilage degeneration and chondrocyte apoptosis. However, molecular mechanisms underlying the association between mitophagy and OA remain unclear. Here, we aimed to investigate the role of the autophagy receptor protein optineurin (OPTN) in OA, and explore the effects of dietary intervention on OA symptoms and its relationship with OPTN-mediated mitophagy. Our findings showed the downregulation of OPTN in patients with OA. Using an Optn-knockout mouse model, we demonstrated that OPTN deficiency leads to impaired mitophagy, resulting in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and chondrocyte apoptosis. Furthermore, fasting prevented OA progression by activating OPTN-mediated mitophagy and maintaining mitochondrial homeostasis in mice. The present study revealed a novel mechanism by which OPTN-mediated mitophagy influences chondrocytes and the OA phenotype in Optn-knockout mice, suggesting that OPTN-mediated mitophagy plays a crucial role in OA development and progression. This study provides new insights into the pathogenesis of OA and offers a potential avenue for the development of novel drugs targeting OPTN to mitigate OA progression.
    DOI:  https://doi.org/10.1038/s42003-025-07541-x
  11. PLoS Pathog. 2025 Jan 13. 21(1): e1012872
    Calcium-mediated mitochondrial fission and mitophagy drive glycolysis to facilitate arterivirus proliferation.
    Zhe Sun, Zicheng Ma, Wandi Cao, Chenlong Jiang, Lei Guo, Kesen Liu, Yanni Gao, Juan Bai, Jiang Pi, Ping Jiang, Xing Liu.
      Mitochondria, recognized as the "powerhouse" of cells, play a vital role in generating cellular energy through dynamic processes such as fission and fusion. Viruses have evolved mechanisms to hijack mitochondrial function for their survival and proliferation. Here, we report that infection with the swine arterivirus porcine reproductive and respiratory syndrome virus (PRRSV), manipulates mitochondria calcium ions (Ca2+) to induce mitochondrial fission and mitophagy, thereby reprogramming cellular energy metabolism to facilitate its own replication. Mechanistically, PRRSV-induced mitochondrial fission is caused by elevated levels of mitochondria Ca2+, derived from the endoplasmic reticulum (ER) through inositol 1,4,5-triphosphate receptor (IP3R)-voltage-dependent anion channel 1 (VDAC1)-mitochondrial calcium uniporter (MCU) channels. This process is associated with increased mitochondria-associated membranes (MAMs), mediated by the upregulated expression of sigma non-opioid intracellular receptor 1 (SIGMAR1). Elevated mitochondria Ca2+ further activates the Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-dynamin-related protein 1 (DRP1) signaling pathway, which interacts with mitochondrial fission protein 1 (FIS1) and mitochondrial dynamics proteins of 49 kDa (MiD49) to promote mitochondrial fission. PRRSV infection, alongside mitochondrial fission, triggers mitophagy via the PTEN-induced putative kinase 1 (PINK1)-Parkin RBR E3 ubiquitin (Parkin) pathway, promoting cellular glycolysis and excessive lactate production to facilitate its own replication. This study reveals the mechanism by which mitochondrial Ca2+ regulates mitochondrial function during PRRSV infection, providing new insights into the interplay between the virus and host cell metabolism.
    DOI:  https://doi.org/10.1371/journal.ppat.1012872
  12. Free Radic Biol Med. 2025 Jan 08. pii: S0891-5849(25)00013-9. [Epub ahead of print]228 267-280
    TREM1 interferes with macrophage mitophagy via the E2F1-mediated TOMM40 transcription axis in rheumatoid arthritis.
    Zhen-Zhen Dai, Jing Xu, Qin Zhang, Han Zhou, Xiao-Man Liu, Hai Li.
      Elevated synovial expression of the triggering receptor expressed on myeloid cells 1 (TREM1) has been identified as a significant biomarker for assessing disease activity in rheumatoid arthritis (RA). The upregulated expression of TREM1, induced by inflammatory mediators in infiltrating macrophages, plays a critical role in synovitis and joint destruction in RA. Our previous sequencing data linked TREM1 activation to aberrant mitophagy. Thus, we explored the efficacy of targeting TREM1 in treating experimental arthritis and its regulatory effect on mitophagy. TREM1 signalling activation was assessed via TREM1, DAP12, and p-SYK levels, and mitophagy was measured through PINK1, PARKIN, and LC3A/B levels. In vitro, TREM1-overexpressing RAW264.7 cells were generated, and the differences in expression and pathways were analyzed via RNA-seq. Changes in the number and morphology of mitochondria and mitophagy in TREM1-overexpressing RAW264.7 cells and normal control were observed via transmission electron microscopy, MitoTracker confocal microscopy and mitochondrial membrane potential analysis. The promotion of TOMM40 gene transcription by TREM1-activated E2F1 was determined via ChIP-PCR and E2F1 siRNA. We found that TREM1 was highly expressed and activated in the synovial tissues of CIA mice concomitant with abnormal mitophagy. The mitochondrial outer membrane transporter TOMM40 was upregulated in experimental arthritis, and the protein levels of PINK1 and LC3B were decreased. RNA-seq analysis indicated that mitophagy-related proteins were extensively downregulated and that the transcription factor E2F1 and the mitochondrial outer membrane transporter TOMM40 were significantly upregulated in TREM1-overexpressing cells. ChIP-PCR revealed that TREM1 overexpression significantly promoted the interaction between E2F1 and TOMM40 gene in RAW264.7 cells. E2F1 knockdown markedly reversed TOMM40 upregulation, mitophagy injury and ROS production in TREM1-overexpressing macrophages but not in control cells. Our study provides preliminary evidence that E2F1 regulates TOMM40 transcription and disrupts mitophagy flux in TREM1-activated macrophages. Inhibiting TREM1 effectively mitigated experimental arthritis by restoring macrophage mitophagy and reducing intracellular ROS levels.
    Keywords:  E2F1/TOMM40 axis; Macrophage; Mitophagy; Rheumatoid arthritis; TREM1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.013
  13. Phytomedicine. 2024 Dec 27. pii: S0944-7113(24)01008-0. [Epub ahead of print]137 156353
    4-hydroxybenzoic acid induces browning of white adipose tissue through the AMPK-DRP1 pathway in HFD-induced obese mice.
    Sang Hee Kim, Woo Yong Park, Gahee Song, Ja Yeon Park, Se Jin Jung, Kwang Seok Ahn, Jae-Young Um.
       BACKGROUND: Beige adipocytes have physiological functions similar to brown adipocytes, which are available to increase energy expenditure through uncoupling protein 1 (UCP1) within mitochondria. Recently, many studies showed white adipocytes can undergo remodeling into beige adipocytes, called "browning", by increasing fusion and fission events referred to as mitochondrial dynamics.
    PURPOSE: In this study, we aimed to investigate the browning effects of 4-hydroxybenzoic acid (4-HA), one of the major compounds of black raspberries.
    METHODS: We examined the mechanism underlying the browning properties of 4-HA focusing on UCP1-dependent non-shivering thermogenesis in 3T3-L1 white adipocytes, high-fat diet (HFD)-induced obese male C57BL/6J mice, and cold-exposed male C57BL/6J mice.
    RESULTS: 4-HA treatment elevates browning markers such as UCP1, T-Box transcription factor 1, and PR domain containing 16, mitochondrial function factors like oxidative phosphorylation complex as well as mitochondrial dynamic-related factors like phosphorylated dynamin-related protein 1 (p-DRP1), DRP1, and mitofusin 1 in 3T3-L1 white adipocytes, which were also confirmed in inguinal white adipose tissue (iWAT) of HFD-induced obese mice. Mdivi-1 blocked the increased DRP1-mediated mitochondrial fission by 4-HA, and even the browning effect of 4-HA was abolished. Furthermore, 4-HA increased AMP-activated protein kinase (AMPK) in both the 3T3-L1 white adipocytes and iWAT of HFD-induced obese mice. Inhibition of AMPK with Compound C also blocked the 4-HA-induced mitochondrial fission and browning effect.
    CONCLUSIONS: 4-HA induces the browning of white adipocytes into beige adipocytes by regulating the DRP1-mediated mitochondrial dynamics through AMPK. These findings suggest that 4-HA could serve as a therapeutic candidate for obesity and related metabolic disorders.
    Keywords:  4-hydroxybenzoic acid; AMPK; DRP1; Mitochondrial dynamics; Obesity
    DOI:  https://doi.org/10.1016/j.phymed.2024.156353
  14. Int J Mol Sci. 2024 Dec 25. pii: 80. [Epub ahead of print]26(1):
    Administration of AICAR, an AMPK Activator, Prevents and Reverses Diabetic Polyneuropathy (DPN) by Regulating Mitophagy.
    Krish Chandrasekaran, Joungil Choi, Mohammad Salimian, Ahmad F Hedayat, James W Russell.
      Diabetic peripheral neuropathy (DPN) is a common complication of diabetes in both Type 1 (T1D) and Type 2 (T2D). While there are no specific medications to prevent or treat DPN, certain strategies can help halt its progression. In T1D, maintaining tight glycemic control through insulin therapy can effectively prevent or delay the onset of DPN. However, in T2D, overall glucose control may only have a moderate impact on DPN, although exercise is clearly beneficial. Unfortunately, optimal exercise may not be feasible for many patients with DPN because of neuropathic foot pain and poor balance. Exercise has several favorable effects on health parameters, including body weight, glycemic control, lipid profile, and blood pressure. We investigated the impact of an exercise mimetic, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), on DPN. AICAR treatment prevented or reversed experimental DPN in mouse models of both T2D and T1D. AICAR in high-fat diet (HFD-fed) mice increased the phosphorylation of AMPK in DRG neuronal extracts, and the ratio of phosphorylated AMPK to total AMPK increased by 3-fold (HFD vs. HFD+AICAR; p < 0.001). Phospho AMP increased the levels of dynamin-related protein 1 (DRP1, a mitochondrial fission marker), increased phosphorylated autophagy activating kinase 1 (ULK1) at Serine-555, and increased microtubule-associated protein light chain 3-II (LC3-II, a marker for autophagosome assembly) by 2-fold. Mitochondria isolated from DRG neurons of HFD-fed had a decrease in ADP-stimulated state 3 respiration (120 ± 20 nmol O2/min in HFD vs. 220 ± 20 nmol O2/min in control diet (CD); p < 0.001. Mitochondria isolated from HFD+AICAR-treated mice had increased state 3 respiration (240 ± 30 nmol O2/min in HFD+AICAR). However, AICAR's protection in DPN in T2D mice was also mediated by its effects on insulin sensitivity, glucose metabolism, and lipid metabolism. Drugs that enhance AMPK phosphorylation may be beneficial in the treatment of DPN.
    Keywords:  AICAR; AMPK; diabetic neuropathy; exercise mimetics; glucose metabolism; intraepidermal nerve fiber density; lipid metabolism; mitochondrial biogenesis; mitochondrial fission; nerve conduction
    DOI:  https://doi.org/10.3390/ijms26010080
  15. Biomed Pharmacother. 2025 Jan 11. pii: S0753-3322(25)00032-0. [Epub ahead of print]183 117838
    Compound K promotes thermogenic signature and mitochondrial biogenesis via the UCP1-SIRT3-PGC1α signaling pathway.
    Jung-Mi Oh, Geonhyeong Kim, Jiho Jeong, Sungkun Chun.
      Compound K (CK), an active ingredient in ginseng, has anti-cancer, anti-inflammatory, and antioxidant properties. However, its effects on thermogenesis and mitochondrial dynamics in white adipose tissue (WAT) adipocytes are not well understood. This study explores CK's impact on thermogenesis and mitochondrial metabolism in cold-exposed mice and mouse stromal vascular fraction (SVF) cells. CK increased the expression of UCP1 and other brown/beige adipocyte markers (Cd137, Cytb, Letm1, Pgc1α, Prdm16, Tbp1, Tbx1, Uqcrc1) and mitochondrial biogenesis/dynamics factors (Cidea, Cox8b, Cycs, Dio2, Drp1, Fis1, Fgf21, Nrf1, Sirt3, Tfam) in 3T3-L1/iWAT SVF cells. CK enhanced mitochondrial respiration, reduced mitochondrial ROS levels, and restored MMP in iWAT SVF cells, leading to the differentiation of WAT into beige adipocytes, and that was also observed in cold-exposed subcutaneous tissue. CK administration to cold-exposed mice reduced fat droplet size and increased the number of mitochondria. Additionally, CK stimulated non-shivering thermogenesis, indicated by the upregulation of thermogenic and mitochondrial division proteins. The browning effect of CK was nullified by SIRT3 knockdown, suggesting that CK induces beige remodeling of WAT by regulating mitochondrial dynamics and SIRT3 expression. These findings suggest CK's potential as a therapeutic agent for obesity and metabolic disorders that promotes the transformation of WAT into a metabolically active beige phenotype.
    Keywords:  Adipose tissue; Beige remodeling; Compound K; Mitochondrial dynamics; SIRT3; Thermogenesis
    DOI:  https://doi.org/10.1016/j.biopha.2025.117838
  16. Int J Biol Macromol. 2025 Jan 08. pii: S0141-8130(25)00200-4. [Epub ahead of print] 139651
    Alcohol dehydrogenase 1 acts as a scaffold protein in mitophagy essential for fungal pathogen adaptation to hypoxic niches within hosts.
    Jin-Li Ding, Li Li, Kang Wei, Hao Zhang, Nemat O Keyhani, Ming-Guang Feng, Sheng-Hua Ying.
      Fungi have evolved diverse physiological adaptations to hypoxic environments. However, the mechanisms mediating such adaptations remain obscure for many filamentous pathogenic fungi. Here, we show that autophagy mediated mitophagy occurs in the insect pathogenic fungus Beauveria bassiana under hypoxic conditions induced by host cellular immune responses. Mitophagy was essential for fungal evasion from insect hemocyte encapsulation, allowing for fungal proliferation and colonization in the host hemocoel. Our data showed that B. bassiana autophagy-related protein 11 (Atg11) interacts with Atg8 as a scaffold mediating mitophagy. The mitochondrial protein Atg43 was demonstrated to act as a receptor for the selective mitophagy, directly interacting with Atg8 for the autophagosomal targeting. Alcohol dehydrogenase BbAdh1, as a novel scaffold protein, participates in mitophagy through interacting with Atg8 and Atg11 under hypoxic stress. BbAdh1 was critical for fungal intracellular redox homeostasis and energy metabolism under hypoxic conditions. These data provide a pathway for mitochondrial degradation via metabolism linked autophagosome- to-vacuole targeting during hypoxic stress. This mitophagy results in depletion of oxidative mitochondrial dependent functions as a cellular adaptation to the low oxygen levels.
    Keywords:  Fungal survival; Hypoxic stress; Mitophagy
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139651
  17. Sci China Life Sci. 2025 Jan 09.
    Insufficient MIRO1 contributes to declined oocyte quality during reproductive aging.
    Zhen-Nan Pan, Hao-Lin Zhang, Kun-Huan Zhang, Jia-Qian Ju, Jing-Cai Liu, Shao-Chen Sun.
      Mitochondrial Rho-GTPase 1 (MIRO1) is an outer mitochondrial membrane protein which regulates mitochondrial transport and mitophagy in mitosis. In present study, we reported the crucial roles of MIRO1 in mammalian oocyte meiosis and its potential relationship with aging. We found that MIRO1 expressed in mouse and porcine oocytes, and its expression decreased in aged mice. MIRO1 deficiency caused the failure of meiotic resumption and polar body extrusion in both mouse and porcine oocytes, which could be rescued by exogenous MIRO1 supplementation. Mass spectrometry data indicated that MIRO1 associated with several cytoskeleton and cell cycle-related proteins, and MIRO1 regulated motor protein Dynein for microtubule-organizing centers (MTOCs) dynamics at germinal vesicle (GV) stage, which determined meiotic resumption. Furthermore, we found that MIRO1 regulated Aurora A and kinesin family member 11 (KIF11) for meiotic spindle assembly in oocytes. Besides, MIRO1 associated with several mitochondria-related proteins dynamic-related protein 1 (DRP1), Parkin and lysosomal-associated membrane protein 2 (LAMP2) for mitochondrial dynamics and mitophagy during oocyte meiosis. Taken together, our results suggested that MIRO1 played pivotal roles in meiotic resumption, spindle assembly and mitochondrial function in mouse and porcine oocytes, and its insufficiency might contribute to the oocyte maturation defects during aging.
    Keywords:  MIRO1; meiosis; meiotic resumption; oocyte; spindle
    DOI:  https://doi.org/10.1007/s11427-024-2700-5
  18. Immunol Res. 2025 Jan 11. 73(1): 30
    The role of mitophagy-related genes in prognosis and immunotherapy of cutaneous melanoma: a comprehensive analysis based on single-cell RNA sequencing and machine learning.
    Jun Tian, Lei Zhang, Kexin Shi, Li Yang.
      Mitophagy, the selective degradation of mitochondria by autophagy, plays a crucial role in cancer progression and therapy response. This study aims to elucidate the role of mitophagy-related genes (MRGs) in cutaneous melanoma (CM) through single-cell RNA sequencing (scRNA-seq) and machine learning approaches, ultimately developing a predictive model for patient prognosis. The scRNA-seq data, bulk transcriptomic data, and clinical data of CM were obtained from publicly available databases. The single-sample gene set enrichment analysis (ssGSEA) and weighted gene co-expression network analysis (WGCNA) were used to identify gene modules associated with mitophagy phenotypes. A machine learning framework employing ten different algorithms was used to develop the prognostic model. Based on scRNA-seq data, we identified 16 distinct cell subpopulations in melanoma, and melanoma cells exhibited significantly higher mitophagy scores. The turquoise module identified via WGCNA showed the strongest correlation with mitophagy scores. A prognostic model incorporating seven genes was developed through machine learning algorithms, achieving an average C-index of 0.754 across training and validation cohorts. Functionally, low-risk patients were enriched in interferon-gamma response and inflammatory processes, whereas high-risk patients showed enrichment in glycolysis regulation and signaling pathways such as KRAS and Wnt/β-catenin. Notably, low-risk patients demonstrated enhanced immune infiltration and greater sensitivity to immunotherapy. RT-qPCR validated the expression level of 7 model genes in human melanoma cell lines and normal melanocyte cell lines. Our study provides a comprehensive understanding of MRGs in melanoma and presents a novel prognostic model. These findings enhance our understanding of the tumor microenvironment and may guide personalized treatment strategies for CM patients.
    Keywords:  Cutaneous melanoma; Immunotherapy; Mitophagy; Prognosis; ScRNA-seq
    DOI:  https://doi.org/10.1007/s12026-025-09593-x
  19. IUBMB Life. 2025 Jan;77(1): e2942
    APOC1 inhibit NKTCL doxorubicin sensitivity by promoting mitophagy.
    Sa Xiao, Jing Kuang, Jiamei Yang, Haili Wang, Yuanyuan Sun, Haipeng Zhang, Zhongyu Zhang, Mengyuan Shi, Kai Qi, Miao Jiang, Yanyan Zhang, Qingjiang Chen, Xudong Zhang.
      NKTCL is a highly aggressive malignant tumor, especially prevalent in the southern regions of China. Although chemotherapy regimens based on ADM have achieved certain therapeutic effects in early treatment, the issue of ADM resistance severely limits the therapeutic efficacy and makes it difficult to improve patient survival rates. Our research results indicate that the expression level of APOC1 is closely related to the sensitivity of NKTCL cells to ADM. The upregulation of APOC1 may promote mitophagy, clear damaged mitochondria, stabilize the intracellular environment, and enhance the tolerance of tumor cells to ADM. Furthermore, APOC1 may further affect the formation of mitophagy and drug resistance by activating specific signaling pathways, such as the STAT3 signaling pathway. Animal experiments further confirm the conclusions of in vitro experiments, showing that APOC1 regulates mitophagy through p-STAT3Tyr705, thereby promoting the drug resistance of NKTCL. These findings provide a new perspective for the development of novel therapeutic strategies targeting APOC1 and its associated signaling pathways, which may help overcome the issue of ADM resistance in NKTCL.
    Keywords:  ADM resistance; APOC1; Mitophagy; NKTCL; STAT3
    DOI:  https://doi.org/10.1002/iub.2942
  20. Skelet Muscle. 2025 Jan 13. 15(1): 2
    Aminoguanidine hemisulfate improves mitochondrial autophagy, oxidative stress, and muscle force in Duchenne muscular dystrophy via the AKT/FOXO1 pathway in mdx mice.
    Shiyue Sun, Tongtong Yu, Joo Young Huh, Yujie Cai, Somy Yoon, Hafiz Muhammad Ahmad Javaid.
       BACKGROUND: Duchenne muscular dystrophy (DMD) is a prevalent, fatal degenerative muscle disease with no effective treatments. Mdx mouse model of DMD exhibits impaired muscle performance, oxidative stress, and dysfunctional autophagy. Although antioxidant treatments may improve the mdx phenotype, the precise molecular mechanisms remain unclear. This study investigates the effects of aminoguanidine hemisulfate (AGH), an inhibitor of reactive oxygen species (ROS), on mitochondrial autophagy, oxidative stress, and muscle force in mdx mice.
    METHODS: Male wild-type (WT) and mdx mice were divided into three groups: WT, mdx, and AGH-treated mdx mice (40 mg/kg intraperitoneally for two weeks) at 6 weeks of age. Gene expression, western blotting, H&E staining, immunofluorescence, ROS assays, TUNEL apoptosis, glutathione activity, and muscle force measurements were performed. Statistical comparisons used one-way ANOVA.
    RESULTS: AGH treatment significantly reduced the protein levels of LC3, and p62 in mdx mice, indicating improved autophagy activity and the ability to clear damaged mitochondria. AGH restored the expression of mitophagy-related genes Pink1 and Parkin and increased Mfn1, rebalancing mitochondrial dynamics. It also increased Pgc1α and mtTFA levels, promoting mitochondrial biogenesis. ROS levels were reduced, with higher Prdx3 and MnSOD expression, improving mitochondrial antioxidant defenses. AGH normalized the GSSG/GSH ratio and decreased glutathione reductase and peroxidase activities, further improving redox homeostasis. Additionally, AGH reduced apoptosis, shown by fewer TUNEL-positive cells and lower caspase-3 expression. Histological analysis revealed decreased muscle damage and fewer embryonic and neonatal myosin-expressing fibers. AGH altered fiber composition, decreasing MyH7 while increasing MyH4 and MyH2. Muscle force improved significantly, with greater twitch and tetanic forces. Mechanistically, AGH modulated the AKT/FOXO1 pathway, decreasing myogenin and Foxo1 while increasing MyoD.
    CONCLUSIONS: AGH treatment restored mitochondrial autophagy, reduced oxidative stress, apoptosis, and altered muscle fiber composition via the AKT/FOXO1 pathway, collectively improving muscle force in mdx mice. We propose AGH as a potential therapeutic strategy for DMD and related muscle disorders.
    Keywords:   Mdx ; Aminoguanidine; Apoptosis; Autophagy; DMD; Mitochondria; ROS
    DOI:  https://doi.org/10.1186/s13395-024-00371-1
  21. Int J Mol Sci. 2024 Dec 24. pii: 44. [Epub ahead of print]26(1):
    ATAD1 Regulates Neuronal Development and Synapse Formation Through Tuning Mitochondrial Function.
    Hao-Hao Yan, Jia-Jia He, Chuanhai Fu, Jia-Hui Chen, Ai-Hui Tang.
      Mitochondrial function is essential for synaptic function. ATAD1, an AAA+ protease involved in mitochondrial quality control, governs fission-fusion dynamics within the organelle. However, the distribution and functional role of ATAD1 in neurons remain poorly understood. In this study, we demonstrate that ATAD1 is primarily localized to mitochondria in dendrites and, to a lesser extent, in spines in cultured hippocampal neurons. We found that ATAD1 deficiency disrupts the mitochondrial fission-fusion balance, resulting in mitochondrial fragmentation. This deficiency also impairs dendritic branching, hinders dendritic spine maturation, and reduces glutamatergic synaptic transmission in hippocampal neuron. To further investigate the underlying mechanism, we employed an ATP hydrolysis-deficient mutant of ATAD1 to rescue the neuronal deficits associated with ATAD1 loss. We discovered that the synaptic deficits are independent of the mitochondrial morphology changes but rely on its ATP hydrolysis. Furthermore, we show that ATAD1 loss leads to impaired mitochondrial function, including decreased ATP production, impaired membrane potential, and elevated oxidative stress. In conclusion, our results provide evidence that ATAD1 is crucial for maintaining mitochondrial function and regulating neurodevelopment and synaptic function.
    Keywords:  ATAD1; mitochondrial dysfunction; neuronal development; synapse formation
    DOI:  https://doi.org/10.3390/ijms26010044
  22. Ann Transl Med. 2024 Dec 24. 12(6): 124
    Erratum: SIRT3-mediated mitochondrial autophagy in refeeding syndrome-related myocardial injury in sepsis rats.
    Editorial Office
      [This corrects the article DOI: 10.21037/atm-22-222.].
    DOI:  https://doi.org/10.21037/atm-2024-53
  23. Int J Mol Sci. 2025 Jan 04. pii: 380. [Epub ahead of print]26(1):
    Plant Secondary Metabolites as Modulators of Mitochondrial Health: An Overview of Their Anti-Oxidant, Anti-Apoptotic, and Mitophagic Mechanisms.
    Julia Anchimowicz, Piotr Zielonka, Slawomir Jakiela.
      Plant secondary metabolites (PSMs) are a diverse group of bioactive compounds, including flavonoids, polyphenols, saponins, and terpenoids, which have been recognised for their critical role in modulating cellular functions. This review provides a comprehensive analysis of the effects of PSMs on mitochondrial health, with particular emphasis on their therapeutic potential. Emerging evidence shows that these metabolites improve mitochondrial function by reducing oxidative stress, promoting mitochondrial biogenesis, and regulating key processes such as apoptosis and mitophagy. Mitochondrial dysfunction, a hallmark of many pathologies, including neurodegenerative disorders, cardiovascular diseases, and metabolic syndrome, has been shown to benefit from the protective effects of PSMs. Recent studies show that PSMs can improve mitochondrial dynamics, stabilise mitochondrial membranes, and enhance bioenergetics, offering significant promise for the prevention and treatment of mitochondrial-related diseases. The molecular mechanisms underlying these effects, including modulation of key signalling pathways and direct interactions with mitochondrial proteins, are discussed. The integration of PSMs into therapeutic strategies is highlighted as a promising avenue for improving treatment efficacy while minimising the side effects commonly associated with synthetic drugs. This review also highlights the need for future research to elucidate the specific roles of individual PSMs and their synergistic interactions within complex plant matrices, which may further optimise their therapeutic utility. Overall, this work provides valuable insights into the complex role of PSMs in mitochondrial health and their potential as natural therapeutic agents targeting mitochondrial dysfunction.
    Keywords:  alkaloids; cardiovascular diseases; metabolic diseases; mitochondrial dysfunction; neurodegenerative diseases; plant secondary metabolites; polyphenols; saponins; side effects; terpenoids
    DOI:  https://doi.org/10.3390/ijms26010380
  24. Nat Commun. 2025 Jan 11. 16(1): 596
    Engineered hypoxia-responsive albumin nanoparticles mediating mitophagy regulation for cancer therapy.
    Wenyan Wang, Shun-Yu Yao, Jingjing Luo, Chendi Ding, Qili Huang, Yao Yang, Zhaoqing Shi, Jiachan Lin, Yu-Chen Pan, Xiaowei Zeng, Dong-Sheng Guo, Hongzhong Chen.
      Hypoxic tumors present a significant challenge in cancer therapy due to their ability to adaptation in low-oxygen environments, which supports tumor survival and resistance to treatment. Enhanced mitophagy, the selective degradation of mitochondria by autophagy, is a crucial mechanism that helps sustain cellular homeostasis in hypoxic tumors. In this study, we develop an azocalix[4]arene-modified supramolecular albumin nanoparticle, that co-delivers hydroxychloroquine and a mitochondria-targeting photosensitizer, designed to induce cascaded oxidative stress by regulating mitophagy for the treatment of hypoxic tumors. These nanoparticles are hypoxia-responsive and release loaded guest molecules in hypoxic tumor cells. The released hydroxychloroquine disrupts the mitophagy process, thereby increasing oxidative stress and further weakening the tumor cells. Additionally, upon laser irradiation, the photosensitizer generates reactive oxygen species independent of oxygen, inducing mitochondria damage and mitophagy activation. The dual action of simultaneous spatiotemporal mitophagy activation and mitophagy flux blockade results in enhanced autophagic and oxidative stress, ultimately driving tumor cell death. Our work highlights the effectiveness of hydroxychloroquine-mediated mitophagy blockade combined with mitochondria-targeted photosensitizer for cascade-amplified oxidative stress against hypoxic tumors.
    DOI:  https://doi.org/10.1038/s41467-025-55905-y
  25. J Orthop Surg Res. 2025 Jan 10. 20(1): 35
    17β-estradiol promotes osteogenic differentiation of BMSCs by regulating mitophagy through ARC.
    Jingcun Shi, Jin Wen, Longwei Hu.
      The study aims to elucidate the mechanism through which 17β-estradiol facilitates osteogenic differentiation in bone marrow mesenchymal stem cells (BMSCs). In our study, lentiviral transfection was employed to establish apoptosis repressor with caspase recruitment domain (ARC) knockdown or overexpression in BMSCs. The impact of 17β-estradiol on ARC expression was assessed using western blot, RT-PCR and immunofluorescence. Techniques such as ALP staining, ALP activity assay, western blot, RT-PCR and immunofluorescence staining were utilized to examine the influence of ARC expression levels on the osteogenic differentiation of BMSCs and the osteoclastic differentiation of Raw264.7 cell lines. Mitophagy flux levels in BMSCs were detected using the mitophagy detection kit. RNA sequencing and bioinformatics analyses were conducted to explore potential mechanisms of ARC regulation in BMSCs osteogenic differentiation. To sum up, 17β-estradiol can modulate bone homeostasis by adjusting ARC expression. ARC stimulates mitophagy in BMSCs via MAPK/Akt pathway, identifying ARC as a promising therapeutic target for postmenopausal osteoporosis (PMOP) treatment.
    Keywords:  17β-estradiol; ARC; BMSCs; MAPK; Mitophagy; Osteogenic differentiation
    DOI:  https://doi.org/10.1186/s13018-024-05400-9
  26. Int J Mol Sci. 2024 Dec 24. pii: 8. [Epub ahead of print]26(1):
    Effects of Exercise Training on Cardiac Mitochondrial Functions in Diabetic Heart: A Systematic Review.
    Iqbal Ali Shah, Shahid Ishaq, Shin-Da Lee, Bor-Tsang Wu.
      A diabetic heart is characterized by fibrosis, autophagy, oxidative stress, and altered mitochondrial functions. For this review, three databases (PubMed, EMBASE, and Web of Science) were searched for articles written in English from September 2023 to April 2024. Studies that used exercise training for at least 3 weeks and which reported positive, negative, or no effects were included. The CAMARADES checklist was used to assess the quality of the included studies, and ten studies (CAMARADES scores 4-7/10) were included. Nine studies showed that exercise training improved cardiac mitochondrial oxidative phosphorylation by decreasing ROS, increasing electron transport chain activity, and enhancing the production of ATP. Eight studies indicated that exercise training ameliorated mitochondrial biogenesis by increasing the levels of AMPK, PGC-1α, Akt, Irisin, and Sirtuin-III. Moreover, four studies focused on mitochondrial dynamics and concluded that exercise training helped decrease the levels of mitochondrial fission factor and dynamin-related protein- 1. Finally, six studies revealed improvements in mitochondrial physiological characteristics such as size, potential, and permeability. Our findings demonstrate the beneficial effects of exercise training on cardiac mitochondrial function in diabetic hearts. Exercise training improves cardiac mitochondrial physiological characteristics, oxidative phosphorylation, biogenesis, and dynamics.
    Keywords:  diabetic heart; exercise training; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial function; mitochondrial oxidative phosphorylation
    DOI:  https://doi.org/10.3390/ijms26010008
  27. Cancer Cell Int. 2025 Jan 13. 25(1): 11
    Deapioplatycodin D inhibits glioblastoma cell proliferation by inducing BNIP3L-mediated incomplete mitophagy.
    Yu Sun, Guangze Zhu, Renshuang Zhao, Yaru Li, Hongyang Li, Yunyun Liu, Ningyi Jin, Xiao Li, Yiquan Li, Tiemei Liu.
      Deapioplatycodin D (DPD) is a triterpenoid saponin natural compound isolated from the Chinese herb Platycodon grandiflorum that has antiviral and antitumor properties. This study aimed to investigate the effects of DPD on glioblastoma (GBM) cells and to determine its intrinsic mechanism of action. Using a CCK8 assay, it was found that DPD significantly inhibited the growth of GBM cells. DPD-treated GBM cells contained swollen and degenerated mitochondria with empty vesicular bilayer membrane-like autophagic vesicle structures in the periphery of the mitochondria under transmission electron microscopy. DPD activated autophagy in GBM cells and induced a blockage of autophagic flux in the late stage. Transcriptomics identified differences in mitophagy-related genes, and analysis of the levels of the corresponding proteins indicated that mitophagy in GBM cells was induced mainly through BNIP3L. Increased expression of BNIP3L disrupts the Bcl-2-Beclin-1 complex, thereby releasing Beclin-1 and activating autophagy. Autophagy was inhibited after silencing of BNIP3L and overexpression of Bcl-2 in GBM cells, and the growth inhibitory effect of DPD was significantly reduced. This result demonstrated that DPD induces mitophagy in GBM cells through BNIP3L. Finally, activation of incomplete mitophagy in GBM cells by DPD through BNIP3L in vivo was demonstrated by establishing a mouse subcutaneous xenograft tumor model. In this study, in vitro and in vivo experiments established that DPD inhibited GBM cell growth by inducing BNIP3L-mediated incomplete mitophagy, which provides an experimental basis for studying new treatments of GBM.
    Keywords:  BNIP3L; Deapioplatycodin D; Glioblastoma; Mitophagy
    DOI:  https://doi.org/10.1186/s12935-025-03636-x
  28. Biochem Pharmacol. 2025 Jan 10. pii: S0006-2952(25)00013-9. [Epub ahead of print] 116751
    Pym-18a, a novel pyrimidine derivative ameliorates glucocorticoid induced osteoblast apoptosis and promotes osteogenesis via autophagy and PINK 1/Parkin mediated mitophagy induction.
    Sonu Khanka, Sumit K Rastogi, Krishna Bhan Singh, Kriti Sharma, Shahid Parwez, Mohammad Imran Siddiqi, Arun K Sinha, Ravindra Kumar, Divya Singh.
      Glucocorticoid-induced osteoporosis (GIOP) is the most common type of secondary osteoporosis, marked by reduced bone density and impaired osteoblast function. Current treatments have serious side effects, highlighting the need for new drug candidates. Pyrimidine derivatives have been noted for their potential in suppressing osteoclastogenesis, but their effects on osteogenesis and GIOP remain underexplored. Our recent study identified a novel pyrimidine derivative, Pym-18a, which enhances osteoblast functions. In this study, Pym-18a was found to mitigate the detrimental effects of Dexamethasone (Dex) in osteoblast cells and in GIOP in Balb/C mice. Pretreatment with Pym-18a followed by Dex (100 µM) for 24 h restored osteoblast alkaline phosphatase activity and viability. Pym-18a reduced Dex-induced apoptosis and reactive oxygen species (ROS) generation at cellular and mitochondrial levels and preserved mitochondrial membrane potential. Dex impaired autophagy and mitophagy, but Pym-18a pretreatment increased expression of autophagy markers (LC3II) and mitophagy markers (PINK1, Parkin, TOM20) while decreasing P62 expression. The osteogenic effects of Pym-18a were diminished in the presence of 3-MA (an autophagy inhibitor). In silico studies showed mTOR inhibition by Pym-18a, corroborated by its suppression of Dex-induced mTOR activation. In vivo, Pym-18a (10 mg/kg) significantly improved bone microarchitecture, trabecular connectivity, and strength, and corrected P1NP and CTX levels altered by Dex. Pym-18a also promoted autophagy, mitophagy, and suppressed mTOR activation in GIOP mice. Overall, Pym-18a mitigates detrimental effect of Dex by modulating autophagy and PINK/Parkin-mediated mitophagy through mTOR inhibition, suggesting it as a potential novel therapeutic option for GIOP.
    Keywords:  Autophagy; Glucocorticoid; Mitophagy; Osteoblast apoptosis; Oxidative stress; Pym-18a (N-(5-Bromo-4-(4-bromophenyl)-6-(2,4,5-trimethoxyphenyl) pyrimidin-2-yl) hexanamide)
    DOI:  https://doi.org/10.1016/j.bcp.2025.116751
  29. Sci Transl Med. 2025 Jan 15. 17(781): eadn8699
    Epithelial OPA1 links mitochondrial fusion to inflammatory bowel disease.
    TRR241 IBDome Consortium
      Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion-related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 (OPA1), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium (Opa1i∆IEC) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1i∆IEC mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1-deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1-like protein in organoids derived from Opa1i∆IEC mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.
    DOI:  https://doi.org/10.1126/scitranslmed.adn8699
  30. Microsc Microanal. 2025 Jan 13. pii: ozae122. [Epub ahead of print]
    Continuity of Mitochondrial Budding: Insights from BS-C-1 Cells by In Situ Cryo-electron Tomography.
    Judy Z Hu, Lijun Qiao, Xianhai Zhao, Chang-Jun Liu, Guo-Bin Hu.
      Mitochondrial division is a fundamental biological process essensial for cellular functionality and vitality. The prevailing hypothesis that dynamin related protein 1 (Drp1) provides principal control in mitochondrial division, in which it also involves the endoplasmic reticulum (ER) and the cytoskeleton, does not account for all the observations. Therefore. the hypothesis may be incomplete. Our previous study in HeLa cells led to a new hypothesis of mitochondrial division by budding. To follow-up our previous study, we employed in situ cryo-electron tomography to visualize mitochondrial budding in the intact healthy monkey kidney cells (BS-C-1 cells). Our findings reaffirm single and multiple mitochondrial budding, consistent with our observations in HeLa cells. Notably, the budding regions vary significantly in diameter and length, which may represent different stages of budding. More interestingly, neither rings nor ring-like structures, nor the wrapping of ER tubes was observed in the budding regions, suggesting mitochondrial budding is independent from Drp1 and ER. Meanwhile, we uncovered direct interactions between mitochondria and large vesicles that are distinct from small mitochondrial-derived vesicles and extracellular mitovesicles. We propose that these interacting vesicles may have mitochondrial origins.
    Keywords:   in situ cryo-electron tomography; cryo-electron microscopy (Cryo-EM); cryo-electron tomography (Cryo-ET); mitochondrial budding; mitochondrial division; mitochondrial dynamics
    DOI:  https://doi.org/10.1093/mam/ozae122
  31. Free Radic Biol Med. 2025 Jan 08. pii: S0891-5849(25)00014-0. [Epub ahead of print]228 360-378
    OAB-14 alleviates mitochondrial impairment through the SIRT3-dependent mechanism in APP/PS1 transgenic mice and N2a/APP cells.
    Na Zheng, Ruo-Lin Cao, Dan-Yang Liu, Peng Liu, Xin-Yu Zhao, Shu-Xin Zhang, Min Huang, Zhong-Hui Zheng, Guo-Liang Chen, Li-Bo Zou.
      Alzheimer's disease (AD) is a progressive degenerative disease that affects a growing number of elderly individuals worldwide. OAB-14, a novel chemical compound developed by our research group, has been approved by the China Food and Drug Administration (FDA) for clinical trials in patients with AD (approval no. YD-OAB-220210). Previous studies have shown that OAB-14 enhances cognitive function in APP/PS1 transgenic mice and ameliorates abnormal mitochondrial morphology in the hippocampus. Mitochondrial dysfunction is a major risk factor for the development of AD, and maintaining healthy mitochondrial morphology and function is essential for improving the pathological changes and symptoms of AD. However, the protective effects of OAB-14 on mitochondria in AD and the underlying mechanisms remain unclear. This study aimed to investigate the protective effects of OAB-14 on the mitochondria of APP/PS1 transgenic mice and N2a/APP cells. Treatment with OAB-14 restored impaired mitochondrial function, mitochondrial dynamics, mitophagy, and mitochondrial DNA (mtDNA) in APP/PS1 transgenic mice and N2a/APP cells. In APP/PS1 transgenic mice and N2a/APP cells, OAB-14-treated elevated the expression and activity of SIRT3, decreased mitochondrial acetylation, and reduced mitochondrial reactive oxygen species (mtROS) levels. OAB-14 also attenuated mitochondrial acetylation, improved mitochondrial dynamics and mitophagy, and mitigated mtDNA damage in a SIRT3-dependent manner. In addition, OAB-14 suppressed mitochondrial Aβ accumulation in the hippocampus of APP/PS1 transgenic mice. This study provides further clarification on the potential therapeutic mechanisms of OAB-14 in the treatment of AD and lays the groundwork for future drug applications.
    Keywords:  Alzheimer’s disease; Mitochondria; OAB-14; SIRT3
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.01.014
  32. Circ Res. 2025 Jan 17. 136(2): 209-210
    Targeting Endothelial Cell Mitochondrial Quality Control in PAH.
    Mahin Gadkari, Karthik Suresh.
      
    Keywords:  Editorials; endothelial cells; mitochondrial diseases; pulmonary arterial hypertension; vascular diseases
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325940
  33. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jan 20. pii: 1673-4254(2025)01-0035-08. [Epub ahead of print]45(1): 35-42
    Buyang Huanwu Decoction reduces mitochondrial autophagy in rheumatoid arthritis synovial fibroblasts in hypoxic culture by inhibiting the BNIP3-PI3K/Akt pathway.
    Junping Zhan, Shuo Huang, Qingliang Meng, Wei Fan, Huimin Gu, Jiakang Cui, Huilian Wang.
       OBJECTIVES: To investigate the role of the BNIP3-PI3K/Akt signaling pathway in mediating the inhibitory effect of Buyang Huanwu Decoction (BYHWT) on mitochondrial autophagy in human synovial fibroblasts from rheumatoid arthritis patients (FLS-RA) cultured under a hypoxic condition.
    METHODS: Forty normal Wistar rats were randomized into two groups (n=20) for daily gavage of BYHWT or distilled water for 7 days to prepare BYHWT-medicated or control sera. FLS-RA were cultured in routine condition or exposed to hypoxia (10% O2) for 24 h wigh subsequent treatment with IL-1β, followed by treatment with diluted BYHWT-medicated serum (5%, 10% and 20%) or control serum. AnnexinV-APC/7-AAD double staining and T-AOC kit were used for detecting apoptosis and total antioxidant capacity of the cells, and the changes in ROS, ATP level, mitochondrial membrane potential and Ca2+ homeostasis were analyzed. The changes in mRNA and protein expressions of BNIP3, PI3K and AKT and mRNA expressions of LC3, Beclin-1 and P62 were detected using RT-qPCR and Western blotting.
    RESULTS: Treatment with BYHWT-medicated serum dose-dependently lowered apoptosis rate of IL-1β-induced FLS-RA with hypoxic exposure. The treatment significantly decreased T-AOC concentration, increased ROS production, autophagosome formation and ATPase levels, and lowered mitochondrial membrane potential and Ca2+ level in the cells. In IL-1β-induced FLS-RA with hypoxic exposure, treatment with BYHWT-medicated serum significantly increased BNIP3 protein expression, decreased the protein expressions of PI3K and AKT, increased the mRNA expressions of BNIP3 and P62, and lowered the mRNA expressions of PI3K, AKT, LC3 and Beclin-1 without significantly affecting Beclin-1 protein expression. The cells treated with 5% and 10% BYHWT-medicated serum showed no significant changes in LC3 expression.
    CONCLUSIONS: BYHWT inhibits mitochondrial autophagy in IL-1β-induced FLS-RA with hypoxic exposure possibly by inhibiting BNIP3-mediated PI3K/AKT signaling pathway.
    Keywords:  BNIP3-PI3K/Akt; Buyang Huanwu Decoction; hypoxia; mitochondrial autophagy; rheumatoid arthritis; synovial fibroblast
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.01.05
  34. Biochim Biophys Acta Mol Basis Dis. 2025 Jan 11. pii: S0925-4439(25)00013-4. [Epub ahead of print]1871(3): 167668
    TFEB activator protects against ethanol toxicity-induced cardiac injury by restoring mitophagy and autophagic flux.
    Mengxue Zhao, Ruocheng Zhang, Xiuzhu Chen, Peixuan Li, Hui Yang, Bin Gao, Baoxin Li, Weina Zhou, Yuanyuan Wang, Yunliang Zhang, Li Zhong, Rui Guo.
      Excessive alcohol consumption is a major cause of alcoholic cardiomyopathy (ACM) and myocardial injury. This study aims to investigate the role of transcription factor EB (TFEB) in ethanol-induced cardiac anomalies using a murine model, AC16 human cardiomyocytes, and human plasma. Wild-type mice treated with a TFEB activator (Compound 1) or vehicle (25 mg/kg/d) were challenged with or without ethanol (3 g/kg/d, i.p.) for three consecutive days. Cardiac geometry and function were evaluated by echocardiography. The expressions of TFEB, molecules related to mitochondria, markers of apoptosis, mitophagy and lysosomes were examined in heart tissues and AC16 cardiomyocytes. Mitochondrial function, lysosome activity, and their localizations were measured in AC16 cardiomyocytes. Levels of TFEB and autophagic markers were also detected in human serum from healthy individuals and patients with ACM. Ethanol administration in mice induced severe cardiac dysfunction accompanied by upregulated P62 and LC3B, downregulated TFEB, lysosomal markers and mitophagy-associated receptors in heart tissues. Ethanol toxicity also led to reduced mitochondrial and lysosomal activity. Interestingly, TFEB activation mitigated the detrimental effects caused by ethanol. Inhibition of autophagy abolished the anti-apoptotic effect of TFEB in AC16 cells. In conclusion, TFEB is beneficial in ethanol-induced cardiac anomalies by reducing apoptosis, recovering lysosomal activity, and restoring proper mitophagy and autophagic flux.
    Keywords:  Alcoholic cardiomyopathy; Apoptosis; Autophagic flux; Ethanol toxicity; Mitophagy; TFEB
    DOI:  https://doi.org/10.1016/j.bbadis.2025.167668
  35. J Mol Cell Cardiol Plus. 2024 Sep;9 100085
    Cardiac-targeted delivery of a novel Drp1 inhibitor for acute cardioprotection.
    Jarmon G Lees, David W Greening, David A Rudd, Jonathon Cross, Ayeshah A Rosdah, Xiangfeng Lai, Tsung Wu Lin, Ren Jie Phang, Anne M Kong, Yali Deng, Simon Crawford, Jessica K Holien, Derek J Hausenloy, Hsin-Hui Shen, Shiang Y Lim.
      Dynamin-related protein 1 (Drp1) is a mitochondrial fission protein and a viable target for cardioprotection against myocardial ischaemia-reperfusion injury. Here, we reported a novel Drp1 inhibitor (DRP1i1), delivered using a cardiac-targeted nanoparticle drug delivery system, as a more effective approach for achieving acute cardioprotection. DRP1i1 was encapsulated in cubosome nanoparticles with conjugated cardiac-homing peptides (NanoDRP1i1) and the encapsulation efficiency was 99.3 ± 0.1 %. In vivo, following acute myocardial ischaemia-reperfusion injury in mice, NanoDRP1i1 significantly reduced infarct size and serine-616 phosphorylation of Drp1, and restored cardiomyocyte mitochondrial size to that of sham group. Imaging by mass spectrometry revealed higher accumulation of DRP1i1 in the heart tissue when delivered as NanoDRP1i1. In human cardiac organoids subjected to simulated ischaemia-reperfusion injury, treatment with NanoDRP1i1 at reperfusion significantly reduced cardiac cell death, contractile dysfunction, and mitochondrial superoxide levels. Following NanoDRP1i1 treatment, cardiac organoid proteomics further confirmed reprogramming of contractile dysfunction markers and enrichment of the mitochondrial protein network, cytoskeletal and metabolic regulation networks when compared to the simulated injury group. These proteins included known cardioprotective regulators identified in human organoids and in vivo murine studies following ischaemia-reperfusion injury. DRP1i1 is a promising tool compound to study Drp1-mediated mitochondrial fission and exhibits promising therapeutic potential for acute cardioprotection, especially when delivered using the cardiac-targeted cubosome nanoparticles.
    Keywords:  Cardiac organoids; Cubosome; Dynamin-related protein 1; Mitochondria; Myocardial ischaemia-reperfusion injury
    DOI:  https://doi.org/10.1016/j.jmccpl.2024.100085
  36. Biochem Pharmacol. 2025 Jan 08. pii: S0006-2952(25)00012-7. [Epub ahead of print]232 116750
    Cordycepin alleviates metabolic dysfunction-associated liver disease by restoring mitochondrial homeostasis and reducing oxidative stress via Parkin-mediated mitophagy.
    Hai-Ying Tian, Dao-Jiang Yu, Teng Xie, Meng-Xia Xu, Yu-Hao Wang, Xi-Lu Sun, Xin-Meng Zhou, Ying-Xuan Han, Qing-Qing Liao, Yu-Jie Zhao, Juan Liao, Mohamed El-Kassas, Xiao-Dong Sun, Yuan-Yuan Zhang.
      The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) keeps rising with only a few drugs available. The present study aims to investigate the effects and mechanisms of cordycepin on MASLD. Male C57BL/6 mice were induced with a 90-day high-fat diet (HFD) and intraperitoneal administration with streptozotocin to establish MASLD murine model. Then they were randomly divided into the HFD and cordycepin groups (15, 30, 45 mg/kg). Cordycepin was orally given for 30 days. Serum total cholesterol (TC), triacylglyceride (TG), and aspartate aminotransferase (AST) levels were measured. L02 cells were induced by oleate acid (OA) or lipopolysaccharides (LPS), and treated with cordycepin or combined with inhibitors including chloroquine, 3-Methyladenine, and compound C. Atg7 and Parkin were knocked down in L02 cells using siRNA. Oil Red O and Nile Red staining for measuring lipid deposition. Mitochondria were visualized by transfection with mCherry-TOMM20-N10. Quantitative real-time PCR, Western blotting, and immunofluorescence staining were used to determine expressions of key molecules in inflammation, lipid metabolism, mitochondria homeostasis, and oxidative stress. Cordycepin significantly mitigated lipid deposition and ballooning in the livers of MASLD mice. Serum TC, TG, and AST levels were decreased by cordycepin. Cordycepin alleviated OA-induced lipid deposition and LPS-induced inflammation in L02 cells, attenuated oxidative stress, promoted autophagy, and maintained the autophagic flux by activating AMP-activated protein kinase (AMPK). Cordycepin reduced the accumulation of impaired mitochondria by enhancing Parkin-dependent mitophagy and promoting mitochondrial biogenesis. Cordycepin alleviates MASLD by restoring mitochondrial homeostasis and reducing oxidative stress via activating the Parkin-mediated mitophagy.
    Keywords:  Autophagy; Cordycepin; Metabolic dysfunction-associated steatotic liver disease; Mitochondria homeostasis; Nonalcoholic fatty liver disease; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bcp.2025.116750
  37. Tissue Cell. 2025 Jan 07. pii: S0040-8166(25)00002-3. [Epub ahead of print]93 102722
    PIM1 enhances insulin secretion and inhibits ferroptosis of high glucose-induced pancreatic β-cells through strengthening PINK1/Parkin-mediated mitophagy via inactivating JNK/p38 signaling pathway.
    Bingjie Fan, Lili Yin, A 'ni Wang, Fei Li, Shuguang Han.
       BACKGROUND: Diabetes mellitus (DM), a chronic metabolic disease, is characterized by long-term hyperglycemia resulting from the defect of insulin production and insulin resistance. The damage and dysfunction of pancreatic β-cells is a main link in DM development.
    METHODS: In this work, pancreatic β-cell line INS-1E cells were exposed to 30 mM glucose for 48 h to construct an in vitro DM model. For gain-of-function experiments, HG-treated INS-1E cells were transfected with Oe-PIM1 to thoroughly discuss the biological role of PIM1 in HG-injured pancreatic β-cells. Furthermore, to probe into whether JNK/p38 signaling involved in the protective role of PIM1 in HG-injured pancreatic β-cells, HG-treated INS-1E cells were pre-treated with a JNK activator anisomycin (0.01 μM) for 1 h for rescue experiments.
    RESULTS: It was verified that HG treatment obviously downregulated PIM1 expression in INS-1E cells. PIM1 overexpression enhanced insulin secretion, inhibited ferroptosis and strengthened PINK1/Parkin-mediated mitophagy of HG-treated INS-1E cells. PIM1 overexpression inactivated JNK/p38 signaling pathway in HG-treated INS-1E cells. Activation of JNK/p38 signaling pathway partially abolished the strengthening effects of PIM1 overexpression on PINK1/Parkin-mediated mitophagy in HG-treated INS-1E cells. Upregulation of PIM1 strengthened PINK1/Parkin-mediated mitophagy in HG-injured pancreatic β-cells via inactivating JNK/p38 signaling pathway. Besides, activation of JNK/p38 signaling pathway partially abolished the enhancing effects of PIM1 overexpression on insulin secretion and the suppressive effects of PIM1 overexpression on ferroptosis in HG-treated INS-1E cells. Upregulation of PIM1 enhanced insulin secretion and inhibited ferroptosis in HG-injured pancreatic β-cells via inactivating JNK/p38 signaling pathway.
    CONCLUSION: In a word, upregulation of PIM1 may alleviate HG-induced pancreatic β-cell injury through strengthening PINK1/Parkin-mediated mitophagy via inactivating JNK/p38 signaling pathway.
    Keywords:  Diabetes mellitus; JNK/p38 signaling pathway; Mitophagy; PIM1; Pancreatic β-cells
    DOI:  https://doi.org/10.1016/j.tice.2025.102722
  38. Cell Death Discov. 2025 Jan 10. 11(1): 2
    PSMA2 promotes chemo- and radioresistance of oral squamous cell carcinoma by modulating mitophagy pathway.
    Chun-I Wang, Cheng-Yi Chen, Ting-Wen Chen, Chun-Chia Cheng, Shu-Wen Hong, Tsung-You Tsai, Kai-Ping Chang.
      Oral cavity squamous cell carcinoma (OSCC) represents the most prevalent malignancy among head and neck squamous cell carcinomas (HNSCCs). Standard treatment modalities include surgical resection combined with radiation and chemotherapy. However, locoregional failure remains a critical issue affecting the prognosis of OSCC patients, largely due to tumor resistance against radiation or chemotherapy. In this study, we established a gene database related to OSCC recurrence and identified PSMA2 as a novel molecule influencing prognosis in OSCC patients. An independent Taiwanese cohort confirmed that elevated PSMA2 transcript levels were associated with poorer prognosis and contributed to the chemo- and radioresistance phenotype in OSCC. Furthermore, we confirmed that PSMA2 regulates cell cycle, mitochondrial dysfunction, and mitophagy, thereby contributing to carcinogenesis and resistance. Notably, mitophagy inducer exhibit antitumor effects in PSMA2-overexpressing OSCC xenograft mouse model. Collectively, our results provide a mechanistic understanding of the atypical function of PSMA2 in promoting OSCC recurrence.
    DOI:  https://doi.org/10.1038/s41420-025-02286-2
  39. Nan Fang Yi Ke Da Xue Xue Bao. 2025 Jan 20. pii: 1673-4254(2025)01-0027-08. [Epub ahead of print]45(1): 27-34
    Yiqi Yangyin Huazhuo Tongluo Formula alleviates diabetic podocyte injury by regulating miR-21a-5p/FoxO1/PINK1-mediated mitochondrial autophagy.
    Kelei Guo, Yingli Li, Chenguang Xuan, Zijun Hou, Songshan Ye, Linyun Li, Liping Chen, Li Han, Hua Bian.
       OBJECTIVES: To investigate the protective effect of Yiqi Yangyin Huazhuo Tongluo Formula (YYHT) against high glucose-induced injury in mouse renal podocytes (MPC5 cells) and the possible mechanism.
    METHODS: Adult Wistar rats were treated with 19, 38, and 76 g/kg YYHT or saline via gavage for 7 days to prepare YYHT-medicated or blank sera for treatment of MPC5 cells cultured in high glucose (30 mmol/L) prior to transfection with a miR-21a-5p inhibitor or a miR-21a-5p mimic. The changes in miR-21a-5p expressions and the mRNA levels of FoxO1, PINK1, and Parkin in the treated cells were detected with qRT-PCR, and the protein levels of nephrin, podocin, FoxO1, PINK1, and Parkin were detected with Western blotting. Autophagic activity in the cells were evaluated with MDC staining. The effect of miR-21a-5p mimic on FoxO1 transcription and the binding of miR-21a-5p to FoxO1 were examined with luciferase reporter gene assay and radioimmunoprecipitation assay.
    RESULTS: MPC5 cells exposed to high glucose showed significantly increased miR-21a-5p expression, lowered expressions of FoxO1, PINK1, and Parkin1 mRNAs, and reduced levels of FoxO1, PINK1, parkin, nephrin, and podocin proteins and autophagic activity. Treatment of the exposed cells with YYHT-medicated sera and miR-21a-5p inhibitor both significantly enhanced the protein expressions of nephrin and podocin, inhibited the expression of miR-21a-5p, increased the mRNA and protein expressions of FoxO1, PINK1 and Parkin, and upregulated autophagic activity of the cells. Transfection with miR-21a-5p mimic effectively inhibited the transcription of FoxO1 and promoted the binding of miR-21a-5p to FoxO1 in MPC5 cells, and these effects were obviously attenuated by treatment with YYHT-medicated sera.
    CONCLUSIONS: YYHT-medicated sera alleviate high glucose-induced injury in MPC5 cells by regulating miR-21a-5p/FoxO1/PINK1-mediated mitochondrial autophagy.
    Keywords:  Yiqi Yangyin Huazhuo Tongluo Formula; diabetic nephropathy; miR-21/FoxO1/PINK1; mitochondrial autophagy; podocyte injury
    DOI:  https://doi.org/10.12122/j.issn.1673-4254.2025.01.04
  40. Aging Dis. 2025 Jan 14.
    NR1D1 Inhibition Enhances Autophagy and Mitophagy in Alzheimer's Disease Models.
    Shi-Qi Zhang, Zhangming Niu, Alexander Anisimov, Fang Shi, Shenglong Deng, Xianglu Xiao, Shu-Qin Cao, Jun-Ping Pan, He-Ling Wang, Maria J Lagartos-Donate, Nihal Gullu Bozbas, Ping-Jie Wang, Ruixue Ai, Yan Li, Guang Yang, Sofie Lautrup, Evandro F Fang.
      Alzheimer's disease (AD) is marked by extracellular beta-amyloid (Aβ) plaques and intracellular Tau tangles, leading to progressive cognitive decline and neuronal dysfunction. Impaired autophagy, a process by which a cell breaks down and destroys damaged or abnormal proteins and other substances, contributes to AD progression. This study investigated Nuclear Receptor Subfamily 1 Group D Member 1 (NR1D1) as a potential therapeutic target for modulating autophagy. We show that NR1D1 depletion significantly enhances autophagic flux and mitophagy in human cell lines as well as wildtype and AD Caenorhabditis elegans (C. elegans) models. Our findings revealed that NR1D1 knockdown increased autophagy markers and activated the proteins Sirtuin 1 (SIRT1) and CTSB cathepsin B (Cathepsin B), both linked to autophagy function. In 5 familial AD mutations (5xFAD) mice, Nr1d1 knockdown restored the expression level of autophagy markers. C. elegans experiments revealed that depletion of the worm ortholog of NR1D1, nhr-85, improved neuronal mitophagy, enhanced associative memory in amyloid-β models, and extended lifespan. These findings suggest NR1D1 as a promising therapeutic target for improving cellular autophagy mechanisms in AD.
    DOI:  https://doi.org/10.14336/AD.2024.1654
  41. Am J Transl Res. 2024 ;16(12): 7983-7993
    Effects of Astragalus polysaccharide on the structure and function of skeletal muscle in D-galactose-induced C57BL/6J mice.
    Deqing Chen, Yongxin Wu, Yingxiao Zhang, Hailing Yang, Qian Xiao.
       OBJECTIVE: To investigate the effects of Astragalus polysaccharide (APS) on skeletal muscle structure and function in D-galactose (D-gal)-induced C57BL/6J mice.
    METHODS: Eighteen male C57BL/6J mice of specific pathogen-free (SPF) grade, aged 8 weeks, were selected and divided into three groups: a control group (0.9% saline gavage for 16 weeks), a D-gal group (subcutaneous injection of 200 mg/kg D-galactose in the upper neck region, once daily for 8 weeks), and a D-gal + APS group (subcutaneous injection of 200 mg/kg D-galactose, once daily for 8 weeks, with concurrent administration of 100 mg/kg APS by gavage for 8 weeks). Body composition of the mice was assessed using the ImpediVET Laboratory Composition Measurement Analyzer. The pathological structure of the skeletal muscles was examined using hematoxylin and eosin (HE) staining, and the microstructure and mitochondrial alterations in skeletal muscle were observed under transmission electron microscopy. Protein expression levels of LC3II and PINK1 in skeletal muscle tissues were analyzed using Western blotting analysis.
    RESULTS: Compared to the control group, the D-gal-treated mice demonstrated substantial declines in grip strength, the cross-sectional area (CSA) of gastrocnemius muscle fibers, gastrocnemius weight, and the gastrocnemius weight-to-body weight ratio. APS administration markedly improved these parameters in the D-gal-treated mice. H&E staining showed muscle atrophy and senescence in the D-gal-treated mice, accompanied by deformed muscle cell morphology, which was mitigated by APS gavage. The D-gal-treated mice displayed swelling, cristae fracture, lysis, or complete loss, alongside reduced autophagy and increased lengths of bright bands, myofibrillar myonules, and H bands. However, administration of APS alleviated mitochondrial damage, promoted mitophagy, and reduced the lengths of these muscle tissue bands. Additionally, D-gal treatment significantly reduced LC3II and PINK1 protein expression in muscle tissues, while APS treatment notably elevated their expression levels.
    CONCLUSION: APS gavage ameliorates the structural and functional impairments in muscle tissues of the D-gal-treated mice by promoting mitochondrial autophagy.
    Keywords:  Astragalus polysaccharide; C57BL/6J mice; D-galactose; skeletal muscle
    DOI:  https://doi.org/10.62347/CQDL1155
  42. Toxicol Rep. 2025 Jun;14 101874
    Modulation of copper-induced neurotoxicity by monoisoamyl 2,3-dimercaptosuccinic acid loaded nanoparticles through inhibition of mitophagy and reduction of oxidative stress in SH-SY5Y cells.
    Akshada Mhaske, Rahul Shukla, S J S Flora.
      Copper (Cu2 +) dysregulation, often stemming from ATP7B gene mutations, exacerbates neurological disorders like Huntington's, Alzheimer's, and Parkinson's diseases. Monoisoamyl 2,3-dimercaptosuccinic acid (MiADMSA) shows promise in mitigating Cu2+ induced neurotoxicity by chelating intracellular Cu2+ ions, reducing oxidative stress, and restoring antioxidant enzyme function. However, challenges such as poor bioavailability hinder its therapeutic efficacy. Nano-delivery systems offer a solution by improving MiADMSA's solubility, stability, and targeted delivery, potentially minimizing off-target effects. In this study, MiADMSA was loaded into a polymer conjugated with lipoic acid (LA) and human serum albumin (HSA) using a coacervation crosslinking method. The prepared nanoparticles were optimized using a Box-Behnken design. Evaluation in SH-SY5Y cells revealed promising neuroprotective effects against Cu2+ induced neurotoxicity, highlighting the potential of MiADMSA-loaded nanocarriers as a therapeutic strategy for neurodegenerative diseases associated with metal dysregulation.
    Keywords:  Apoptosis; Box-Behnken design; Metal chelation; MiADMSA; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.toxrep.2024.101874
  43. J Proteome Res. 2025 Jan 13.
    Structural Dynamics of the Ubiquitin Specific Protease USP30 in Complex with a Cyanopyrrolidine-Containing Covalent Inhibitor.
    Darragh P O'Brien, Hannah B L Jones, Yuqi Shi, Franziska Guenther, Iolanda Vendrell, Rosa Viner, Paul E Brennan, Emma Mead, Tryfon Zarganes-Tzitzikas, John B Davis, Adán Pinto-Fernández, Katherine S England, Emma J Murphy, Andrew P Turnbull, Benedikt M Kessler.
      Inhibition of the mitochondrial deubiquitinating (DUB) enzyme USP30 is neuroprotective and presents therapeutic opportunities for the treatment of idiopathic Parkinson's disease and mitophagy-related disorders. We integrated structural and quantitative proteomics with biochemical assays to decipher the mode of action of covalent USP30 inhibition by a small-molecule containing a cyanopyrrolidine reactive group, USP30-I-1. The inhibitor demonstrated high potency and selectivity for endogenous USP30 in neuroblastoma cells. Enzyme kinetics and hydrogen-deuterium eXchange mass spectrometry indicated that the inhibitor binds tightly to regions surrounding the USP30 catalytic cysteine and positions itself to form a binding pocket along the thumb and palm domains of the protein, thereby interfering its interaction with ubiquitin substrates. A comparison to a noncovalent USP30 inhibitor containing a benzosulfonamide scaffold revealed a slightly different binding mode closer to the active site Cys77, which may provide the molecular basis for improved selectivity toward USP30 against other members of the DUB enzyme family. Our results highlight advantages in developing covalent inhibitors, such as USP30-I-1, for targeting USP30 as treatment of disorders with impaired mitophagy.
    Keywords:  Hydrogen−Deuterium eXchange-Mass spectrometry; activity-based protein profiling mass spectrometry; cyanopyrrolidine inhibitors; enzyme kinetics; mitophagy; molecular docking; ubiquitin specific protease USP30
    DOI:  https://doi.org/10.1021/acs.jproteome.4c00618
  44. Neurochem Int. 2025 Jan 09. pii: S0197-0186(24)00254-7. [Epub ahead of print]183 105927
    The role of mitochondrial remodeling in neurodegenerative diseases.
    Duanqin Guan, Congmin Liang, Dongyan Zheng, Shizhen Liu, Jiankun Luo, Ziwei Cai, He Zhang, Jialong Chen.
      Neurodegenerative diseases are a group of diseases that pose a serious threat to human health, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD) and Amyotrophic Lateral Sclerosis (ALS). In recent years, it has been found that mitochondrial remodeling plays an important role in the onset and progression of neurodegenerative diseases. Mitochondrial remodeling refers to the dynamic regulatory process of mitochondrial morphology, number and function, which can affect neuronal cell function and survival by regulating mechanisms such as mitochondrial fusion, division, clearance and biosynthesis. Mitochondrial dysfunction is an important intrinsic cause of the pathogenesis of neurodegenerative diseases. Mitochondrial remodeling abnormalities are involved in energy metabolism in neurodegenerative diseases. Pathological changes in mitochondrial function and morphology, as well as interactions with other organelles, can affect the energy metabolism of dopaminergic neurons and participate in the development of neurodegenerative diseases. Since the number of patients with PD and AD has been increasing year by year in recent years, it is extremely important to take effective interventions to significantly reduce the number of morbidities and to improve people's quality of life. More and more researchers have suggested that mitochondrial remodeling and related dynamics may positively affect neurodegenerative diseases in terms of neuronal and self-adaptation to the surrounding environment. Mitochondrial remodeling mainly involves its own fission and fusion, energy metabolism, changes in channels, mitophagy, and interactions with other cellular organelles. This review will provide a systematic summary of the role of mitochondrial remodeling in neurodegenerative diseases, with the aim of providing new ideas and strategies for further research on the treatment of neurodegenerative diseases.
    Keywords:  Biosynthesis; Mitochondrial quality control; Mitochondrial remodeling; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.neuint.2024.105927
  45. Int J Mol Sci. 2024 Dec 25. pii: 83. [Epub ahead of print]26(1):
    Recombinant Follicle-Stimulating Hormone and Luteinizing Hormone Enhance Mitochondrial Function and Metabolism in Aging Female Reproductive Cells.
    Li-Te Lin, Chia-Jung Li, Yi-Shan Lee, Kuan-Hao Tsui.
      Ovarian aging significantly impacts female fertility, with mitochondrial dysfunction emerging as a key factor. This study investigated the effects of recombinant follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on mitochondrial function and metabolism in aging female reproductive cells. Human granulosa cells (HGL5) were treated with FSH/LH or not. Mitochondrial function was assessed through various assays, including mitochondrial mass, membrane potential, ROS levels, and ATP production. Mitochondrial dynamics and morphology were analyzed using MitoTracker staining. Cellular respiration was measured using a Seahorse Bioenergetics Analyzer. Metabolic reprogramming was evaluated through gene expression analysis and metabolite profiling. In vivo effects were studied using aging mouse oocytes. FSH/LH treatment significantly improved mitochondrial function in aging granulosa cells, increasing mitochondrial mass and membrane potential while reducing ROS levels. Mitochondrial dynamics showed a shift towards fusion and elongation. Cellular respiration, ATP production, and spare respiratory capacity were enhanced. FSH/LH-induced favorable alterations in cellular metabolism, favoring oxidative phosphorylation. In aging mouse oocytes, FSH/LH treatment improved in vitro maturation and mitochondrial health. In conclusion, FSH/LH supplementation ameliorates age-related mitochondrial dysfunction and improves cellular metabolism in aging female reproductive cells.
    Keywords:  FSH/LH supplementation; cellular metabolism; mitochondrial function; ovarian aging; reproductive medicine
    DOI:  https://doi.org/10.3390/ijms26010083
  46. Adv Sci (Weinh). 2025 Jan 17. e2409644
    Youthful Stem Cell Microenvironments: Rejuvenating Aged Bone Repair Through Mitochondrial Homeostasis Remodeling.
    Xinfeng Zhou, Xin Tian, Jianan Chen, Yantong Li, Nanning Lv, Hao Liu, Tao Liu, Huilin Yang, Xi Chen, Yong Xu, Fan He.
      Extracellular matrix (ECM) derived from mesenchymal stem cells regulates antioxidant properties and bone metabolism by providing a favorable extracellular microenvironment. However, its functional role and molecular mechanism in mitochondrial function regulation and aged bone regeneration remain insufficiently elucidated. This proteomic analysis has revealed a greater abundance of proteins supporting mitochondrial function in the young ECM (Y-ECM) secreted by young bone marrow-derived mesenchymal stem cells (BMMSCs) compared to the aged ECM (A-ECM). Further studies demonstrate that Y-ECM significantly rejuvenates mitochondrial energy metabolism in adult BMMSCs (A-BMMSCs) through the promotion of mitochondrial respiratory functions and amelioration of oxidative stress. A-BMMSCs cultured on Y-ECM exhibited enhanced multi-lineage differentiation potentials in vitro and ectopic bone formation in vivo. Mechanistically, silencing of silent information regulator type 3 (SIRT3) gene abolished the protective impact of Y-ECM on A-BMMSCs. Notably, a novel composite biomaterial combining hyaluronic acid methacrylate hydrogel microspheres with Y-ECM is developed, which yielded substantial improvements in the healing of bone defects in an aged rat model. Collectively, these findings underscore the pivotal role of Y-ECM in maintaining mitochondrial redox homeostasis and present a promising therapeutic strategy for the repair of aged bone defects.
    Keywords:  SIRT3; aged bone defects; bone marrow‐derived mesenchymal stem cells; mitochondrial energy metabolism; youthful extracellular matrix
    DOI:  https://doi.org/10.1002/advs.202409644
  47. Acta Pharm Sin B. 2024 Dec;14(12): 5435-5450
    Nanoengineered mitochondria enable ocular mitochondrial disease therapy via the replacement of dysfunctional mitochondria.
    Yi Wang, Nahui Liu, Lifan Hu, Jingsong Yang, Mengmeng Han, Tianjiao Zhou, Lei Xing, Hulin Jiang.
      Leber's hereditary optic neuropathy (LHON) is an ocular mitochondrial disease that involves the impairment of mitochondrial complex I, which is an important contributor to blindness among young adults across the globe. However, the disorder has no available cures, since the approved drug idebenone for LHON in Europe relies on bypassing complex I defects rather than fixing them. Herein, PARKIN mRNA-loaded nanoparticle (mNP)-engineered mitochondria (mNP-Mito) were designed to replace dysfunctional mitochondria with the delivery of exogenous mitochondria, normalizing the function of complex I for treating LHON. The mNP-Mito facilitated the supplementation of healthy mitochondria containing functional complex I via mitochondrial transfer, along with the elimination of dysfunctional mitochondria with impaired complex I via an enhanced PARKIN-mediated mitophagy process. In a mouse model induced with a complex I inhibitor (rotenone, Rot), mNP-Mito enhanced the presence of healthy mitochondria and exhibited a sharp increase in complex I activity (76.5%) compared to the group exposed to Rot damage (29.5%), which greatly promoted the restoration of ATP generation and mitigation of ocular mitochondrial disease-related phenotypes. This study highlights the significance of nanoengineered mitochondria as a promising and feasible tool for the replacement of dysfunctional mitochondria and the repair of mitochondrial function in mitochondrial disease therapies.
    Keywords:  Complex I defect; Engineered mitochondria; Idebenone; Leber's hereditary optic neuropathy; Mitochondrial disease; Mitochondrial function; Mitochondrial transfer; Nanoparticle
    DOI:  https://doi.org/10.1016/j.apsb.2024.08.007
  48. Neural Regen Res. 2025 Jan 13.
    Stress signaling caused by mitochondrial import malfunction can be terminated by SIFI: importance of stress response silencing.
    Grace Hohman, Michael Shahid, Mohamed A Eldeeb.
      
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-01169
  49. Immun Ageing. 2025 Jan 10. 22(1): 4
    Disrupted mitochondrial morphology and function exacerbate inflammation in elderly-onset ulcerative colitis.
    Mengmeng Zhang, Hong Lv, Xiaoyin Bai, Gechong Ruan, Qing Li, Kai Lin, Hong Yang, Jiaming Qian.
       BACKGROUND: The characteristics of ulcerative colitis (UC) in the elderly are quite different from the young population. Mitochondrial injury is a key mechanism regulating both aging and inflammation. This study aims to reveal the role of mitochondrial damage in the pathogenesis of adult- and elderly-onset UC.
    METHODS: RNA-sequencing of colonic mucosa from adult- and elderly-onset UC patients was performed. Mitochondria-related differentially expressive genes (mDEGs) and immune cell infiltration analysis were identified and performed in colonic tissues from UC patients. Mice aged 6-8 weeks and 20-24 months were administered 2% dextran sodium sulphate (DSS) for 7 days to induce colitis. Mitochondrial morphological changes and ATP levels were evaluated in the colons of mice. Mechanistically, we explored the association of key mDEG with reactive oxygen species (ROS), oxygen consumption rates, NLRP3/IL-1β pathway in HCT116 cell line.
    RESULTS: Thirty mDEGs were identified between adult- and elderly-onset UC, which were related primarily to mitochondrial respiratory function and also had significant correlation with different infiltrates of immune cells. Compared with young colitis mice, DSS-induced colitis in the aged mice exhibited more severe inflammation, damaged mitochondrial structure and lower ATP levels in colonic tissues. ALDH1L1 was identified as a hub DEG through protein-protein interaction networks of RNA-seq, which was downregulated in UC patients or colitis mice versus healthy controls. In tumor necrosis factor-alpha-stimulated HCT116 cells, mitochondrial ROS, NLRP3 and IL-1β expression increased less and mitochondrial respiration had an upregulated trend after knocking down ALDH1L1.
    CONCLUSION: There are significant differences in mitochondrial structure, ATP production and mitochondria-related gene expression between adult- and elderly-onset UC, which have a potential link with cytokine pathways and immune microenvironment. The more prominent mitochondrial injury may be a key factor for more severe inflammatory response and poorer outcome in elderly-onset UC.
    Keywords:  Elderly; Immune infiltration; Inflammatory response; Mitochondrial damage; Ulcerative colitis
    DOI:  https://doi.org/10.1186/s12979-024-00494-5
  50. Biol Reprod. 2025 Jan 15. pii: ioaf010. [Epub ahead of print]
    Effect of introducing somatic mitochondria into an early embryo on zygotic gene activation†.
    Yoshihiro Hayashi, Hanako Bai, Masashi Takahashi, Tomohiro Mitani, Manabu Kawahara.
      Unlike differentiated somatic cells, which possess elongated mitochondria, undifferentiated cells, such as those of preimplantation embryos, possess round, immature mitochondria. Mitochondrial morphology changes dynamically during cell differentiation in a process called mitochondrial maturation. The significance of the alignment between cell differentiation and mitochondrial maturity in preimplantation development remains unclear. In this study, we analyzed mouse embryos into which liver-derived somatic mitochondria were introduced (SM-embryos). Most SM-embryos were arrested at the two-cell stage. Some of the introduced somatic mitochondria became round, while others remained elongated and large. RNA-sequencing revealed a disruption of both minor and major zygotic gene activation (ZGA) in SM-embryos. Minor ZGA did not terminate before major ZGA, and the onset of major ZGA was inhibited, as shown by histone modification analyses of histone H3 lysine 4 trimethylation and histone H3 lysine 27 acetylation. Further analysis of metabolites involved in histone modification regulation in SM-embryos showed a significantly lower NAD+/NADH ratio in SM-embryos than in control embryos. Additionally, the mitochondrial membrane potential, an indicator of mitochondrial function, was lower in SM-embryos than in control embryos. Our results demonstrated that introducing somatic mitochondria into an embryo induces mitochondrial dysfunction, thereby disrupting metabolite production, leading to a disruption in ZGA and inducing developmental arrest. Our findings reveal that the alignment between cell differentiation and mitochondrial maturity is essential for early embryonic development.
    Keywords:  Histone modifications; Mitochondria; Mitochondrial remodeling; Preimplantation mouse embryo; Zygotic gene activation
    DOI:  https://doi.org/10.1093/biolre/ioaf010
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