bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–12–15
53 papers selected by
Gavin McStay, Liverpool John Moores University
  1. Depleting chemoresponsive mitochondrial fission mediator DRP1 does not mitigate sarcoma resistance.
  2. High-Throughput Screening of an FDA-Approved Compound Library Reveals a Novel GAS6 Receptor Agonist for Therapeutic Intervention in Septic Myocardial and microvascular Injury via Modulation of Danger-Associated Molecular Patterns.
  3. Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
  4. Phosphoglycerate mutase 1-mediated dephosphorylation and degradation of Dusp1 disrupt mitochondrial quality control and exacerbate endotoxemia-induced myocardial dysfunction.
  5. OPA1 deficiency induces mitophagy through PINK1/Parkin pathway during bovine oocytes maturation.
  6. Isoliquiritin targeting m5C RNA methylation improves mitophagy in doxorubicin-induced myocardial cardiotoxicity.
  7. Ceramide synthase 6 induces mitochondrial dysfunction and apoptosis in hemin-treated neurons by impairing mitophagy through interacting with sequestosome 1.
  8. Mitochondrial fission is required for thermogenesis in brown adipose tissue.
  9. Mitophagy Regulates Kidney Diseases.
  10. Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1.
  11. Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
  12. Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.
  13. Matrine relieved DHAV-1-induced hepatocyte excessive interferon and pyroptosis by activating mitophagy.
  14. Sulforaphane, Urolithin A, and ZLN005 induce time-dependent alterations in antioxidant capacity, mitophagy, and mitochondrial biogenesis in muscle cells.
  15. Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.
  16. Mitochondrial Alterations in Alzheimer's Disease: Insight from the 5xFAD Mouse Model.
  17. Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
  18. A Mitochondria-Targeting and Peroxynitrite-Activatable Ratiometric Fluorescent Probe for Precise Tracking of Oxidative Stress-Induced Mitophagy.
  19. Parkin-TLR4-NLRP3 Axis Directs Melatonin to Alleviate Atrazine-Induced Immune Impairment in Splenic Macrophages.
  20. Circular RNA SCMH1 suppresses KMO expression to inhibit mitophagy and promote functional recovery following stroke.
  21. Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
  22. Hydrogen restores central tryptophan and metabolite levels and maintains mitochondrial homeostasis to protect rats from chronic mild unpredictable stress damage.
  23. Nepetin limits NLRP3 inflammasome activation and alleviates NLRP3-driven inflammatory diseases via PINK1-dependent mitophagy.
  24. Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis.
  25. Mitigating mitochondrial dysfunction and neuroinflammation by hematoma aspiration in a new surgical model for severe intracerebral hemorrhage.
  26. GRIM-19-mediated induction of mitochondrial STAT3 alleviates systemic sclerosis by inhibiting fibrosis and Th2/Th17 cells.
  27. Role of mitophagy in spinal cord ischemia-reperfusion injury.
  28. BCR::ABL1-induced mitochondrial morphological alterations as a potential clinical biomarker in chronic myeloid leukemia.
  29. Epigenetic regulation of mitochondrial fission and cardiac fibrosis via sFRP3 promoter methylation.
  30. The segmented flavivirus Alongshan virus reduces mitochondrial mass by degrading STAT2 to suppress the innate immune response.
  31. Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.
  32. Mitochondrial remodelling supports migration in white-crowned sparrows (Zonotrichia leucophrys).
  33. Retraction notice to "Sirt3-mediated mitochondrial fission regulates the colorectal cancer stress response by modulating the Akt/PTEN signalling pathway" [Biomed. Pharmacother. 105 (2018) 1172-1182].
  34. Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer.
  35. PGC-1α Promotes mitochondrial biosynthesis and energy metabolism of goose fatty liver.
  36. Carvacrol acetate activated Nrf2 modulates mitophagy for the treatment of neurocyte oxidative stress induced by chlorpyrifos.
  37. MARCH5 Promotes the Progression of Thyroid cancer by Regulating Mitochondrial Autophagy Protein FUNDC1-mediated Pyroptosis.
  38. Deficiency of DEK proto-oncogene alleviates allergic rhinitis by inhibiting RhoA/Ezrin-mediated mitochondrial fission.
  39. Modulation of mitochondrial dynamics genes and mtDNA during embryonic development and under UVB exposure.
  40. Jinlida granules alleviate podocyte apoptosis and mitochondrial dysfunction via the AMPK/PGC‑1α pathway in diabetic nephropathy.
  41. Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension.
  42. Ergothioneine-rich Lentinula edodes mushroom extract restores mitochondrial functions in senescent HT22 cells.
  43. Functionalized Nanozyme Microcapsules Targeting Deafness Prevention via Mitochondrial Homeostasis Remodeling.
  44. Inhibition of miR-30d-5p promotes mitochondrial autophagy and alleviates high glucose-induced injury in podocytes.
  45. Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
  46. Bioactive phosphorus dendrimers deliver protein/drug to tackle osteoarthritis via cooperative macrophage reprogramming.
  47. Phosphocreatine-mediated enhancement of mitochondrial function for accelerated healing of diabetic foot ulcers through the PGC-1α-NRF-1 signaling pathway.
  48. Heme Oxygenase-1 Overexpression Activates the IRF1/DRP1 Signaling Pathway to Promote M2-Type Polarization of Spinal Cord Microglia.
  49. FUNDC1 predicts Poor Prognosis and promotes Progression and Chemoresistance in Endometrial Carcinoma.
  50. Immune dysregulation of decidual NK cells mediated by GRIM19 downregulation contributes to the occurrence of recurrent pregnancy loss.
  51. Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.
  52. Progress in the mechanism of functional dyspepsia: roles of mitochondrial autophagy in duodenal abnormalities.
  53. Unraveling morphine tolerance: CCL2 induces spinal cord apoptosis via inhibition of Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis.
  1. Life Sci Alliance. 2025 Feb;pii: e202402870. [Epub ahead of print]8(2):
    Depleting chemoresponsive mitochondrial fission mediator DRP1 does not mitigate sarcoma resistance.
    Karolina Borankova, Matyas Solny, Maria Krchniakova, Jan Skoda.
      Specific patterns of mitochondrial dynamics have been repeatedly reported to promote drug resistance in cancer. However, whether targeting mitochondrial fission- and fusion-related proteins could be leveraged to combat multidrug-resistant pediatric sarcomas is poorly understood. Here, we demonstrated that the expression and activation of the mitochondrial fission mediator DRP1 are affected by chemotherapy exposure in common pediatric sarcomas, namely, rhabdomyosarcoma and osteosarcoma. Unexpectedly, decreasing DRP1 activity through stable DRP1 knockdown neither attenuated sarcoma drug resistance nor affected growth rate or mitochondrial network morphology. The minimal impact on sarcoma cell physiology, along with the up-regulation of fission adaptor proteins (MFF and FIS1) detected in rhabdomyosarcoma cells, suggests an alternative DRP1-independent mitochondrial fission mechanism that may efficiently compensate for the lack of DRP1 activity. By exploring the upstream mitophagy and mitochondrial fission regulator, AMPKα1, we found that markedly reduced AMPKα1 levels are sufficient to maintain AMPK signaling capacity without affecting chemosensitivity. Collectively, our findings challenge the direct involvement of DRP1 in pediatric sarcoma drug resistance and highlight the complexity of yet-to-be-characterized noncanonical regulators of mitochondrial dynamics.
    DOI:  https://doi.org/10.26508/lsa.202402870
  2. Int J Biol Sci. 2024 ;20(15): 6222-6240
    High-Throughput Screening of an FDA-Approved Compound Library Reveals a Novel GAS6 Receptor Agonist for Therapeutic Intervention in Septic Myocardial and microvascular Injury via Modulation of Danger-Associated Molecular Patterns.
    Haowen Zhuang, Chun Li, Lingjun Wang, Bei Zhou, Zhijiang Guo, Yusheng Huang, Bo Deng, Yulin Ouyang, Junxiong Qiu, Xing Chang, Wei Wang, Junyan Wang.
      PGAM5 and VDAC1 have both been reported to regulate mitophagy. However, the mechanisms by which they regulate sepsis-induced inflammatory microvascular injury remain unverified. In previous studies, we established the role of this regulatory axis in various phenotypic processes, including mitophagy, mitochondrial biogenesis, the mitochondrial unfolded protein response, and mitochondrial dynamics, while further confirming the interactive regulatory proteins within this axis. However, the validation and elucidation of these regulatory phenotypes have primarily focused on ischemic heart diseases such as ischemic myocardial injury and heart failure. Sepsis-related myocardial injury is currently recognized as a significant cardiac impairment, and although there are cardioprotective and nutritional agents available for supportive therapy, fundamental research validating the upstream targets and mechanisms of microvascular injury is still lacking. Based on our previous research, we further explored the role of mitophagy dysfunction mediated by VDAC1 and its upstream regulatory protein PGAM5 in sepsis-induced coronary microvascular injury. We also confirmed the material basis and metabolic pathway regulation targeting the PGAM5- VDAC1 interactive mechanism with relevant drugs. Our findings suggest that PGAM5-mediated mitophagy dysfunction may be a crucial factor leading to sepsis-induced microvascular injury, primarily interacting with VDAC1-mediated mitochondrial membrane dysfunction. Animal experiments revealed that cardiac-specific knockout of PGAM5 could reverse LPS-induced coronary microvascular injury and inflammatory damage, restoring cardiac ejection function and mitophagy functionality. In vitro studies also confirmed that the PGAM5-VDAC1 interaction can normalize mitophagy, restoring the normal morphology and structure of mitochondria while maintaining normal mitochondrial energy metabolism levels and respiratory chain function. Further pharmacological research indicated that the active ingredients of traditional Chinese medicine-Puerarin (TCM, a GAS6 Receptor Agonist) can target the PGAM5- VDAC1 axis to regulate mitophagy and inhibit LPS-induced necrotic apoptosis in cardiomyocytes, potentially reversing mitochondrial pathway-related cardiac injury. TCM may emerge as a prospective therapeutic agent targeting the PGAM5- VDAC1 axis.
    Keywords:  PGAM5; VDAC1; mitochondria; mitophagy; septic cardiomyopathy
    DOI:  https://doi.org/10.7150/ijbs.104427
  3. iScience. 2024 Dec 20. 27(12): 111384
    Phosphorylation of Optineurin by protein kinase D regulates Parkin-dependent mitophagy.
    Robert Weil, Emmanuel Laplantine, Messaouda Attailia, Anne Oudin, Shannel Curic, Aya Yokota, Elie Banide, Pierre Génin.
      Degradation of damaged mitochondria, a process called mitophagy, plays a role in mitochondrial quality control and its dysfunction has been linked to neurodegenerative pathologies. The PINK1 kinase and the ubiquitin ligase Parkin-mediated mitophagy represents the most common pathway in which specific receptors, including Optineurin (Optn), target ubiquitin-labeled mitochondria to autophagosomes. Here, we show that Protein Kinases D (PKD) are activated and recruited to damaged mitochondria. Subsequently, PKD phosphorylate Optn to promote a complex with Parkin leading to enhancement of its ubiquitin ligase activity. Paradoxically, inhibiting PKD activity enhances the interaction between Optn and LC3, promotes the recruitment of Parkin to mitochondria, and increases the mitophagic function of Optn. This enhancement of mitophagy is characterized by increased production of mitochondrial ROS and a reduction in mitochondrial mass. The PKD kinases may therefore regulate Optn-dependent mitophagy by amplifying the Parkin-mediated degradation signals to improve the cell response against oxidative stress damage.
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111384
  4. Theranostics. 2024 ;14(19): 7488-7504
    Phosphoglycerate mutase 1-mediated dephosphorylation and degradation of Dusp1 disrupt mitochondrial quality control and exacerbate endotoxemia-induced myocardial dysfunction.
    Rongjun Zou, Wanting Shi, Mingxian Chen, Miao Zhang, Dan Wu, Haixia Li, Hao Zhou, Yukun Li, Weihui Lu, Chao Li, Xiaoping Fan.
      Rationale: Endotoxemia, caused by lipopolysaccharides, triggers systemic inflammation and myocardial injury by disrupting mitochondrial homeostasis. This study examines the roles of dual specificity phosphatase 1 (Dusp1) and phosphoglycerate mutase family member 1 (Pgam1) in this process. Methods: This study utilized cardiomyocyte-specific Dusp1 knockout (Dusp1Cko ) and transgenic (Dusp1Tg ) mice, alongside Pgam1 knockout (Pgam1Cko ) mice, subjected to LPS-induced endotoxemia. Echocardiography was performed to assess cardiac function. Mitochondrial integrity was evaluated using molecular techniques, including qPCR and Seahorse assays. Additionally, molecular docking studies and Western blot analyses were conducted to explore the interaction between Pgam1 and Dusp1. Results: Using single-cell sequencing and human sample databases, Dusp1 emerged as a novel biomarker for endotoxemia-induced myocardial dysfunction. Experiments with cardiomyocyte-specific Dusp1 knockout (Dusp1Cko ) and Dusp1 transgenic (Dusp1Tg ) mice showed that Dusp1 deficiency worsens, while overexpression improves, heart function during LPS-induced myocardial injury. This effect is mediated by regulating inflammation and cardiomyocyte viability. Molecular analyses revealed that LPS exposure leads to Dusp1 dephosphorylation at Ser364, increasing its degradation. Stabilizing Dusp1 phosphorylation enhances mitochondrial function through mitochondrial quality control (MQC), including dynamics, mitophagy, and biogenesis. Functional studies identified Pgam1 as an upstream phosphatase interacting with Dusp1. Pgam1 ablation reduced LPS-induced cardiomyocyte dysfunction and mitochondrial disorder. Conclusions: Pgam1-mediated dephosphorylation of Dusp1 disrupts mitochondrial quality control, leading to myocardial dysfunction in endotoxemia. Targeting the Pgam1-Dusp1 axis represents a promising therapeutic strategy for improving cardiac outcomes in patients with endotoxemia.
    Keywords:  Dusp1; LPS; Pgam1; endotoxemia; mitochondrial quality control
    DOI:  https://doi.org/10.7150/thno.102647
  5. Theriogenology. 2024 Dec 04. pii: S0093-691X(24)00497-7. [Epub ahead of print]234 51-63
    OPA1 deficiency induces mitophagy through PINK1/Parkin pathway during bovine oocytes maturation.
    Tiancang Han, Yuhan Zhao, Anhui Jiao, Zhaoyang Sun, Hongbo Zhang, Dazhuo Zhao, Haijun Wang, Qingshan Gao.
      In vitro embryo production (IVP) technology has been increasingly applied to beef cattle breeding. In vitro maturation (IVM) technology is the basis of IVP. However, the quality of in vitro-generated mature oocytes is still poor. Mitochondria are the energy factories of oocytes, so they are crucial for oocyte quality. OPA1 is a protein located on the mitochondrial inner membrane, and its main function is to mediate mitochondrial inner membrane fusion. This work demonstrated that OPA1 is expressed at different stages of meiosis in bovine oocytes. The inhibition of OPA1 activity resulted in a reduced rate of first polar body excretion from bovine oocytes and disruption of the spindle structure. OPA1 deficiency impacted mitochondria by leading to mitochondrial dysfunction, promoting mitochondrial fission, and inducing mitophagy through the PINK1/Parkin pathway. Taken together, our findings suggest that OPA1 is essential for bovine oocyte maturation and that OPA1 deficiency leads to mitochondrial dysfunction and promotes mitochondrial fission as well as mitophagy.
    Keywords:  Bovine oocyte; Mitophagy; OPA1; PINK1; Parkin
    DOI:  https://doi.org/10.1016/j.theriogenology.2024.12.004
  6. Phytomedicine. 2024 Dec 01. pii: S0944-7113(24)00948-6. [Epub ahead of print]136 156293
    Isoliquiritin targeting m5C RNA methylation improves mitophagy in doxorubicin-induced myocardial cardiotoxicity.
    Jiaqi Fu, Li Cheng, Jie Zhang, Runjie Sun, Manya Yu, Muyun Wu, Suzhen Li, Xing Cui.
       BACKGROUND: Doxorubicin (DOX)-induced myocardial cardiotoxicity (DIC) severely limits its clinical application, and there is no optimal therapeutic agent available. Recent studies revealed that activation of BNIP3-mediated mitophagy and the inhibition of m5C RNA methylation played a crucial role in DIC. Isoliquiritin (ISL) has remarkable cardiac protective effect. But its potential mechanisms against DIC still remains unknown.
    PURPOSE: To investigate the therapeutic effect and potential mechanism of Isoliquiritin(ISL) on doxorubicin(DOX)-induced myocardial cardiotoxicity(DIC).
    METHODS: Bioinformatics analyses and network pharmacology were carried out to identify effective target of ISL against DIC. Molecular docking and surface-plasmon resonance (SPR) were used to confirm the predict. The mechanism of ISL regulating mitophagy through M5C methylation to improve DIC was demonstrated in vitro and in vivo experiments. The methylation modification was verified by MeRIP-qPCR. Cell model of DIC was constructed to evaluate mitochondrial function by measuring cell viability, myocardial enzyme level, mitochondrial quality, mCherry-EGFP analysis and TEM morphometry with the application of mitophagy inhibitor (Baf A1) and inducer (CCCP). Myocardial injury in mice with DIC was assessed by survival rate, myocardial enzyme level, HE staining, echocardiography and detection of mitophagy markers.
    RESULTS: The decreased level of m5C writer TRDMT1 and mitochondrial marker (BNIP3) were chosen for the research. After the docking and SPR verification between ISL and TRDMT1, the improvement of ISL on TRDMT1 and TRDMT1-associated m5C level of BNIP3 was identified. In vitro and in vivo experiments showed that the cardiac markers, heart function, and mitochondrial function were recovered after ISL application. Meanwhile, the results manifested that there was blocked autophagy flow indicated by mCherry-EGFP analysis, then the suppressed mitophagy caused the mitochondria damage associated cell death. ISL could alleviate the autophagy block, and Baf A1 couldn't influnce the ISL effect. Compared to CCCP group, Mitochondrial maker TOMM20 significantly elevated treated with both CCCP and DOX, indicating that DOX impaired mitophagy for clearing damaged mitochondrial proteins. After ISL treated, a higher level of co-localization between mitochondrial and BNIP3 was observed, inducing restoration of mitochondrial function.
    CONCLUSION: This study showed that ISL may exert cardioprotective role restoring BNIP3-mediated mitophagy by targeting TRDMT1 to alleviate DOX-induced macro-autophagy-dependent protein homeostasis and acquired blocking of mitophagy, providing a new idea for the clinical treatment of DIC.
    Keywords:  BNIP3; Cardiotoxicity; Doxorubicin; Isoliquiritin; Mitophagy; m5C RNA methylation
    DOI:  https://doi.org/10.1016/j.phymed.2024.156293
  7. Free Radic Biol Med. 2024 Dec 04. pii: S0891-5849(24)01122-5. [Epub ahead of print]227 282-295
    Ceramide synthase 6 induces mitochondrial dysfunction and apoptosis in hemin-treated neurons by impairing mitophagy through interacting with sequestosome 1.
    Aoqian Xu, Yikui Liu, Baofeng Wang, Qixiang Zhang, Yuxiao Ma, Yuxiao Xue, Zhuohang Wang, Qingfang Sun, Yuhao Sun, Liuguan Bian.
      Intracerebral hemorrhage (ICH) is a severe subtype of stroke linked to high morbidity and mortality rates. However, the underlying mechanisms of neuronal injury post-ICH remain poorly understood. In this study, we investigated sphingolipid metabolism alterations in neurons using lipidomics and explored the regulatory mechanisms involved. Western blot and live-cell imaging were applied to detect mitochondrial quality and mitophagy level. We found a significant upregulation of ceramide synthase 6 (CERS6)-related C16 ceramide biosynthesis after hemin treatment. Knockdown of CERS6 notably ameliorated mitochondrial dysfunction and reduced neuronal apoptosis. Additionally, impaired neuronal mitophagy was observed after hemin treatment, which was restored by CERS6 knockdown. Mechanistically, CERS6 impaired mitophagy by interacting with sequestosome 1, leading to mitochondrial dysfunction and neuronal apoptosis. Our study explored the relationship between ceramide metabolism and mitophagy in neurons, revealing the pro-apoptotic role of CERS6 while providing a potential therapeutic target for patients with ICH.
    Keywords:  Apoptosis; Ceramide synthase 6; Intracerebral hemorrhage; Lipidomic; Mitochondria; Mitophagy; Neuron; Sphingolipid
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.018
  8. PLoS One. 2024 ;19(12): e0312352
    Mitochondrial fission is required for thermogenesis in brown adipose tissue.
    Yuta Ibayashi, Nao Hasuzawa, Seiji Nomura, Masaharu Kabashima, Ayako Nagayama, Shimpei Iwata, Miyuki Kitamura, Kenji Ashida, Yoshinori Moriyama, Ken Yamamoto, Masatoshi Nomura, Lixiang Wang.
      Brown adipose tissue (BAT) thermogenesis is pivotal for maintaining body temperature and energy balance. Mitochondrial morphology is dynamically controlled by a balance between fusion and fission, which is crucial for cell differentiation, response to metabolic insults, and heat production. Dynamin-related protein 1 (Drp1) is a key regulator of mitochondrial fission. This study investigates the role of Drp1 in BAT development and thermogenesis by generating Drp1-deficient mice. These mice were created by crossing Drp1 floxed mice with fatty acid-binding protein 4-Cre (aP2-Cre) transgenic mice, resulting in aP2-Cre+/-Drp1flox/flox (aP2-Drp1f/f) mice. The aP2-Drp1f/f mice exhibited severe BAT and brain hypoplasia, with the majority dying within 48 hours postnatally, highlighting Drp1's crucial role in neonatal survival. Impaired thermogenic responses were observed in aP2-Drp1f/f mice, characterized by significantly decreased expression of thermogenic and lipogenic genes in BAT. Ultrastructural analysis revealed disrupted mitochondrial morphology and reduced lipid droplet content in BAT. The few surviving adult aP2-Drp1f/f mice also showed impaired BAT and brain development, along with BAT thermogenesis dysfunction during cold exposure. Our findings underscore the essential role of Drp1-mediated mitochondrial fission in BAT thermogenesis and neonatal survival, providing insights into potential therapeutic approaches for metabolic disorders.
    DOI:  https://doi.org/10.1371/journal.pone.0312352
  9. Kidney Dis (Basel). 2024 Dec;10(6): 573-587
    Mitophagy Regulates Kidney Diseases.
    Xiaolu Fan, Linlin Wu, Fengqi Wang, Dong Liu, Xufeng Cen, Hongguang Xia.
       Background: Mitophagy is a crucial process involved in maintaining cellular homeostasis by selectively eliminating damaged or surplus mitochondria. As the kidney is an organ with a high dynamic metabolic rate and abundant mitochondria, it is particularly crucial to control mitochondrial quality through mitophagy. Dysregulation of mitophagy has been associated with various renal diseases, including acute and chronic kidney diseases, and therefore a better understanding of the links between mitophagy and these diseases may present new opportunities for therapeutic interventions.
    Summary: Mitophagy plays a pivotal role in the development of kidney diseases. Upregulation and downregulation of mitophagy have been observed in various kidney diseases, such as renal ischemia-reperfusion injury, contrast-induced acute kidney injury, diabetic nephropathy, kidney fibrosis, and several inherited renal diseases. A growing body of research has suggested that PINK1 and Parkin, the main mitophagy regulatory proteins, represent promising potential therapeutic targets for kidney diseases. In this review, we summarize the latest insights into how the progression of renal diseases can be mitigated through the regulation of mitophagy, while highlighting their performance in clinical trials.
    Key Message: This review comprehensively outlines the mechanisms of mitophagy and its role in numerous kidney diseases. While early research holds promise, most mitophagy-centered therapeutic approaches have yet to reach the clinical application stage.
    Keywords:  Acute kidney injury; Alport syndrome; Chronic kidney disease; Mitophagy; Parkin
    DOI:  https://doi.org/10.1159/000541486
  10. Pharmacol Res. 2024 Dec 04. pii: S1043-6618(24)00483-3. [Epub ahead of print]210 107538
    Epithelial mitochondrial fission-mediated PANoptosis is crucial for ulcerative colitis and its inhibition by saquinavir through Drp1.
    Zhiming Ye, Mingxia Deng, Yang Yang, Yuanming Song, Liangkun Weng, Wanchen Qi, Ping Ding, Yihang Huang, Can Yu, Yan Wang, Yixing Wu, Yan Zhang, Shaoying Yuan, Wenkai Nie, Luyong Zhang, Cheng Zeng.
      Ulcerative colitis (UC) is characterized by increased cell death in intestinal epithelial cell (IEC), which compromises gut barrier function and activates inflammation. Aberrant mitochondrial dynamics have been implicated in various forms of cell death, but it is currently unclear if they play a role in IEC death and colitis pathogenesis. This study aims to investigate the contribution of aberrant mitochondrial dynamics to colitis progression using cellular models, animal models, and clinical samples. The results revealed that IEC in mice with Dextran sulfate sodium salt (DSS)-induced colitis exhibited dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and Z-DNA binding protein 1 (ZBP1)-dependent PANoptosis, which is a combination of apoptosis, necroptosis, and pyroptosis. However, these processes and the pathogenesis of DSS-induced colitis were significantly attenuated in IEC-specific Drp1 heterozygous knockout mice. Importantly, ZBP1-PANoptosis and Drp1-mediated mitochondrial fission were observed in IEC of UC patients, exhibiting a positive correlation with disease severity. Mechanistically, hyperactivated mitochondrial fission induced mitochondrial reactive oxygen species production leading to PANoptosis through ZBP1 sulfenylation at Cys327 independently of its Zα domain. Saquinavir, an FDA-approved drug identified through in-silico screening alongside in vivo and in vitro experiments, inhibits mitochondrial fission thereby enhancing therapeutic efficacy in mice with colitis.
    Keywords:  Drp1; Mitochondrial fission; PANoptosis; Saquinavir; Ulcerative colitis; ZBP1
    DOI:  https://doi.org/10.1016/j.phrs.2024.107538
  11. Autophagy. 2024 Dec 12. 1-16
    Inhibition of the PI3K-AKT-MTORC1 axis reduces the burden of the m.3243A>G mtDNA mutation by promoting mitophagy and improving mitochondrial function.
    Chih-Yao Chung, Kritarth Singh, Preethi Sheshadri, Gabriel E Valdebenito, Anitta R Chacko, María Alicia Costa Besada, Xiao Fei Liang, Lida Kabir, Robert D S Pitceathly, Gyorgy Szabadkai, Michael R Duchen.
      Mitochondrial DNA (mtDNA) encodes genes essential for oxidative phosphorylation. The m.3243A>G mutation causes severe disease, including myopathy, lactic acidosis and stroke-like episodes (MELAS) and is the most common pathogenic mtDNA mutation in humans. We have previously shown that the mutation is associated with constitutive activation of the PI3K-AKT-MTORC1 axis. Inhibition of this pathway in patient fibroblasts reduced the mutant load, rescued mitochondrial bioenergetic function and reduced glucose dependence. We have now investigated the mechanisms that select against the mutant mtDNA under these conditions. Basal macroautophagy/autophagy and lysosomal degradation of mitochondria were suppressed in the mutant cells. Pharmacological inhibition of any step of the PI3K-AKT-MTORC1 pathway activated mitophagy and progressively reduced m.3243A>G mutant load over weeks. Inhibition of autophagy with bafilomycin A1 or chloroquine prevented the reduction in mutant load, suggesting that mitophagy was necessary to remove the mutant mtDNA. Inhibition of the pathway was associated with metabolic remodeling - mitochondrial membrane potential and respiratory rate improved even before a measurable fall in mutant load and proved crucial for mitophagy. Thus, maladaptive activation of the PI3K-AKT-MTORC1 axis and impaired autophagy play a major role in shaping the presentation and progression of disease caused by the m.3243A>G mutation. Our findings highlight a potential therapeutic target for this otherwise intractable disease.Abbreviation: ΔΨm: mitochondrial membrane potential; 2DG: 2-deoxy-D-glucose; ANOVA: analysis of variance; ARMS-qPCR: amplification-refractory mutation system quantitative polymerase chain reaction; Baf A1: bafilomycin A1; BSA: bovine serum albumin; CQ: chloroquine; Cybrid: cytoplasmic hybrid; CYCS: cytochrome c, somatic; DCA: dichloroacetic acid; DMEM: Dulbecco's modified Eagle's medium; DMSO: dimethylsulfoxide; EGFP: enhanced green fluorescent protein; LC3B-I: carboxy terminus cleaved microtubule-associated protein 1 light chain 3 beta; LC3B-II: lipidated microtubule-associated protein 1 light chain 3 beta; LY: LY290042; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MELAS: mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MFC: mitochondrial fragmentation count; mt-Keima: mitochondrial-targeted mKeima; mtDNA: mitochondrial DNA/mitochondrial genome; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; OA: oligomycin+antimycin A; OxPhos: oxidative phosphorylation; DPBS: Dulbecco's phosphate-buffered saline; PPARGC1A/PGC-1α: PPARG coactivator 1 alpha; PPARGC1B/PGC-1β: PPARG coactivator 1 beta; PI3K: phosphoinositide 3-kinase; PINK1: PTEN induced kinase 1; qPCR: quantitative polymerase chain reaction; RNA-seq: RNA sequencing; RP: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; WT: wild-type.
    Keywords:  PI3K-AKT-MTORC1; m.3243A>G; mitochondria; mitophagy; mtDNA mutations; nutrient signaling
    DOI:  https://doi.org/10.1080/15548627.2024.2437908
  12. Nat Commun. 2024 Dec 13. 15(1): 10681
    Mitochondrial dynamics govern whole-body regeneration through stem cell pluripotency and mitonuclear balance.
    Xue Pan, Yun Zhao, Yucong Li, Jiajia Chen, Wenya Zhang, Ling Yang, Yuanyi Zhou Xiong, Yuqing Ying, Hao Xu, Yuhong Zhang, Chong Gao, Yuhan Sun, Nan Li, Liangyi Chen, Zhixing Chen, Kai Lei.
      Tissue regeneration is a complex process involving large changes in cell proliferation, fate determination, and differentiation. Mitochondrial dynamics and metabolism play a crucial role in development and wound repair, but their function in large-scale regeneration remains poorly understood. Planarians offer an excellent model to investigate this process due to their remarkable regenerative abilities. In this study, we examine mitochondrial dynamics during planarian regeneration. We find that knockdown of the mitochondrial fusion gene, opa1, impairs both tissue regeneration and stem cell pluripotency. Interestingly, the regeneration defects caused by opa1 knockdown are rescued by simultaneous knockdown of the mitochondrial fission gene, drp1, which partially restores mitochondrial dynamics. Furthermore, we discover that Mitolow stem cells exhibit an enrichment of pluripotency due to their fate choices at earlier stages. Transcriptomic analysis reveals the delicate mitonuclear balance in metabolism and mitochondrial proteins in regeneration, controlled by mitochondrial dynamics. These findings highlight the importance of maintaining mitochondrial dynamics in large-scale tissue regeneration and suggest the potential for manipulating these dynamics to enhance stem cell functionality and regenerative processes.
    DOI:  https://doi.org/10.1038/s41467-024-54720-1
  13. Poult Sci. 2024 Nov 27. pii: S0032-5791(24)01179-9. [Epub ahead of print]104(1): 104601
    Matrine relieved DHAV-1-induced hepatocyte excessive interferon and pyroptosis by activating mitophagy.
    Weiran Wang, Xiang Fu, Bolin Gu, Mengxin Hu, Jiaguo Liu.
      Duck hepatitis A virus type 1 (DHAV-1) is a significant pathogen affecting ducklings, capable of causing rapid mortality and adversely impacting the development of the duck industry. Matrine, the primary active ingredient in various Chinese herbal medicines, has demonstrated antiviral and anti-inflammatory properties. Nevertheless, the effects and mechanisms of action of matrine against DHAV-1 infection remain unclear. This research investigates the effects of matrine on DHAV-1 infection and elucidates the mechanisms involved. We found that matrine mitigated the excessive retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling response, pyroptosis, and mitochondrial damage induced by DHAV-1 in duckling livers and duck embryonic hepatocytes (DEHs). Additionally‌, by incorporating the autophagy inhibitor chloroquine, we observed that the effects of matrine on the regulation of excessive interferon (IFN) production, pyroptosis, mitochondrial damage, and oxidative stress were reversed. Overall, matrine inhibited excessive IFN production and pyroptosis by promoting mitophagy, suggesting that matrine may act as a possible therapeutic agent for addressing DHAV-1 infection and other viral hepatitis.
    Keywords:  DHAV-1; Matrine; Mitophagy; Pyroptosis; RLR signaling
    DOI:  https://doi.org/10.1016/j.psj.2024.104601
  14. Sports Med Health Sci. 2025 Jan;7(1): 16-27
    Sulforaphane, Urolithin A, and ZLN005 induce time-dependent alterations in antioxidant capacity, mitophagy, and mitochondrial biogenesis in muscle cells.
    Neushaw Moradi, Sabrina Champsi, David A Hood.
      Efficient signal transduction that mediates mitochondrial turnover is a strong determinant of metabolic health in skeletal muscle. Of these pathways, our focus was aimed towards the enhancement of antioxidant capacity, mitophagy, and mitochondrial biogenesis. While physical activity is an excellent inducer of mitochondrial turnover, its ability to ubiquitously activate and enhance mitochondrial turnover prevents definitive differentiation of the contribution made by each pathway. Therefore, we employed three agents, Sulforaphane (SFN), Urolithin A (UroA), and ZLN005 (ZLN), which are activators of important biological markers involved in antioxidant signaling, mitophagy, and biogenesis, respectively. We investigated the time-dependent changes in proteins related to each mechanism in C2C12 myotubes. SFN treatment resulted in increased nuclear localization of the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) after 4 ​hour (h), with subsequent 2-fold increases in the antioxidant enzymes Nicotinamide Quinone Oxidoreductase 1 (NQO1) and Heme-Oxygenase-1 (HO-1) by 24 ​h and 48 ​h. Mitochondrial respiration and ATP production were significantly increased by both 24 h and 48 ​h. UroA showed a 2-fold increase in AMP-activated Protein Kinase (AMPK) after 4 ​h, which led to a modest 30% increase in whole cell mitophagy markers p62 and LC3, after 48 ​h. This was accompanied by a reduction in cellular Reactive Oxygen Species (ROS), detected with the CellROX Green reagent. Mitophagy flux measurements showed mitophagy activation as both LC3-II and p62 flux increased with UroA at 24-h and 48-h time points, respectively. Finally, AMPK activation was observed by 4 ​h, in addition to a 2-fold increase in Mitochondrial Transcription Factor A (TFAM) promoter activity by 24 ​h of ZLN treatment following transient transfection of a TFAM promoter-luciferase construct. Mitochondrial respiration and ATP production were enhanced by 24 ​h. Our results suggest that early time points of treatment increase upstream pathway activity, whereas later time points represent the increased phenotypic expression of related downstream markers. Our findings suggest that the spatiotemporal progression of these mechanisms following drug treatment is another important factor to consider when examining subcellular changes towards mitochondrial turnover in muscle.
    Keywords:  AMPK; Exercise mimetic; Mitochondria; Nrf-2; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.smhs.2024.03.011
  15. bioRxiv. 2024 Nov 26. pii: 2024.11.24.624947. [Epub ahead of print]
    Mitophagy Facilitates Cytosolic Proteostasis to Preserve Cardiac Function.
    David R Rawnsley, Moydul Islam, Chen Zhao, Yasaman Kargar Gaz Kooh, Adelita Mendoza, Honora Navid, Minu Kumari, Xumin Guan, John T Murphy, Jess Nigro, Attila Kovacs, Kartik Mani, Nathaniel Huebsch, Xiucui Ma, Abhinav Diwan.
       Background: Protein quality control (PQC) is critical for maintaining sarcomere structure and function in cardiac myocytes, and mutations in PQC pathway proteins, such as CRYAB (arginine to glycine at position 120, R120G) and BAG3 (proline to lysine at position 209, P209L) induce protein aggregate pathology with cardiomyopathy in humans. Novel observations in yeast and mammalian cells demonstrate mitochondrial uptake of cytosolic protein aggregates. We hypothesized that mitochondrial uptake of cytosolic protein aggregates and their removal by mitophagy, a lysosomal degradative pathway essential for myocardial homeostasis, facilitates cytosolic protein quality control in cardiac myocytes.
    Methods: Mice with inducible cardiac myocyte specific ablation of TRAF2 (TRAF2icKO), which impairs mitophagy, were assessed for protein aggregates with biochemical fractionation and super-resolution imaging in comparison to floxed controls. Induced pluripotent stem cell (iPSC)-derived cardiac myocytes with R120G knock-in to the CRYAB locus were assessed for localization of the CRYAB protein. Transgenic mice expressing R120G CRYAB protein (R120G-TG) were subjected to both TRAF2 gain-of-function (with AAV9-cardiac Troponin T promoter-driven TRAF2 transduction) and TRAF2 loss-of-function (with tamoxifen-inducible ablation of one Traf2 allele) in cardiac myocytes to determine the effect of mitophagy modulation on cardiac structure, function, and protein aggregate pathology.
    Results: Cardiomyocyte-specific ablation of TRAF2 results accumulation of mitochondrial and cytosolic protein aggregates and DESMIN mis-localization to protein aggregates. Isolated mitochondria take up cardiomyopathy-associated aggregate-prone cytosolic chaperone proteins, namely arginine to glycine (R120G) CRYAB mutant and proline to lysine (P209L) BAG3 mutant. R120G-CRYAB mutant protein increasingly localizes to mitochondria in human and mouse cardiomyocytes. R120G-TG mice demonstrate upregulation of TRAF2 in the mitochondrial fraction with increased mitophagy as compared with wild type. Adult-onset inducible haplo-insufficiency of TRAF2 resulted in accelerated mortality, impaired left ventricular systolic function and increased protein aggregates in R120G-TG mice as compared with controls. Conversely, AAV9-mediated TRAF2 transduction in R120G-TG mice reduced mortality and attenuated left ventricular systolic dysfunction, with reduced protein aggregates and restoration of normal localization of DESMIN, a cytosolic scaffolding protein chaperoned by CRYAB, as compared with control AAV9-GFP group.
    Conclusions: TRAF2-mediated mitophagy in cardiac myocytes facilitates removal of cytosolic protein aggregates and can be stimulated to ameliorate proteotoxic cardiomyopathy.
    DOI:  https://doi.org/10.1101/2024.11.24.624947
  16. Mol Neurobiol. 2024 Dec 11.
    Mitochondrial Alterations in Alzheimer's Disease: Insight from the 5xFAD Mouse Model.
    Elif Nedret Keskinoz, Musa Celik, Ezgi Sila Toklucu, Kerem Birisik, Alev Erisir, Devrim Oz-Arslan.
      Mitochondrial dysfunction is increasingly recognized as a key factor in Alzheimer's disease (AD) pathogenesis, but the precise relationship between mitochondrial dynamics and proteinopathies in AD remains unclear. This study investigates the role of mitochondrial dynamics and function in the hippocampal tissue and peripheral blood mononuclear cells (PBMCs) of 5xFAD transgenic mice, as a model of AD. The levels of mitochondrial fusion proteins OPA1 and MFN2 and fission proteins DRP1 and phospho-DRP1 (S616) at 3, 6, and 9 months of age were assessed. Western blot analysis revealed significantly lower levels of OPA1 and MFN2 in the hippocampus of 6- and 9-month-old transgenic (TG) 5xFAD mice compared to controls (CTR), while DRP1 and pDRP1 levels were increased in 9-month-old TG mice. Additionally, MFN2 were decreased in the PBMCs of 9-month-old TG mice, indicating systemic mitochondrial alterations. Ultrastructural analysis of hippocampal tissues showed substantial alterations in mitochondrial morphology, including abnormalities in size and shape, a preponderance of teardrop-shaped mitochondria, and alterations in the somatic mitochondria-ER complex. Notably, mitochondria-associated ER contact sites were more distant in TG mice, suggesting functional impairments. Flow cytometric measurements demonstrated decreased mitochondrial membrane potential and mass, along with increased superoxide production, in the PBMCs of TG mice, particularly at 9 months, highlighting compromised mitochondrial function. Levels of key mitochondrial proteins including VDAC, TOM2O, and mitophagy-related protein PINK1 levels altered in both central and peripheral tissue of TG mice. These findings suggest that mitochondrial dysfunction and altered dynamics are early events in AD development in 5xFAD mice, manifesting in both central and peripheral tissues, and support the notion that mitochondrial abnormalities are an integral component of AD pathology. These insights might lead to the development of targeted therapies that modulate mitochondrial dynamics and function to mitigate AD progression.
    Keywords:  Electron microscopy; Flow cytometry; MERCs; Mitochondrial dynamics; Western blot
    DOI:  https://doi.org/10.1007/s12035-024-04632-4
  17. bioRxiv. 2024 Nov 26. pii: 2024.11.25.625249. [Epub ahead of print]
    Mitochondrial and Microtubule Defects in Exfoliation Glaucoma.
    Arunkumar Venkatesan, Marc Ridilla, Nileyma Castro, J Mario Wolosin, Jessica L Henty-Ridilla, Barry E Knox, Preethi S Ganapathy, Jamin S Brown, Anthony F DeVincentis, Sandra Sieminski, Audrey M Bernstein.
      Exfoliation Syndrome (XFS) is an age-related systemic condition characterized by large aggregated fibrillar material deposition in the anterior eye tissues. This aggregate formation and deposition on the aqueous humor outflow pathway are significant risk factors for developing Exfoliation Glaucoma (XFG), a secondary open-angle glaucoma. XFG is a complex, multifactorial late-onset disease that shares common features of neurodegenerative diseases, such as altered cellular processes with increased protein aggregation, impaired protein degradation, and oxidative and cellular stress. XFG patients display decreased mitochondrial membrane potential and mitochondrial DNA deletions. Here, using Tenon Capsule Fibroblasts (TFs) from Normal (No Glaucoma) and XFG patients, we found that XFG TFs have impaired mitochondrial bioenergetics and increased reactive oxygen species (ROS) accumulation. These defects are associated with mitochondrial abnormalities as XFG TFs exhibit smaller mitochondria that contain dysmorphic cristae, with an increase in mitochondrial localization to lysosomes and slowed mitophagy flux. Mitochondrial dysfunction in the XFG TFs was associated with an increase in the dynamics of the microtubule cytoskeleton, decreased acetylated tubulin, and increased HDAC6 activity. Treatment of XFG TFs with a mitophagy inducer, Urolithin A, and a mitochondrial biogenesis inducer, NAD + precursor, Nicotinamide Ribose, improved mitochondrial bioenergetics and reduced ROS accumulation. Our results demonstrate abnormal mitochondria in XFG TFs and suggest that mitophagy inducers may represent a potential class of therapeutics for reversing mitochondrial dysfunction in XFG patients.
    DOI:  https://doi.org/10.1101/2024.11.25.625249
  18. Anal Chem. 2024 Dec 09.
    A Mitochondria-Targeting and Peroxynitrite-Activatable Ratiometric Fluorescent Probe for Precise Tracking of Oxidative Stress-Induced Mitophagy.
    Xianzhi Chai, Xiuhua Ma, Lu-Lu Sun, Yuqing Hu, Weijian Zhang, Shiyao Zhang, Jiaqi Zhou, Liangliang Zhu, Hai-Hao Han, Xiao-Peng He.
      Mitochondria are the energy factory of cells and can be easily damaged by reactive oxygen species (ROS) because of the frequent occurrence of oxidative stress. Abnormality in mitophagy is often associated with many diseases including inflammation, cancer, and aging. While previously developed fluorescent probes mainly focus on detecting just ROS or mitophagy, quite rare studies have endeavored to comprehensively capture the entire mitophagic process, encompassing both the production of ROS and the induction of mitophagy. Herein, we report a new ratiometric fluorescent probe NA-DP for tracking peroxynitrite (ONOO-) as well as the subsequent oxidative stress-induced mitophagy. To a naphthalimide-based dye, an ONOO--responsive diphenyl phosphinate moiety and the mitochondria-targeting triphenylphosphonium group were attached. The probe showed a highly selective response to ONOO- through an addition-elimination reaction with diphenyl phosphinate. Owing to its outstanding pH stability and organelle-targeting ability, NA-DP was successfully used to detect mitophagy induced by oxidative stress after the generation of ONOO-. In the meantime, the probe was also used to track starvation-induced mitophagy and indicate that starvation-induced mitophagy is independent of ONOO-. Therefore, NA-DP has the ability to precisely track oxidative stress-induced mitophagy by distinguishing it from starvation-induced mitophagy. This study offers a new chemical tool to study the relationship between ROS generation and mitophagy.
    DOI:  https://doi.org/10.1021/acs.analchem.4c03759
  19. J Pineal Res. 2024 Nov;76(8): e70014
    Parkin-TLR4-NLRP3 Axis Directs Melatonin to Alleviate Atrazine-Induced Immune Impairment in Splenic Macrophages.
    Shuo Liu, Tian-Ning Yang, Yu-Xiang Wang, Xiang-Yu Ma, Yu-Sheng Shi, Yi Zhao, Jin-Long Li.
      Atrazine (ATR) is a widespread environmental herbicide that seriously affects agricultural work and human safety. Melatonin (MLT) as an endogenous neuroendocrine hormone is widely found in animals and plants, which have antioxidant and anti-inflammatory effects. Pink1/Parkin-mediated mitophagy keeps normal physiological processes by degrading damaged mitochondria in cells. Therefore, we investigated the potential role and mechanism of MLT in ATR-induced toxic injury of the spleen. The results showed that MLT alleviated ATR-induced unclear boundary between the white pulp and the red pulp of the spleen. It is also shown that ATR resulted in swollen mitochondria, partial extinction of mitochondrial membranes and cristae, and increased mitophagy under the action of MLT. ATR-induced reactive oxygen species (ROS) activates the Pink1/Parkin pathway, which guides mitophagy development and then causes the activation of TLR4/NF-κB inflammatory pathway. Meanwhile, these damages further exacerbated the production of NLRP3 inflammasomes, leading to spleen necrosis. Interestingly, these changes were improved after MLT treatment. Collectively, we found that MLT alleviates ATR-induced immune impairment in splenic macrophages via regulating Parkin-TLR4-NLRP3 axis which elucidates the effect of melatonin on the spleen and provides a novel perspective on melatonin in splenic inflammatory injury treatment.
    Keywords:  Atrazine; Parkin; melatonin; mitophagy; spleen injury
    DOI:  https://doi.org/10.1111/jpi.70014
  20. Theranostics. 2024 ;14(19): 7292-7308
    Circular RNA SCMH1 suppresses KMO expression to inhibit mitophagy and promote functional recovery following stroke.
    Yu Wang, Ying Bai, Yang Cai, Yuan Zhang, Ling Shen, Wen Xi, Zhongqiu Zhou, Lian Xu, Xue Liu, Bing Han, Honghong Yao.
      Rationale: Metabolic dysfunction is one of the key pathological events after ischemic stroke. Disruption of cerebral blood flow impairs oxygen and energy substrate delivery, leading to mitochondrial oxidative phosphorylation dysfunction and cellular bioenergetic stress. Investigating the effects of circSCMH1, a brain repair-related circular RNA, on metabolism may identify novel therapeutic targets for stroke treatment. Methods: CircSCMH1 was encapsulated into brain-targeting extracellular vesicles (EVs) mediated by rabies virus glycoprotein (RVG). Using a mouse model of photothrombotic (PT) stroke, we employed metabolomics and transcriptomics, combined with western blotting and behavioral experiments, to identify the metabolic targets regulated in RVG-circSCMH1-EV-treated mice. Additionally, immunofluorescence staining, chromatin immunoprecipitation (ChIP), pull-down, and western blotting were utilized to elucidate the underlying mechanisms. Results: The targeted delivery of circSCMH1 via RVG-EVs was found to promote post-stroke brain repair by enhancing mitochondrial fusion and inhibiting mitophagy through suppression of kynurenine 3-monooxygenase (KMO) expression. Mechanistically, circSCMH1 exerted its inhibitory effect on KMO expression by binding to the transcription activator STAT5B, thereby impeding its nuclear translocation. Conclusions: Our study reveals a novel mechanism by which circSCMH1 downregulates KMO expression, thereby enhancing mitochondrial fusion and inhibiting mitophagy, ultimately facilitating post-stroke brain repair. These findings shed new light on the role of circSCMH1 in promoting stroke recovery and underscore its potential as a therapeutic target for the treatment of ischemic stroke.
    Keywords:  KMO; STAT5B; circSCMH1; functional recovery; ischemic stroke
    DOI:  https://doi.org/10.7150/thno.99323
  21. Brain Commun. 2024 ;6(6): fcae404
    Opa1 and MT-Nd6 mutations induce early mitochondrial changes in the retina and prelaminar optic nerve of hereditary optic neuropathy mouse models.
    Jacques Bureau, Florence Manero, Olivier Baris, Alexia Bodin, Christophe Verny, Arnaud Chevrollier, Guy Lenaers, Philippe Codron.
      Hereditary optic neuropathies, including dominant optic atrophy and Leber's hereditary optic neuropathy, are genetic disorders characterized by retinal ganglion cell degeneration leading to vision loss, mainly associated with mitochondrial dysfunction. In this study, we analysed mitochondrial distribution and ultrastructure in the retina and longitudinal optic nerve sections of pre-symptomatic hereditary optic neuropathies mouse models with Opa1 and Nd6 deficiency to identify early mitochondrial changes. Our results show significant mitochondrial fragmentation and increased mitophagy in Opa1+/- mice, indicating early mitochondrial changes prior to neuronal loss. Conversely, Nd6P25L mice exhibited mitochondrial hypertrophy, suggesting an adaptive response to compensate for altered energy metabolism. These pre-symptomatic mitochondrial changes were mainly observed in the unmyelinated portion of the retinal ganglion cell axons, where the transmission of the visual information requires high energy expenditure, constituting the specific point of vulnerability in hereditary optic neuropathies. These findings highlight early focal mitochondrial changes prior to neuronal loss in hereditary optic neuropathies and provide insight into pre-symptomatic therapeutic approaches.
    Keywords:  Leber hereditary optic neuropathy; Opa1; dominant optic atrophy; hereditary optic neuropathy; mitochondria
    DOI:  https://doi.org/10.1093/braincomms/fcae404
  22. Neurochem Int. 2024 Dec 07. pii: S0197-0186(24)00241-9. [Epub ahead of print]182 105914
    Hydrogen restores central tryptophan and metabolite levels and maintains mitochondrial homeostasis to protect rats from chronic mild unpredictable stress damage.
    Jiaxin Li, Gaimei Hao, Yupeng Yan, Ming Li, Gaifen Li, Zhengmin Lu, Zhibo Sun, Yanjing Chen, Haixia Liu, Yukun Zhao, Meng Wu, Xiangxin Bao, Yong Wang, Yubo Li.
       BACKGROUND AND PURPOSE: The field of hydrogen medicine has garnered extensive attention since Professor Ohsawa established that low concentrations of hydrogen (2%-4%) exert antioxidant effects. The present study aimed to evaluate the therapeutic effect of molecular hydrogen in a CUMS rat model.
    METHODS: A total of 40 SD rats were randomly divided into a control group, a model group, a hydrogen group, and a positive drug group. Four weeks post-modeling, hydrogen inhalation and other treatments were administered. Behavioral, biochemical, and immunohistochemical evaluations were performed after treatment.
    RESULTS: Hydrogen inhalation alleviated depressive behavior and hippocampal neuronal damage in CUMS rats, as well as restored the levels of neurotransmitters, inflammatory factors, and oxidative stress. Moreover, it maintained mitochondrial homeostasis and up-regulated the expression of PGC-1α, PINK1, and Parkin.
    CONCLUSIONS: The results collectively indicated that hydrogen significantly attenuated CUMS-induced depressive-like behavior and monoamine neurotransmitter deficiency, as well as protected the brain from oxidative stress and inflammatory damage and effectively preserved mitochondrial homeostasis.
    Keywords:  Chronic mild unpredictable stress; Depression; Hydrogen; Mitochondrial autophagy; Mitochondrial biogenesis
    DOI:  https://doi.org/10.1016/j.neuint.2024.105914
  23. Free Radic Biol Med. 2024 Dec 07. pii: S0891-5849(24)01131-6. [Epub ahead of print]227 420-433
    Nepetin limits NLRP3 inflammasome activation and alleviates NLRP3-driven inflammatory diseases via PINK1-dependent mitophagy.
    Wen-Jie Bu, Si-Si Li, Chang Liu, Yue-Hua Wang, Jian-Rong Lu, Chao-Run Dong, Dong-Jie Zheng, Zhe-Yu Fan, Yi Yu, Wei Zhang, Yun-Long Bai.
      The NLRP3 inflammasome plays a pivotal role in the progression of inflammatory diseases. Mitochondrial damage, oxidative stress and mitochondrial DNA (mtDNA) leak are the key upstream factors for NLRP3 inflammasome activation. Nepetin (Nep), a naturally occurring flavonoid found with anti-inflammatory properties; however, whether it can affect the NLRP3 inflammasome activation and its precise anti-inflammatory mechanism remains unclear. In this study, we demonstrated that Nep enhances PINK1-mediated ubiquitin phosphorylation, which promotes mitophagy and subsequently inhibits NLRP3 inflammasome activation and pyroptosis in macrophages. The administration of Nep to macrophages alleviated of mitochondrial damage, reduced mitochondrial superoxide production, restored mitochondrial membrane potential and prevented the mtDNA leakage. These findings provide compelling evidence for the antioxidant effect of Nep. Furthermore, the pivotal function of mitophagy in the NLRP3 inflammasome inhibitory impact of Nep was substantiated through the utilisation of mitophagy inhibitors and siRNA techniques. Notably, Nep increased survival and reduced organ damage in mice with systemic inflammation by inhibiting NLRP3 inflammasome activation. In addition, Nep suppressed NLRP3 inflammasome activation in obese mice, which led to reduced white adipose and liver inflammation, thereby ameliorating insulin resistance. In conclusion, our findings suggest that Nep is a potent NLRP3 inflammasome inhibitor and a promising candidate for the development of anti-inflammatory therapies.
    Keywords:  IL-1β; Inflammatory disease; Mitophagy; NLRP3 inflammasome; Nepetin; PINK1
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.027
  24. Eur J Med Chem. 2024 Dec 07. pii: S0223-5234(24)01037-7. [Epub ahead of print]283 117155
    Hypoxia-selective prodrug restrains tumor cells through triggering mitophagy and inducing apoptosis.
    Fangjie Wang, Lairong Song, Qianqian Xu, Ang Jia, Xiangwei Meng, Hongfei Jiang, Renshuai Zhang.
      Hypoxia is a common feature of various solid tumors, which reduces the sensitivity of tumor cells to both radiotherapy and chemotherapy. However, hypoxia also presents an opportunity for tumor-selective therapy. The prodrug strategy, leveraging the hypoxic nature of the tumor microenvironment, shows significant potential for clinical application. Here we present CHD-1, a hypoxia-activated antitumor prodrug that activates in hypoxic environments, effectively inhibiting hypoxic tumor cells while exhibiting no toxicity to normoxic cells. CHD-1 impairs mitochondrial morphology and membrane potential of hypoxic tumor cells, further triggers excessive mitophagy and induces apoptosis. Moreover, prodrug CHD-1 significantly inhibits HeLa xenograft growth in vivo, and shows lower toxicity than parent molecule in an acute toxicity assessment in animal models. This study introduces a promising hypoxia-activated antitumor prodrug with strong potential for further development in hypoxic tumor therapy.
    Keywords:  Antitumor agents; Chalcone derivatives; Hypoxia; Mitophagy; Prodrugs; Safety profile
    DOI:  https://doi.org/10.1016/j.ejmech.2024.117155
  25. Exp Neurol. 2024 Dec 07. pii: S0014-4886(24)00424-2. [Epub ahead of print] 115098
    Mitigating mitochondrial dysfunction and neuroinflammation by hematoma aspiration in a new surgical model for severe intracerebral hemorrhage.
    Wei-Fen Hu, Chien-Hui Lee, Cheng-Yoong Pang, Hsin-Yi Huang, Sheng-Tzung Tsai, Po-Kai Wang, Mu-Ting Shih, Pei-Ying Cheah, Yi-Feng Wu, Andy Po-Yi Tsai, Kuan-Yin Tseng, Mikko Airavaara, Hock-Kean Liew.
       BACKGROUND: Intracerebral hemorrhage (ICH) is associated with a large hematoma that causes compression, increased intracranial pressure (IICP), midline shift, and brain herniation, and may ultimately lead to death. Urgent surgical removal of the large hematoma can ameliorate these injuries, which would be life-saving, but has not improved clinical outcome. A suitable animal model that mimics the clinically relevant human severe ICH injury requiring surgical hematoma evacuation is urgently needed. Here, we established a novel model of severe ICH in rats allowing aspiration of the hematoma and studying the effects of mitochondrial dysfunction in ICH.
    METHODS: Severe ICH was induced by intra-striatal injection of 0.6 U of collagenase in 3 μl sterile saline over 15 min. Aspiration of approximately 75 % of the total hematoma was performed 6 h after induction of severe ICH. The effects of hematoma aspiration on hematoma volume, mortality, oxidative stress, ATP levels, mitochondrial dysfunction, and neurological function were measured in rats.
    RESULTS: Severe ICH induction increased hematoma volume, neurological deficits, and mortality. Hematoma aspiration abolished mortality and significantly reduced hematoma volume, and neurological deficits. In addition, hematoma aspiration ameliorated the pronounced mitochondrial dysfunction responsible for the failure of energy production and excessive oxidative stress associated with severe hemorrhagic injury. Hematoma aspiration also modulated mitochondrial biogenesis and mitophagy, thereby promoting mitochondrial homeostasis. Markers of neuroinflammation, including iNOS, MMP9, and MPO, were elevated in severe ICH but attenuated by hematoma aspiration.
    CONCLUSION: This study established an animal model of severe ICH and provides valuable insights into the complex pathogenesis of severe ICH. The results showed that hematoma aspiration effectively ameliorates mitochondrial dysfunction, oxidative stress, and neuroinflammation, highlighting its potential as a therapeutic intervention.
    Keywords:  Animal model; Hematoma aspiration; Hemorrhagic stroke; Mitochondrial dysfunction; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.expneurol.2024.115098
  26. Exp Mol Med. 2024 Dec 06.
    GRIM-19-mediated induction of mitochondrial STAT3 alleviates systemic sclerosis by inhibiting fibrosis and Th2/Th17 cells.
    Ha Yeon Jeong, Jin-Sil Park, Jeong Won Choi, Kun Hee Lee, Seung Cheon Yang, Hye Yeon Kang, Sang Hee Cho, Seon-Yeong Lee, A Ram Lee, Youngjae Park, Sung-Hwan Park, Mi-La Cho.
      The gene associated with the retinoid-IFN-induced mortality-19 (GRIM-19) protein is a regulator of a cell death regulatory protein that inhibits STAT3, which is a critical transcription factor for interleukin (IL)-17-producing T (Th17) cells and a key integrator of extracellular matrix accumulation in systemic sclerosis (SSc). This protein is also a component of mitochondrial complex I, where it directly binds to STAT3 and recruits STAT3 to the mitochondria via the mitochondrial importer Tom20. In this study, the role of GRIM19 and its relationship with STAT3 in SSc development was investigated using a murine model of SSc. We observed a decrease in the level of GRIM-19 in the lesional skin of mice with bleomycin-induced SSc, which was negatively correlated with the level of STAT3. Overexpression of GRIM-19 reduced dermal thickness and fibrosis and the frequency of Th2 and Th17 cells in SSc mice. Mitophagic dysfunction promoted fibrosis in mice lacking PINK1, which is a mitophagy inducer. In an in vitro system, the overexpression of GRIM-19 increased the level of mitochondrial STAT3 (mitoSTAT3), induced mitophagy, and alleviated fibrosis progression. MitoSTAT3 overexpression hindered the development of bleomycin-induced SSc by reducing fibrosis. These results suggest that GRIM-19 is an effective therapeutic target for alleviating the development of SSc by increasing mitophagy.
    DOI:  https://doi.org/10.1038/s12276-024-01366-0
  27. Neural Regen Res. 2024 Dec 07.
    Role of mitophagy in spinal cord ischemia-reperfusion injury.
    Yanni Duan, Fengguang Yang, Yibao Zhang, Mingtao Zhang, Yujun Shi, Yun Lang, Hongli Sun, Xin Wang, Hongyun Jin, Xuewen Kang.
      Spinal cord ischemia-reperfusion injury, a severe form of spinal cord damage, can lead to sensory and motor dysfunction. This injury often occurs after traumatic events, spinal cord surgeries, or thoracoabdominal aortic surgeries. The unpredictable nature of this condition, combined with limited treatment options, poses a significant burden on patients, their families, and society. Spinal cord ischemia-reperfusion injury leads to reduced neuronal regenerative capacity and complex pathological processes. In contrast, mitophagy is crucial for degrading damaged mitochondria, thereby supporting neuronal metabolism and energy supply. However, while moderate mitophagy can be beneficial in the context of spinal cord ischemia-reperfusion injury, excessive mitophagy may be detrimental. Therefore, this review aims to investigate the potential mechanisms and regulators of mitophagy involved in the pathological processes of spinal cord ischemia-reperfusion injury. The goal is to provide a comprehensive understanding of recent advancements in mitophagy related to spinal cord ischemia-reperfusion injury and clarify its potential clinical applications.
    DOI:  https://doi.org/10.4103/NRR.NRR-D-24-00668
  28. Cancer Sci. 2024 Dec 09.
    BCR::ABL1-induced mitochondrial morphological alterations as a potential clinical biomarker in chronic myeloid leukemia.
    Kohjin Suzuki, Naoki Watanabe, Satoru Torii, Satoko Arakawa, Kiyosumi Ochi, Shun Tsuchiya, Kazuhiro Yamada, Yoko Kawamura, Sadao Ota, Norio Komatsu, Shigeomi Shimizu, Miki Ando, Tomoiku Takaku.
      The BCR::ABL1 oncogene plays a crucial role in the development of chronic myeloid leukemia (CML). Previous studies have investigated the involvement of mitochondrial dynamics in various cancers, revealing potential therapeutic strategies. However, the impact of BCR::ABL1 on mitochondrial dynamics remains unclear. In this study, we demonstrated that BCR::ABL1 is sufficient to induce excessive mitochondrial fragmentation by activating dynamin-related protein (DRP)1 through the mitogen-activated protein kinase (MAPK) pathway. Leukocytes obtained from patients with CML and the BCR::ABL1-positive cell lines exhibited increased mitochondrial fragmentation compared to leukocytes obtained from healthy donors and BCR::ABL1-negative cells. Furthermore, the analysis of BCR::ABL1-transduced cells showed increased phosphorylation of DRP1 at serine 616 and extracellular signal-regulated kinase (ERK) 1/2. Moreover, the inhibition of DRP1 and upstream mitogen-activated extracellular signal-regulated kinase (MEK) 1/2 suppressed mitochondrial fragmentation. Strikingly, DRP1 inhibition effectively reduced the viability of BCR::ABL1-positive cells and induced necrotic cell death. Additionally, a label-free artificial intelligence-driven flow cytometry successfully identified not only the BCR::ABL1-transduced cells but also peripheral leukocytes from CML patients by assessing mitochondrial morphological alterations. These findings suggested the crucial role of BCR::ABL1-induced mitochondrial fragmentation in driving BCR::ABL1-positive cell proliferation, and the potential use of mitochondrial morphological alterations as a clinical biomarker for the label-free detection of CML cells.
    Keywords:  BCR::ABL1; artificial intelligence; chronic myeloid leukemia; ghost cytometry; mitochondria
    DOI:  https://doi.org/10.1111/cas.16424
  29. Cell Mol Life Sci. 2024 Dec 07. 81(1): 483
    Epigenetic regulation of mitochondrial fission and cardiac fibrosis via sFRP3 promoter methylation.
    Shun-Xiang Jiang, Ze-Yu Zhou, Bin Tu, Kai Song, Li-Chan Lin, Zhi-Yan Liu, Wei Cao, Jian-Yuan Zhao, Hui Tao.
      In the process of cardiac fibrosis, the balance between the Wnt/β-catenin signalling pathway and Wnt inhibitory factor genes plays an important role. Secreted frizzled-related protein 3 (sFRP3), a Wnt inhibitory factor, has been linked to epigenetic mechanisms. However, the underlying role of epigenetic regulation of sFRP3, which is crucial in fibroblast proliferation and migration, in cardiac fibrosis have not been elucidated. Therefore, we aimed to investigate epigenetic and transcription of sFRP3 in cardiac fibrosis. Using clinical samples and animal models, we investigated the role of sFRP3 promoter methylation in potentially enhancing cardiac fibrosis. We also attempted to characterize the underlying mechanisms using an isoprenaline-induced cardiac fibrosis mouse model and cultured primary cardiac fibroblasts. Hypermethylation of sFRP3 was associated with perpetuation of fibroblast activation and cardiac fibrosis. Additionally, mitochondrial fission, regulated by the Drp1 protein, was found to be significantly altered in fibrotic hearts, contributing to fibroblast proliferation and cardiac fibrosis. Epigenetic modification of sFRP3 promoter methylation also influenced mitochondrial dynamics, linking sFRP3 repression to excessive mitochondrial fission. Moreover, sFRP3 hypermethylation was mediated by DNA methyltransferase 3A (DNMT3A) in cardiac fibrosis and fibroblasts, and DNMT3A knockdown demethylated the sFRP3 promoter, rescued sFRP3 loss, and ameliorated the isoprenaline-induced cardiac fibrosis and cardiac fibroblast proliferation, migration and mitochondrial fission. Mechanistically, DNMT3A was shown to epigenetically repress sFRP3 expression via promoter methylation. We describe a novel epigenetic mechanism wherein DNMT3A represses sFRP3 through promoter methylation, which is a critical mediator of cardiac fibrosis and mitochondrial fission. Our findings provide new insights for the development of preventive measures for cardiac fibrosis.
    Keywords:  Cardiac fibroblast; Cardiac fibrosis; DNMT3A; Migration; Mitochondrial fission; Proliferation; SFRP3
    DOI:  https://doi.org/10.1007/s00018-024-05516-5
  30. J Virol. 2024 Dec 10. e0130124
    The segmented flavivirus Alongshan virus reduces mitochondrial mass by degrading STAT2 to suppress the innate immune response.
    Yinghua Zhao, Liyan Sui, Mingming Pan, Fangyu Jin, Yuan Huang, Shu Fang, Mengmeng Wang, Lihe Che, Wenbo Xu, Nan Liu, Haicheng Gao, Zhijun Hou, Fang Du, Zhengkai Wei, Lesley Bell-Sakyi, Jixue Zhao, Kaiyu Zhang, Yicheng Zhao, Quan Liu.
      Alongshan virus (ALSV) is a newly discovered pathogen in the Flaviviridae family, characterized by a unique multi-segmented genome that is distantly related to the canonical flaviviruses. Understanding the pathogenic mechanism of this emerging segmented flavivirus is crucial for the development of effective intervention strategies. In this study, we demonstrate that ALSV can infect various mammalian cells and induce the expression of antiviral genes. Furthermore, ALSV is sensitive to IFN-β, but it has developed strategies to counteract the host's type I IFN response. Mechanistically, ALSV's nonstructural protein NSP1 interacts with and degrades human STAT2 through an autophagy pathway, with species-dependent effects. This degradation directly inhibits the expression of interferon-stimulated genes (ISGs). Additionally, NSP1-mediated degradation of STAT2 disrupts mitochondrial dynamics, leading to mitophagy and inhibition of mitochondrial biogenesis. This, in turn, suppresses the host's innate immune response. Interestingly, we found that inhibiting mitophagy using 3-methyladenine and enhancing mitochondrial biogenesis with the PPARγ agonist pioglitazone can reverse NSP1-mediated inhibition of ISGs, suggesting that promoting mitochondrial mass could serve as an effective antiviral strategy. Specifically, the NSP1 methyltransferase domain binds to the key sites of F175/R176 located in the coiled-coil domain of STAT2. Our findings provide valuable insights into the intricate regulatory cross talk between ALSV and the host's innate immune response, shedding light on the pathogenesis of this emerging segmented flavivirus and offering potential intervention strategies.IMPORTANCEAlongshan virus (ALSV), a segmented flavivirus belonging to the Flaviviridae family, was first identified in individuals who had been bitten by ticks in Northeastern China. ALSV infection is responsible for causing Alongshan fever, a condition characterized by various clinical symptoms, including fever, headache, skin rash, myalgia, arthralgia, depression, and coma. There is an urgent need for effective antiviral therapies. Here, we demonstrate that ALSV is susceptible to IFN-β but has developed mechanisms to counteract the host's innate immune response. Specifically, the ALSV nonstructural protein NSP1 interacts with STAT2, leading to its degradation via an autophagy pathway that exhibits species-dependent effects. Additionally, NSP1 disrupts mitochondrial dynamics and suppresses mitochondrial biogenesis, resulting in a reduction in mitochondrial mass, which ultimately contributes to the inhibition of the host's innate immune response. Interestingly, we found that inhibiting mitophagy and promoting mitochondrial biogenesis can reverse NSP1-mediated suppression of innate immune response by increasing mitochondrial mass. These findings provide valuable insights into the molecular mechanisms of ALSV pathogenesis and suggest potential therapeutic targets against ALSV infection.
    Keywords:  Alongshan virus; NSP1; STAT2; innate immune response; mitochondrial mass; segmented flavivirus
    DOI:  https://doi.org/10.1128/jvi.01301-24
  31. bioRxiv. 2024 Nov 26. pii: 2024.11.24.625107. [Epub ahead of print]
    Autophagy inhibition induces AML cell death and enhances the efficacy of chemotherapy under hypoxia.
    Eunice S Wang, Hannah R S Fay, Kaitlyn M Dykstra, Michael N Phelps, Matthew Johnson, Annemarie Harrigan, Marianna C Giorgi.
      Outcomes of relapsed/refractory acute myeloid leukemia (AML) are poor, and strategies to improve outcomes are urgently needed. One important factor promoting relapse and chemoresistance is the ability of AML cells to thrive in vivo within an intrinsically hypoxic bone marrow microenvironment. Here we show that human AML cells exhibit enhanced autophagy, specifically mitophagy (i.e., increased accumulation of mitochondria and decreased mitochondrial membrane potential) under hypoxia. To target this pathway, we investigated the activity of the potent chloroquine-derived autophagy inhibitor, Lys05, on human AML cells, patient samples, and patient derived xenograft models. Inhibition of autophagy by Lys05 in AML cells prevented removal of damaged mitochondria and preferentially enhanced cell death under hypoxia mirroring the marrow microenvironment. Lys05 eradicated human AML cells of all genotypes including p53 mutant cells. Lys05 treatment in primary AML xenografted mice decreased CD34+CD38- human cells and prolonged overall survival. Moreover, Lys05 overcame hypoxia-induced chemoresistance and improved the efficacy of cytarabine, venetoclax, and azacytidine in vitro and in vivo in AML models. Our results demonstrate the importance of autophagy, specifically mitophagy, as a critical survival and chemoresistance mechanism of AML cells under hypoxic marrow conditions. Therapeutic targeting of this pathway in future clinical studies for AML is warranted.
    DOI:  https://doi.org/10.1101/2024.11.24.625107
  32. Proc Biol Sci. 2024 Dec;291(2036): 20242409
    Mitochondrial remodelling supports migration in white-crowned sparrows (Zonotrichia leucophrys).
    Paulo H C Mesquita, Emma M Rhodes, Kang Nian Yap, Breanna J Mueller, Geoffrey E Hill, Wendy R Hood, Andreas N Kavazis.
      The migratory movements undertaken by birds are among the most energetically demanding behaviours observed in nature. Mitochondria are the source of aerobic energy production on which migration depends, but a key component of mitochondrial function, mitochondrial remodelling, has not been investigated in the context of bird migration. We measured markers of mitochondrial remodelling in the skeletal muscles of the Gambel's (migratory) and Nuttall's (non-migratory) white-crowned sparrows within and outside migratory periods. Gambel's were collected in (i) a non-migration period (baseline), (ii) preparation to depart for spring migration (pre-migration) and (iii) active autumn migration (mid-migration). Nuttall's were collected at timepoints corresponding to baseline and mid-migration in Gambel's. Across all sampling periods, we found that migratory birds had greater mitochondrial remodelling compared with non-migratory birds. Furthermore, birds from the migratory population also displayed flexibility, increasing several markers of mitochondrial remodelling (e.g. NRF1, OPA1 and Drp1) pre- and during migration. Further, the greater levels of mitochondrial remodelling and its upregulation during migration were specific to the pectoralis muscle used in flapping flight. Our study is the first to show that mitochondrial remodelling supports migration in Gambel's white-crowned sparrows, indicating a highly specific and efficient phenotype supporting the increased energetic demands of migration.
    Keywords:  bird migration; mitochondrial dynamics; mitochondrial fusion; mitochondrial physiology; skeletal muscle
    DOI:  https://doi.org/10.1098/rspb.2024.2409
  33. Biomed Pharmacother. 2024 12 09. pii: S0753-3322(24)01582-8. [Epub ahead of print] 117696
    Retraction notice to "Sirt3-mediated mitochondrial fission regulates the colorectal cancer stress response by modulating the Akt/PTEN signalling pathway" [Biomed. Pharmacother. 105 (2018) 1172-1182].
    Yan Wang, Xiaohui Sun, Kaihua Ji, Liqing Du, Chang Xu, Ningning He, Jinhan Wang, Yang Liu, Qiang Liu.
      
    DOI:  https://doi.org/10.1016/j.biopha.2024.117696
  34. J Adv Res. 2024 Dec 06. pii: S2090-1232(24)00559-9. [Epub ahead of print]
    Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer.
    Zhi Xiong, Rui-Lin Zhuang, Shun-Li Yu, Zhao-Xiang Xie, Shi-Rong Peng, Ze-An Li, Bing-Heng Li, Jun-Jia Xie, Yi-Ning Li, Kai-Wen Li, Hai Huang.
       INTRODUCTION: Cancer-associated fibroblasts (CAFs) are a critical component of the tumor microenvironment, being implicated in enhancing tumor growth and fostering drug resistance. Nonetheless, the mechanisms underlying their function in prostate cancer (PCa) remain incompletely understood, which is essential for devising effective therapeutic strategies.
    OBJECTIVES: The main objective of this study was to explore the mechanisms by which CAFs mediate PCa growth and chemoresistance.
    METHODS: We validated through data analysis and experimentation that CAFs significantly impact PCa cell proliferation and chemoresistance. Subsequently, we conducted a comprehensive proteomic analysis of the conditioned media from CAFs and PCa cells and identified angiopoietin-like protein 4 (ANGPTL4) as a key factor. We employed ELISA and multiplex immunofluorescence assays, all of which indicated that ANGPTL4 was primarily secreted by CAFs.Next, we conducted metabolomics analysis, GST pull-down assays, Co-IP, and other experiments to explore the specific molecular mechanisms of ANGPTL4 and its precise effects on PCa cells. Through drug screening, we identified Quercetin 3-O-(6'-galactopyranosyl)-β-D-galactopyranoside (QGGP) as an effective inhibitor of CAFs function. Finally, we thoroughly assessed the therapeutic potential of QGGP both as a monotherapy and in combination with docetaxel in PCa cells RESULTS: We discovered that the extracrine factor ANGPTL4 is primarily expressed in CAFs in PCa. When ANGPTL4 binds to IQ motif-containing GTPase-activating protein 1 (IQGAP1) on the PCa cell membrane, it activates the Raf-MEK-ERK-PGC1α axis, promoting mitochondrial biogenesis and OXPHOS metabolism, and thereby facilitating PCa growth and chemoresistance. Furthermore, virtual and functional screening strategies identified QGGP as a specific inhibitor of IQGAP1 that promotes its degradation. Combined with docetaxel treatment, QGGP can reverse the effects of CAFs and improve the responsiveness of PCa to chemotherapy.
    CONCLUSIONS: This study uncovers a paracrine mechanism of chemoresistance in PCa and proposes that targeting the stroma could be a therapeutic choice.
    Keywords:  ANGPTL4; Cancer-associated fibroblasts; Chemosensitivity; Mitochondria; Prostate cancer
    DOI:  https://doi.org/10.1016/j.jare.2024.12.003
  35. Poult Sci. 2024 Dec 01. pii: S0032-5791(24)01195-7. [Epub ahead of print]104(1): 104617
    PGC-1α Promotes mitochondrial biosynthesis and energy metabolism of goose fatty liver.
    Jiahui Li, Mengqing Lv, Zijin Yuan, Jing Ge, Tuoyu Geng, Daoqing Gong, Minmeng Zhao.
      To investigate the functions of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the goose fatty liver, a total of 30 healthy 63-day-old male Landes geese were selected and randomly assigned to control group and overfeeding group. The overexpression or RNA interference assay of PGC-1α was performed in goose primary hepatocytes. Our data showed that the PGC-1α expression was increased in fatty liver. The abundance of mitochondrial biosynthesis-related and energy metabolism-related genes, including mitochondrial transcription factor A (TFAM), mitochondrial transcription factor B1 (TFB1M), mitochondrial transcription factor B2 (TFB2M), nuclear respiratory factor 1 (NRF1), DNA topoisomerase I mitochondrial (TOP1MT), peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC-1β), sirtuin 3 (SIRT3), mitochondrially encoded cytochrome B (CYTB), and AMP-activated protein kinase alpha (AMPKα) were significantly increased in fatty liver. The abundance of TFAM, TFB1M, TFB2M, NRF1, and TOP1MT transcript was induced by PGC-1α overexpression, but inhibited by PGC-1α interference in primary hepatocytes. The mRNA expression levels of PGC-1β, SIRT3, SIRT5, CYTB, and AMPKα were significantly enhanced after PGC-1α overexpression. However, the mRNA expression levels of PGC-1β, SIRT5 and AMPKα were decreased after PGC-1α interference. Furthermore, we observed a significant increase in the mitochondrial DNA (mtDNA) copy number, the activity of mitochondrial respiratory chain complex Ⅳ (MRCC Ⅳ), succinate dehydrogenase (SDH), malate dehydrogenase (MDH), and the NAD+/NADH ratio in fatty liver. But the activity of MRCC Ⅴ, as well as the levels of ADP and ATP in fatty liver were reduced. Additionally, the mtDNA copy number, the activity of MRCC Ⅰ, MRCC Ⅲ-Ⅴ, SDH, and MDH, and NAD+/NADH ratio were enhanced by PGC-1α overexpression; Whereas the mtDNA copy number, the activity of MRCC Ⅰ, SDH, and MDH, and the ratio of NAD+/NADH were inhibited by PGC-1α interference. In conclusion, these findings suggest that PGC-1α improves mitochondrial biosynthesis and energy metabolism in goose fatty liver, which may be an adaptive mechanism for goose fatty liver to cope with steatosis.
    Keywords:  Energy metabolism; Goose fatty liver; Mitochondria; Mitochondrial biosynthesis; PGC-1α
    DOI:  https://doi.org/10.1016/j.psj.2024.104617
  36. Ecotoxicol Environ Saf. 2024 Dec 06. pii: S0147-6513(24)01560-4. [Epub ahead of print]289 117484
    Carvacrol acetate activated Nrf2 modulates mitophagy for the treatment of neurocyte oxidative stress induced by chlorpyrifos.
    Hong-Ling Zhou, Bei-Bei Wang, Xu-Li Fan, Xiao-Min Zhang, Ying Song.
      This study explored the protective effect and potential mechanism of carvacrol acetate (CAA) on the oxidation of chlorpyrifos (CPF). A model of oxidative stimulus damage was established in Sprague-Dawley rats by subcutaneous injection of the CPF poison. PC12 cells were used to construct an oxidative injury model using CPF, and the protective effects and mechanism of action of CAA against CPF-induced oxidative damage were explored in vitro. The key role of Nuclear factor erythroid-2-related factor 2 (Nrf2) in alleviating CPF-induced damage via CAA was further confirmed by administering Nrf2 inhibitors to PC12 cells. Administration of CAA significantly enhanced the locomotor ability of the rats, alleviated neuronal pathological alterations, and increased the number of Nissl bodies, while increasing autophagic bodies. In vitro, CAA promoted cell survival and augmented the mitochondrial membrane potential. It decreased both intra- and extracellular levels of reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase (SOD), while markedly elevating mitochondrial DNA (mtDNA) copy number. Moreover, PC12 cells treated with Nrf2 inhibitors failed to exhibit any improvement in survival rate when treated with CAA after a toxic insult. Furthermore, ROS and MDA levels were not significantly reduced, SOD enzyme activity did not increase, and mitochondrial membrane potential and mtDNA copy number did not improve. Western blot analysis showed that the expression of Tfam, Beclin1, and LC3II/LC3I proteins in the CAA group decreased significantly after Nrf2 inhibition. These findings suggest that CAA modulates mitochondrial function and autophagy by regulating the Nrf2 signalling pathway to mitigate the toxic damage. Finally, the effect of the autophagy inhibitor, 3-MA, on PC12 cells suggests that CAA promotes mitophagy by participating in the Nrf2 pathway, thereby preventing CPF-induced oxidative stress damage.
    Keywords:  Carvacrol acetate; Chlorpyrifos; Mitophagy; Nrf2; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117484
  37. Appl Biochem Biotechnol. 2024 Dec 12.
    MARCH5 Promotes the Progression of Thyroid cancer by Regulating Mitochondrial Autophagy Protein FUNDC1-mediated Pyroptosis.
    Haili Tang, Jiangang Wang, Guoxiong Ji, Xiaojun Yang, Huan Yang, Xin Chen, Xiaozhou Yang, Huadong Zhao, Xianli He.
      MARCH5 is a key regulatory factor in mitochondria. However, the expression and function of MARCH5 in thyroid cancer (TC) are not yet clear. The research explores the role and the potential mechanism of MARCH5 in the tumorigenesis of TC. MARCH5 expression were measured by qRT-PCR and Western blot. CCK-8 kits were used to measure the cell viability. Cell scratch assay and Tanswell assay were used to measure cell migration and invasion, respectively. The pyroptosis related proteins (NLRP3, caspase-1, GSDMD) and mitochondrial autophagy related proteins (LC3-II, p62, parkin, pink1) were detected. The mitochondrial ROS GSH, MDA, and SOD were detected using commercial kits. Finally, a TC mouse model was constructed to detect the role of MARCH5 in tumor growth in vivo. The results displayed that the expression of MARCH5 was increased in TC patients and cells, and was significantly correlated with prognosis. Functional studies have found that MARCH5 inhibits oxidative stress levels and mitochondrial autophagy in TPC-1 cells. Further research has found that MARCH5 promotes the progression of thyroid cancer by degrading FUNDC1 and inhibiting the mitochondrial autophagy mediated pyroptosis pathway, regulating cell proliferation, migration, and invasion in TPC-1 cells. More importantly, interference with MARCH5 inhibits tumor growth and further development of TC in vivo. In conclusion, MARCH5 promotes the progression of thyroid cancer by degrading FUNDC1 and inhibiting the mitochondrial autophagy mediated pyroptosis, regulating cell proliferation, migration, and invasion. This study provides new theoretical basis for the treatment and prevention of TC in clinical practice.
    Keywords:  FUNDC1; MARCH5; Mitochondrial dysfunction; Pyroptosis; Thyroid cancer
    DOI:  https://doi.org/10.1007/s12010-024-05113-z
  38. Animal Model Exp Med. 2024 Dec 12.
    Deficiency of DEK proto-oncogene alleviates allergic rhinitis by inhibiting RhoA/Ezrin-mediated mitochondrial fission.
    Longzhu Dai, Yongde Jin, Jingmei Chai, Jianing Yang, Jiangang Wang, Mu Chen, Liangchang Li, Chongyang Wang, Guanghai Yan.
       BACKGROUND: Allergic rhinitis (AR) is a kind of immune disease mediated by IgE. We are intrigued by the potential role of DEK proto-oncogene (DEK) in inflammation-related diseases. We investigated the effects and mechanisms of DEK in treating AR, aiming to identify potential new treatment targets for AR.
    METHODS: The AR mouse model was induced by house dust mite (HDM) (1 mg/mL). HNEpCs stimulated by HDM (1 mg/mL) were pretreated for 24 h with or without DEK lentivirus. The effect of DEK knockout or knockdown on AR was evaluated in vitro and in vivo using western blotting, ELISA, flow cytometry, real-time quantitative PCR, immunohistochemistry, HE staining, PAS staining, Diff staining, and immunofluorescence.
    RESULTS: After DEK knockdown, the inflammatory response of AR mice was reduced. In addition, DEK deletion mitigated nasal tissue damage and mitochondrial division. Our further studies showed that DEK deletion or inhibition led to the down-regulation of RhoA activity and decreased phosphorylation of Ezrin and Drp1 proteins, and inhibited mitochondrial division. Overall, DEK deficiency mitigated AR by down-regulating RhoA/Ezrin/Drp1 pathway activity.
    CONCLUSION: DEK alleviates AR through RhoA/Ezrin/Drp1 signaling pathway, which provides a new perspective for developing improved therapies and understanding the pathogenesis of AR.
    Keywords:  DEK; Ezrin; allergic rhinitis; house dust mite; mitochondria
    DOI:  https://doi.org/10.1002/ame2.12523
  39. Comp Biochem Physiol A Mol Integr Physiol. 2024 Dec 09. pii: S1095-6433(24)00217-4. [Epub ahead of print]300 111790
    Modulation of mitochondrial dynamics genes and mtDNA during embryonic development and under UVB exposure.
    Thaline de Quadros, Michael Lorenz Jaramillo, Cairé Barreto, Rafael Diego da Rosa, Madson Silveira de Melo, Evelise Maria Nazari.
      Studies using the embryos of the freshwater prawn Macrobrachium olfersii have reported changes in embryonic cells after exposure to ultraviolet B (UVB) radiation, such as DNA damage and apoptosis activation. Considering the importance of mitochondria in embryonic cells, this study aimed to characterize the aspects of mitochondrial morphofunctionality in M. olfersii embryos and mitochondrial responses to UVB radiation exposure. The coding sequences of genes Tfam, Nrf1, Mfn1, and Drp1 were identified from the transcriptome of M. olfersii embryos. The phylogenetic relationship showed strong amino acid identity and a highly conserved nature of the sequences. Additionally, the number of mitochondrial DNA (mtDNA) copies were higher in the early embryonic days. The results showed that the expression of the analyzed genes was highly regulated during embryonic development, increasing their levels near hatching. Furthermore, when embryos were exposed to UVB radiation, mitochondrial biogenesis was activated, recognized by higher levels of transcripts of genes Tfam and Nrf1, accompanied by mitochondrial fission. Additionally, these mitochondrial events were supported by an increase of mtDNA copies. Our results showed that UVB radiation was able to change the mitochondrial morphofunctionality, and under the current knowledge, certainly compromise embryonic cellular integrity. Additionally, mitochondria is an important cellular target of this radiation and its responses can be used to assess environmental stress caused by UVB radiation in embryos of aquatic species.
    Keywords:  Bioinformatic tool; Embryo; Embryotoxicity; Fusion/fission mitochondrial; Macrobrachium prawn; Ultraviolet radiation
    DOI:  https://doi.org/10.1016/j.cbpa.2024.111790
  40. Int J Mol Med. 2025 Feb;pii: 26. [Epub ahead of print]55(2):
    Jinlida granules alleviate podocyte apoptosis and mitochondrial dysfunction via the AMPK/PGC‑1α pathway in diabetic nephropathy.
    Shengnan Sun, Shurong Yang, Ying Cheng, Ting Fang, Jingru Qu, Lei Tian, Man Zhang, Shi Wu, Bei Sun, Liming Chen.
      Traditional Chinese Medicine (TCM) has demonstrated promising efficacy in managing and preventing the early‑stage diabetic nephropathy (DN). Although the exact mechanisms remain elusive, clinical evidence has suggested that Jinlida granules (JLD) are beneficial in improving renal function among patients with DN. The present study aimed to elucidate the effect of JLD on DN and the underlying molecular mechanism. Therefore, podocyte apoptosis was evaluated using flow cytometry and TUNEL staining, while mitochondrial morphology and function were assessed using transmission electron microscopy, MitoTracker, JC‑1 and reactive oxygen species staining. RNA sequencing analysis was performed to elucidate the mechanism underlying the effect of JLD on DN. Additionally, to investigate the role of peroxisome proliferator‑activated receptor‑γ co‑activator‑1α (PGC‑1α) in mitigating JLD‑induced mitochondrial dysfunction and podocyte apoptosis, MPC5 cells were transfected with the corresponding small interfering RNA constructs. The results showed that JLD effectively improved renal function and mitigated podocyte injury, as well as ameliorated mitochondrial dysfunction and inhibited apoptosis in db/db mice. In vitro experiments further revealed that JLD exerted a protective effect via inhibiting mitochondrial fission and apoptosis in high glucose‑treated podocytes. Furthermore, JLD enhanced the phosphorylation of adenosine monophosphate‑activated protein kinase (AMPK), thus promoting the expression of PGC‑1α, eventually improving apoptosis and mitochondrial homeostasis. Overall, the current study revealed that JLD could improve mitochondrial homeostasis and reduce cell apoptosis in podocytes via activating the AMPK/PGC‑1α pathway, thus providing a theoretical foundation for the clinical management of DN.
    Keywords:  AMPK; DN; Jinlida granules; PGC‑1α; apoptosis; mitochondrial dysfunction
    DOI:  https://doi.org/10.3892/ijmm.2024.5467
  41. Circ Res. 2024 Dec 10.
    Endothelial FUNDC1 Deficiency Drives Pulmonary Hypertension.
    Yandong Pei, Dongfeng Ren, Yuanhao Yin, Jiajia Shi, Qianyuan Ai, Wenxin Hao, Xiaofan Luo, Chenyue Zhang, Yanping Zhao, Chenyu Bai, Lin Zhu, Qiong Wang, Shuangling Li, Yuwei Zhang, Jiangtao Lu, Lin Liu, Lin Zhou, Yuli Wu, Yiqi Weng, Yongle Jing, Chengzhi Lu, Yujie Cui, Hao Zheng, Yanjun Li, Guo Chen, Gang Hu, Quan Chen, Xudong Liao.
       BACKGROUND: Pulmonary hypertension (PH) is associated with endothelial dysfunction. However, the cause of endothelial dysfunction and its impact on PH remain incompletely understood. We aimed to investigate whether the hypoxia-inducible FUNDC1 (FUN14 domain-containing 1)-dependent mitophagy pathway underlies PH pathogenesis and progression.
    METHODS: We first analyzed FUNDC1 protein levels in lung samples from patients with PH and animal models. Using rodent PH models induced by HySu (hypoxia+SU5416) or chronic hypoxia, we further investigated PH pathogenesis and development in response to global and cell-type-specific Fundc1 loss/gain-of-function. We also investigated the spontaneous PH in mice with inducible loss of endothelial Fundc1. In addition, histological, metabolic, and transcriptomic studies were performed to delineate molecular mechanisms. Finally, findings were validated in vivo by compound deficiency of HIF2α (hypoxia-inducible factor 2α; Epas1) and pharmacological intervention.
    RESULTS: FUNDC1 protein levels were reduced in PH lung vessels from clinical subjects and animal models. Global Fundc1 deficiency exacerbated PH, while its overexpression is protective. The effect of FUNDC1 was mediated by endothelial cells rather than smooth muscle cells. Further, inducible loss of endothelial Fundc1 in postnatal mice was sufficient to cause PH spontaneously, whereas augmenting endothelial Fundc1 protected against PH before and after the onset of disease. Mechanistically, Fundc1 deficiency impaired basal mitophagy in endothelial cells, leading to the accumulation of dysfunctional mitochondria, metabolic reprogramming toward aerobic glycolysis, pseudohypoxia, and senescence, likely via a mtROS-HIF2α signaling pathway. Subsequently, Fundc1-deficient endothelial cells increased IGFBP2 (insulin-like growth factor-binding protein 2) secretion that drove pulmonary arterial remodeling to instigate PH. Finally, proof-of-principle in vivo studies showed significant efficacy on PH amelioration by targeting endothelial mitophagy, pseudohypoxia, senescence, or IGFBP2.
    CONCLUSIONS: Collectively, we show that FUNDC1-mediated basal mitophagy is critical for endothelial homeostasis, and its disruption instigates PH pathogenesis. Given that similar changes in FUNDC1 and IGFBP2 were observed in PH patients, our findings are of significant clinical relevance and provide novel therapeutic strategies for PH.
    Keywords:  endothelial cells; hypertension, pulmonary; hypoxia; insulin-like peptides; mitophagy
    DOI:  https://doi.org/10.1161/CIRCRESAHA.124.325156
  42. Neuroscience. 2024 Dec 04. pii: S0306-4522(24)00700-0. [Epub ahead of print]565 277-291
    Ergothioneine-rich Lentinula edodes mushroom extract restores mitochondrial functions in senescent HT22 cells.
    Yasaaswini Apparoo, Chia Wei Phan, Umah Rani Kuppusamy, Eric Chan Wei Chiang.
      A decline in mitochondrial functions associated with ageing is the key factor of free radical generation which contributes to age-related pathologies. Protecting healthy functional mitochondrial networks with antioxidants is critical in promoting healthy ageing. This study aimed to investigate the protective effect of ergothioneine (EGT)-rich Lentinula edodes extract (LE-ETH) against tert-butyl hydroperoxide (t-BHP) assaulted senescent HT22 cells. Mitochondrial function was evaluated by measuring mitochondrial membrane potential (MMP), ATP levels and mitochondrial toxicity. The protective mechanisms were elucidated via the exploration of antioxidant and mitochondrial biogenesis signalling pathways. Our results revealed that a low dose of t-BHP increases mitochondrial toxicity. The pretreatment with 100 µg/mL of LE-ETH and the equimolar concentration of EGT for 8 h significantly improve the mitochondrial function and reduced inflammation. Through gene expression studies, we demonstrated that pretreatment of LE-ETH significantly improves the antioxidant and mitochondrial biogenesis pathway via Nrf2 signaling axis. However, the downstream genes of the mitochondrial biogenesis pathway were unaffected by equimolar EGT concentration. Gas chromatography-mass spectrum (GC-MS) analysis was carried out to identify the bioactive compounds that are present in LE-ETH extract which contributed to its efficacy in improving the mitochondrial functions. A total of 23 compounds consisting of phenols, fatty acids, and sterols were identified in the ethanolic extract. Pentanoic acid was the major compound identified in LE-ETH. These findings demonstrated that EGT-rich L.edodes mushroom is a potential neuroprotective agent which could serve as a potential therapeutic strategy for the preservation of mitochondrial functions in healthy ageing explorations.
    Keywords:  Antioxidant; Ergothioneine; Healthy ageing; Medicinal mushroom; Mitochondrial
    DOI:  https://doi.org/10.1016/j.neuroscience.2024.11.082
  43. Adv Mater. 2024 Dec 11. e2413371
    Functionalized Nanozyme Microcapsules Targeting Deafness Prevention via Mitochondrial Homeostasis Remodeling.
    Shengjie Ge, Aidong Sun, Xinyu Zhou, Ping Niu, Yong Chen, Xiaotao Bao, Meng Yu, Zhenhua Zhong, Jingwu Sun, Guang Li.
      Mitochondrial dysfunction, which is the primary mechanism underlying cisplatin-induced hearing loss, can potentially be mitigated by modulating the redox balance and reprogramming the energy metabolism to remodel mitochondrial homeostasis. Herein, N-acetyl-l-cysteine-derived carbonized polymer dots (NAC CPDs) are embedded into manganese porphyrin-doped metal-organic frameworks and encapsulated using a polydopamine (PDA) coating and gelatin methacryloyl (GelMA) hydrogel to afford functionalized nanozyme microcapsules. Owing to their injectability and adhesion properties, these microcapsules exhibit the advantages of prolonged retention in the middle ear and sustained release in the inner ear. The synergy between the manganese porphyrin and polymer dots results in excellent antioxidant properties. The developed nanozymes activate the PI3K-AKT pathway, reprogramming the energy supply mechanism, and inhibiting the oligomerization of BAX in mitochondria to prevent the leakage of mitochondrial DNA and cytochrome c. Therapeutic efficacy and related mechanisms are validated in vivo. Thus, this study on mitochondrial homeostasis remodeling by nanozyme microcapsules opens a new chapter in the treatment of hearing loss.
    Keywords:  MOF; cisplatin; hearing loss; mitochondria; nanozymes
    DOI:  https://doi.org/10.1002/adma.202413371
  44. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2024 Dec 09. 1-9
    Inhibition of miR-30d-5p promotes mitochondrial autophagy and alleviates high glucose-induced injury in podocytes.
    Ying Cai, Sheng Chen, Xiaoli Jiang, Qiyuan Wu, Bei Guo, Fang Wang.
       OBJECTIVES: To study the role of microRNA (miR)-30d-5p in high glucose-induced podocyte injury.
    METHODS: Podocyte cells were hyperglycated with 30 mmol/L glucose, miR-30d-5p inhibitor and mimic were transfected into podocyte cells, and then podocyte cells were treated with 1 mg/mL 3-methyladenine (3-MA). The transfection efficiency of miR-30d-5p was detected by quantitative reverse transcription PCR. Cell apoptosis was detected by flow cytometry. The expressions of nephrin, microtubule-associated protein light chain 3 (LC3)Ⅱ/LC3Ⅰ, P62, autophagy-related gene 5 (ATG5), PTEN induced putative kinase 1 (PINK1) and PARK2 were detected by Western blotting. The mito-chondrial membrane potential was detected by JC-1 as a fluorescent probe, and adenosine triphosphate (ATP) content in cells was detected by relevant kits.
    RESULTS: In the high glucose-induced podocytes, miR-30d-5p and P62 expressions were upregulated, nephrin, ATG5, PINK1, PARK2 and LC3Ⅱ/LC3Ⅰ expression levels were decreased (all P<0.01). MiR-30d-5p inhibitor reversed the effect of high glucose on the expression of ATG5, PINK1, PARK2, nephrin, LC3Ⅱ/LC3Ⅰ and P62 (all P<0.01). High glucose induced loss of mitochondrial membrane potential and ATP content in podocytes, while inhibition of miR-30d-5p increased membrane potential and ATP content in podocytes. Autophagy inhibitors 3-MA and miR-30d-5p mimics reversed the effects of miR-30d-5p inhibition on apoptosis, autophagy and mitochondrial function of podocytocytes induced by high glucose (all P<0.05).
    CONCLUSIONS: Inhibition of miR-30d-5p may promote mitochondrial autophagy by promoting the expression of ATG5, PINK1, PARK2, resulting in alleviating high glucose-induced podocyte damage.
    Keywords:  Apoptosis; Autophagy; Diabetic nephropathy; High glucose; Mitochondrial function; Podocyte; miR-30d-5p
    DOI:  https://doi.org/10.3724/zdxbyxb-2024-0504
  45. Apoptosis. 2024 Dec 07.
    Mitochondrial CLPB is a pro-survival factor at the onset of granulocytic differentiation of mouse myeloblastic cells.
    Tomasz Wenta, Guanpeng Wang, Tessa Van Buren, Michal Zolkiewski, Anna Zolkiewska.
      Loss-of-function mutations in the CLPB gene lead to congenital neutropenia due to impaired neutrophil differentiation. CLPB, a member of the AAA+ family of proteins, resides in the intermembrane space of mitochondria. The mechanism by which a loss of CLPB elicits defects in the differentiation program of neutrophil precursor cells is not understood. Here, we used 32D clone 3 (32Dcl3) cells, an interleukin-3 (IL-3)-dependent mouse myeloblastic cell line model, to investigate the effects of CLPB knockout on myeloblast-to-neutrophil differentiation in vitro. We found that CLPB-deficient 32Dcl3 cells showed a decreased mitochondrial membrane potential and increased levels of insoluble HAX1 aggregates in mitochondria, as compared to control cells. Despite those abnormalities, CLPB loss did not affect cell proliferation rates in the presence of IL-3 but it increased apoptosis after IL-3 withdrawal and simultaneous induction of cell differentiation with granulocytic colony stimulating factor (G-CSF). CLPB-deficient cells that survived the stress associated with IL-3 withdrawal/G-CSF treatment expressed the same levels of differentiation markers as control cells. Moreover, we found that increased apoptosis of CLPB-deficient cells is linked to production of reactive oxygen species (ROS). N-acetylcysteine, exogenous free fatty acids, or exogenous citrate protected CLPB-deficient 32Dcl3 cells from apoptosis at the onset of differentiation. The protective effect of citrate was abolished by inhibition of ATP-citrate lyase (ACLY), an enzyme that converts cytosolic citrate into acetyl-CoA, a substrate for protein acetylation. We propose that citrate supplementation may help mitigate the effects of CLPB loss by facilitating ACLY-dependent ROS detoxification in granulocytic precursor cells.
    Keywords:  Apoptosis; Mitochondria; Neutropenia; Neutrophil differentiation; Promyeloblast; Reactive oxygen species
    DOI:  https://doi.org/10.1007/s10495-024-02053-1
  46. Biomaterials. 2024 Dec 05. pii: S0142-9612(24)00535-0. [Epub ahead of print]316 122999
    Bioactive phosphorus dendrimers deliver protein/drug to tackle osteoarthritis via cooperative macrophage reprogramming.
    Huxiao Sun, Mengsi Zhan, Yu Zou, Jie Ma, Jiajia Liang, Guo Tang, Regis Laurent, Serge Mignani, Jean-Pierre Majoral, Xiangyang Shi, Mingwu Shen.
      Reprogramming imbalanced synovial macrophages and shaping an immune microenvironment conducive to bone and cartilage growth is crucial for efficient tackling of osteoarthritis (OA). Herein, we present a co-delivery nanosystem based on generation 2 (G2) hydroxyl-terminated bioactive phosphorus dendrimers (G2-OH24) that were loaded with both catalase (CAT) and quercetin (Que). The created G2-OH24/CAT@Que complexes exhibit a uniformly distributed spherical morphology with a size of 138.8 nm, possess robust stability, and induce macrophage reprogramming toward anti-inflammatory M2 phenotype polarization and antioxidation through cooperative CAT-catalyzed oxygen generation, Que-mediated mitochondrial homeostasis restoration, and inherent immunomodulatory activity of dendrimer. Such macrophage reprogramming leads to chondrocyte apoptosis inhibition and osteogenic differentiation of bone mesenchymal stem cells. Administration of G2-OH24/CAT@Que to an OA mouse model results in attenuation of pathological features such as cartilage degeneration, bone erosion, and synovitis through oxidative stress alleviation and inflammatory factor downregulation in inflamed joints. Excitingly, the G2-OH24/CAT@Que also polarized macrophages in adherent effusion monocytes (AEMs) extracted from joint cavity effusions of OA patients to M2 phenotype and downregulated reactive oxygen species levels in AEMs. This study suggests a promising nanomedicine formulation of phosphorus dendrimer-based co-delivery system to effectively tackle OA through the benefits of full-active ingredients of dendrimer, drug, and protein.
    Keywords:  Macrophage polarization; Mitophagy; Osteoarthritis; Phosphorus dendrimers; Protein delivery
    DOI:  https://doi.org/10.1016/j.biomaterials.2024.122999
  47. Tissue Cell. 2024 Dec 10. pii: S0040-8166(24)00375-6. [Epub ahead of print]93 102674
    Phosphocreatine-mediated enhancement of mitochondrial function for accelerated healing of diabetic foot ulcers through the PGC-1α-NRF-1 signaling pathway.
    Eskandar Qaed, Marwan Almoiliqy, Wu Liu, Jingyu Wang, Haitham Saad Al-Mashriqi, Waleed Aldahmash, Mueataz A Mahyoub, Zeyao Tang.
      Diabetic foot ulcers (DFUs) pose a significant clinical challenge due to their slow healing and high risk of complications, which severely affect patient quality of life. Central to the delayed healing observed in DFUs is mitochondrial dysfunction, a critical factor impairing cellular repair processes. Phosphocreatine (PCr), a vital molecule involved in cellular energy buffering and ATP regeneration, has recently emerged as a promising therapeutic candidate for ameliorating mitochondrial dysfunction and enhancing tissue repair. This study explores the novel therapeutic potential of PCr in restoring mitochondrial function and accelerating wound healing in DFUs through both in vitro and in vivo models. Using hyperglycemic human umbilical vein endothelial cells (HUVECs) as an in vitro model and a streptozotocin (STZ)-induced diabetic rat model as an in vivo, we evaluated the impact of PCr treatment on mitochondrial activity and wound repair. PCr treatment notably upregulated key mitochondrial biogenesis markers, including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear respiratory factor 1 (NRF-1), indicating a restoration of mitochondrial function. In vivo, PCr-treated diabetic rats demonstrated significantly accelerated wound closure, enhanced granulation tissue formation, and reduced inflammatory cell infiltration. These findings underscore PCr's potential to address mitochondrial dysfunction and expedite wound healing in DFUs. This study offers promising new insights into PCr as a targeted therapeutic intervention, paving the way for improved patient outcomes in managing diabetic foot ulcers.
    Keywords:  NRF-1; PGC-1α; Phosphocreatine; diabetic foot ulcers; mitochondria; wound healing
    DOI:  https://doi.org/10.1016/j.tice.2024.102674
  48. Drug Dev Res. 2024 Dec;85(8): e70033
    Heme Oxygenase-1 Overexpression Activates the IRF1/DRP1 Signaling Pathway to Promote M2-Type Polarization of Spinal Cord Microglia.
    Wenping Lin, Ziming Cai, Jinzhu Liang, Ping Miao, Ye Ruan, Pian Li, Shuhui Lin, He Tian, Qinghe Yu, Xu He.
      Microglia-mediated neuroinflammatory responses have a critical function in the spinal cord injury (SCI) mechanism, and targeted modulation of microglia activity has emerged as a new therapeutic strategy for SCI. Heme oxygenase 1(HO-1) regulates the close dynamic crosstalk between oxidative stress and inflammatory responses. This investigation aimed to study the molecular pathways by which HO-1 regulates the inflammatory response of microglia. We cultivated primary rat spinal cord microglia and BV2 cell lines and used lipopolysaccharide (LPS) to stimulate microglia to establish an in vitro model. The adeno-associated virus (AAV) was used to induce HO-1 overexpression to observe the effects of HO-1 overexpression on microglia survival, morphological changes, microglia activation, inflammatory cytokines secretion, mitochondrial dynamics, and nucleotide-binding oligomerization domain-like receptor protein (NLRP3) inflammatory complex and nuclear factor-κB (NF-κB) signaling pathways. It was found that HO-1 overexpression was successfully induced using an AAV on microglia in vitro. HO-1 overexpression increased microglia survival and reduced microglia apoptosis in the inflammatory microenvironment. Overexpressed HO-1 inhibited microglia M1-type polarization, downregulated the NF-κB signaling pathway, inhibited NLRP3 inflammatory complex activation, and reduced the secretion of inflammatory factors. Overexpressed HO-1 maintained the stability of mitochondrial dynamics and inhibited excessive mitochondrial cleavage. Further experiments showed that overexpression of HO-1 activated the interferon regulatory factor 1 (IRF1)/dynamin-related protein 1 (DRP1) signaling pathway, thereby promoting microglia M2-type polarization and improving neuronal survival. This study demonstrates that HO-1 activates the IRF1/DRP1 axis, promoting M2 polarization in microglia and attenuating neuroinflammation by suppressing the NF-κB signaling pathway. These outcomes offer new visions and important clues for effectively managing SCI in the clinic.
    Keywords:  dynamin‐related protein 1; inflammation; microenvironment; neuron; spinal cord injury
    DOI:  https://doi.org/10.1002/ddr.70033
  49. J Cancer. 2024 ;15(20): 6490-6504
    FUNDC1 predicts Poor Prognosis and promotes Progression and Chemoresistance in Endometrial Carcinoma.
    Lihua Tang, Jiongyu Chen, Zhaoting Wu, Luanhong Wang, Yaozhen Lai, Zejia Chen, Lin Peng, Li Zhou.
      Absence of effective prognostic biomarkers and therapeutic targets for reversing chemoresistance of endometrial carcinoma (EC) remains a huge challenge for clinicians. Mitophagy plays a crucial role in carcinogenesis and chemoresistance. FUN14 domain-containing protein 1 (FUNDC1) is a novel mitophagy receptor protein involved in tumorigenesis under hypoxic conditions. However, the implication of FUNDC1 in EC progression, chemoresistance in particular, remains unclear. Based on The Cancer Genome Atlas (TCGA) cohort, comprised of 403 EC patients, the association of FUNDC1 mRNA levels with hypoxia-inducible factor 1α (HIF-1α) expression, clinicopathologic features and prognosis in EC was analyzed, and subsequently verified utilizing immunohistochemistry of 288 EC specimens. Analysis of the cohort in TCGA showed that patients with higher FUNDC1 levels exhibited worse OS, with the shortest OS exhibited by patients with co-upregulated FUNDC1 and HIF-1α (P < 0.05). Analysis of the validation cohort indicated that OS and PFS rates of high-FUNDC1 patients were lower than that of low-FUNDC1 group (P < 0.05). Cases with co-downregulation of FUNDC1 and HIF-1α had higher OS and PFS rates than those with co-upregulation of these two proteins (88.8% vs. 71.2%, P = 0.002; 85.6% vs. 71.2%, P = 0.009). Higher FUNDC1 expression was observed in platinum-resistant patients. Multivariate Cox regression analysis revealed that FUNDC1 expression, FIGO stage, lymphatic invasion, depth of myometrial invasion, and ascites were independent risk factors for OS and PFS. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that FUNDC1 was closely related to spliceosome, neurodegeneration pathways of multiple diseases, and cell cycle signaling pathways. Significantly enriched RNA splicing and ncRNA processing were identified in Gene Ontology (GO) analysis. Gene set enrichment analysis (GSEA) indicated that abnormal expression of FUNDC1 was involved in endometrial cancer, NOD-like receptor signaling pathway and cytokine signaling in the immune system. In addition, immune cell infiltration analysis by Tumor Immune Estimation Resources (TIMER) database and the Xiantao academic tool demonstrated that FUNDC1 expression was strongly associated with the infiltration of Th2, NK, Th17, Tem, pDC, neutrophil, MDSC, CD4+ T, and γδ T cells. Knockdown of FUNDC1 using shRNA in HEC-1B and Ishikawa EC cells inhibited proliferation, migration and invasion, accompanied by enhanced chemotherapeutic susceptibility to carboplatin and paclitaxel. Accordingly, FUNDC1 could be a prospective prognostic biomarker and potential therapeutic target for EC.
    Keywords:  Chemotherapy resistance; Endometrial cancer; FUN14 domain-containing protein 1; Mitophagy; Prognostic biomarker
    DOI:  https://doi.org/10.7150/jca.96877
  50. Mol Cell Biochem. 2024 Dec 11.
    Immune dysregulation of decidual NK cells mediated by GRIM19 downregulation contributes to the occurrence of recurrent pregnancy loss.
    Ying Wang, Anliang Guo, Lin Yang, Xiaojuan Han, Qianni Li, Jin Liu, Yilong Han, Yang Yang, Lan Chao.
      In patients with recurrent pregnancy loss (RPL), excessive activation of decidual natural killer (dNK) cells has been widely observed, yet the precise underlying mechanisms remain to be elucidated. We collected decidual specimens from RPL patients and controls to assess GRIM19 expression, activation phenotype, cytotoxic function, inflammatory cytokine secretion, and mitochondrial homeostasis in dNK cells. Furthermore, we established a GRIM19-knockout NK-92MI cell line and a GRIM19 ± C57BL/6J mouse model to investigate the relationship between GRIM19 downregulation and dNK immune dysregulation, ultimately contributing to pregnancy loss. Decidual NK cells from RPL patients exhibited significantly lower GRIM19 expression, accompanied by abnormal hyperactivation, enhanced cytotoxicity, and abnormal mitochondrial activation. In vitro experiments confirmed that reduced GRIM19 expression significantly potentiated the cytotoxicity and pro-inflammatory cytokine secretion of NK-92MI cells, while also promoting mitochondrial homeostasis imbalance. Mouse model studies corroborated that GRIM19 downregulation triggers NK cell homeostasis imbalance, contributing to the occurrence of pregnancy loss. Downregulation of GRIM19 in dNK cells contributes to RPL through hyperactivation and disruption of mitochondrial homeostasis, emphasizing its potential as a diagnostic and therapeutic target.
    Keywords:  Decidual NK cells; GRIM19; Mitochondrion; Recurrent pregnancy loss
    DOI:  https://doi.org/10.1007/s11010-024-05181-z
  51. Am J Physiol Cell Physiol. 2024 Dec 13.
    Sulforaphane treatment mimics contractile activity-induced mitochondrial adaptations in muscle myotubes.
    Sabrina Champsi, David A Hood.
      Mitochondria are metabolic hubs that govern skeletal muscle health. While exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined Sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial ROS emission. Signaling towards biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), Peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggests that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle.
    Keywords:  Nrf-2; PGC-1α; exercise; mitochondrial biogenesis; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpcell.00669.2024
  52. Front Med (Lausanne). 2024 ;11 1491009
    Progress in the mechanism of functional dyspepsia: roles of mitochondrial autophagy in duodenal abnormalities.
    Kexin Zhong, Xiaojuan Du, Yuanyuan Niu, Zhengju Li, Yongbiao Tao, Yuqian Wu, Ruiting Zhang, Linjing Guo, Yurong Bi, Lijuan Tang, Tianyu Dou, Longde Wang.
      Mitochondria are the main source of energy for cellular activity. Their functional damage or deficiency leads to cellular deterioration, which in turn triggers autophagic reactions. Taking mitochondrial autophagy as a starting point, the present review explored the mechanisms of duodenal abnormalities in detail, including mucosal barrier damage, release of inflammatory factors, and disruption of intracellular signal transduction. We summarized the key roles of mitochondrial autophagy in the abnormal development of the duodenum and examined the in-depth physiological and pathological mechanisms involved, providing a comprehensive theoretical basis for understanding the pathogenesis of functional dyspepsia. At present, it has been confirmed that an increase in the eosinophil count and mast cell degranulation in the duodenum can trigger visceral hypersensitive reactions and cause gastrointestinal motility disorders. In the future, it is necessary to continue exploring the molecular mechanisms and signaling pathways of mitochondrial autophagy in duodenal abnormalities. A deeper understanding of mitochondrial autophagy provides important references for developing treatment strategies for functional dyspepsia, thereby improving clinical efficacy and patient quality of life.
    Keywords:  duodenal abnormalities; functional dyspepsia; gastrointestinal dysfunction; mitochondrial autophagy; pathogenesis
    DOI:  https://doi.org/10.3389/fmed.2024.1491009
  53. Brain Behav Immun. 2024 Dec 10. pii: S0889-1591(24)00740-2. [Epub ahead of print]
    Unraveling morphine tolerance: CCL2 induces spinal cord apoptosis via inhibition of Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis.
    Ju Jie, Ren Jihao, Li Zheng, Liu Jie, Peng Xiaoling, Zhao Wei, Gao Feng.
       BACKGROUND: Morphine effectively relieves severe pain but leads to analgesic tolerance with long-term use.The molecular mechanisms underlying morphine tolerance remain incompletely understood. Existing literature suggests that chemokine CCL2, present in the spinal cord, plays a role in central nervous system inflammation, including neuropathic pain. Nevertheless, the precise mechanism through which CCL2 mediates morphine tolerance has yet to be elucidated. Consequently, this study aims to investigate the molecular pathways by which CCL2 contributes to the development of morphine analgesic tolerance.
    METHODS: Rats were administered intrathecal morphine (10 μg/5 μl) twice a day for seven consecutive days to induce a model of morphine nociceptive tolerance. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) were used to detect the expression levels of CCL2 and its related mechanism molecules. Immunofluorescence was used to detect the localization of CCL2 in the spinal cord. Intrathecal injections of inhibitors or agonists to artificially regulate the expression of relevant molecules. The thermal tail-flick experiment was performed to evaluate morphine tolerance in rats.
    RESULTS: Morphine-induced CCL2 expression was significantly increased in spinal cord, while conversely, the expressions of Nrf2 and PGC-1a were downregulated. Immunofluorescence showed that the enhanced immune response of CCL2 mainly co-localized with neurons. In vivo, we confirmed that intrathecally injection of CCL2 inhibitor Bindarit could effectively alleviate the occurrence of apoptosis and alleviate morphine tolerance. Similarly, pretreatment with Nrf2 signaling pathway agonist Oltipraz and PGC-1α agonist ZLN005 also achieved similar results, respectively. ROS Fluorescence Assay Kit indicated that increasing the expression of PGC-1α could alleviate the occurrence of apoptosis by reducing the level of ROS.
    CONCLUSION: Our data emphasize that chemokine CCL2 inhibited the Nrf2 signaling pathway and PGC-1α-mediated mitochondrial biogenesis, alleviating the occurrence of apoptosis in spinal cord, thereby participating in morphine tolerance. This may provide new targets for the treatment of morphine tolerance.
    Keywords:  Apoptosis; CCL2; Mitochondrial biogenesis; Morphine tolerance; Nrf2; PGC-1α
    DOI:  https://doi.org/10.1016/j.bbi.2024.12.011
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