bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–12–01
forty-six papers selected by
Gavin McStay, Liverpool John Moores University
  1. Unveiling a novel signalling pathway involving NRF2 and PGAM5 in regulating the mitochondrial unfolded protein response in stressed cardiomyocytes.
  2. Altered Mitochondrial Unfolded Protein Response and Protein Quality Control promote oxidative distress in Down Syndrome brain.
  3. Retraction of: Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.
  4. ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
  5. Heat Shock Factor HSFA6b Mediates Mitochondrial Unfolded Protein Response in Arabidopsis thaliana.
  6. Procyanidin C1 ameliorates acidic pH stress induced nucleus pulposus degeneration through SIRT3/FOXO3-mediated mitochondrial dynamics.
  7. The dynamin-related protein PfDyn2 is essential for both apicoplast and mitochondrial fission in Plasmodium falciparum.
  8. Zinc Ions Facilitate Metabolic Bioenergetic Recovery Post Spinal Cord Injury by Activating Microglial Mitophagy through the STAT3-FOXO3a-SOD2 Pathway.
  9. Enhanced Parkin-mediated mitophagy mitigates adverse left ventricular remodelling after myocardial infarction: role of PR-364.
  10. Piezo1 exacerbates inflammation-induced cartilaginous endplate degeneration by activating mitochondrial fission via the Ca2+/CaMKII/Drp1 axis.
  11. AMPK regulates Bcl2-L-13-mediated mitophagy induction for cardioprotection.
  12. Mitochondrial Quality Control in Alzheimer's Disease: Insights from Caenorhabditis elegans Models.
  13. Mitochondria-targeting therapeutic strategies for chronic kidney disease.
  14. Self-Healing COCu-Tac Hydrogel Enhances iNSCs Transplantation for Spinal Cord Injury by Promoting Mitophagy via the FKBP52/AKT Pathway.
  15. YAP1 preserves tubular mitochondrial quality control to mitigate diabetic kidney disease.
  16. P2Y6R Inhibition Induces Microglial M2 Polarization by Promoting PINK1/Parkin-Dependent Mitophagy After Spinal Cord Injury.
  17. KPNB1-ATF4 induces BNIP3-dependent mitophagy to drive odontoblastic differentiation in dental pulp stem cells.
  18. Nano-Selenium Modulates NF-κB/NLRP3 Pathway and Mitochondrial Dynamics to Attenuate Microplastic-Induced Liver Injury.
  19. The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.
  20. Soft X-ray tomography analysis of mitochondria dynamics in Saccharomyces cerevisiae.
  21. CgANT2 regulates mitophagy of oyster haemocyte response against bacterial stimulation.
  22. Erratum to "Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation" [Pharmacol Res 206 (2024) 107258].
  23. Dysregulated mitochondrial fission and neurodegeneration proteomic signature in ACSF3-deficient cells.
  24. Fbxo11 maintains mitochondrial function and prevents podocyte injury in adriamycin-induced nephropathy by mediating the ubiquitin degradation of Fosl2.
  25. STAT2/SLC27A3/PINK1-Mediated Mitophagy Remodeling Lipid Metabolism Contributes to Pazopanib Resistance in Clear Cell Renal Cell Carcinoma.
  26. Use of Caenorhabditis elegans to Unravel the Tripartite Interaction of Kynurenine Pathway, UPRmt and Microbiome in Parkinson's Disease.
  27. Prediction of prognosis and immune response in lung adenocarcinoma based on mitophagy and lactate-related gene signatures.
  28. Analysis of mitochondrial DNA replisome in autism spectrum disorder: Exploring the role of replisome genes.
  29. Myricetin Alleviates Silica-Mediated Lung Fibrosis via PPARγ-PGC-1α Loop and Suppressing Mitochondrial Senescence in Epithelial Cells.
  30. FSTL1 Can Be a Promising Target in TMJ Osteoarthritis via Regulating Chondrocyte Mitophagy and Apoptosis.
  31. Comparison of the Mitophagy and Apoptosis Related Gene Expressions in Waste Embryo Culture Medium of Female Infertility Types.
  32. MEHP induced mitochondrial damage by promoting ROS production in CIK cells, leading to apoptosis, autophagy, cell cycle arrest.
  33. Luteolin ameliorates periodontitis by modulating mitochondrial dynamics and macrophage polarization via the JAK2/STAT3 pathway.
  34. cRGD-Conjugated Bilirubin Nanoparticles Alleviate Dry Eye Disease Via Activating the PINK1-Mediated Mitophagy.
  35. DNA sequence and lesion-dependent mitochondrial transcription factor A (TFAM)-DNA-binding modulates DNA repair activities and products.
  36. Antrodia cinnamomea triterpenoids attenuate cardiac hypertrophy via the SNW1/RXR/ALDH2 axis.
  37. MMP8-mediated vascular remodeling in pulmonary hypertension.
  38. [Research progress on the role of mitochondrial dynamics disorder in sepsis-associated acute kidney injury].
  39. The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
  40. Neuroprotective Effects of Ascorbic Acid, Vanillic Acid, and Ferulic Acid in Dopaminergic Neurons of Zebrafish.
  41. [Sulforaphane regulates mitochondrial homeostasis through adenosine monophosphate-activated protein kinase signaling to treat acute carbon monoxide poisoning induced brain injury in rats].
  42. Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.
  43. Exacerbated mitochondrial dynamic abnormalities without evident tau pathology in rapidly progressive Alzheimer's disease.
  44. Activation of sirtuin 3 and maintenance of mitochondrial homeostasis by artemisinin protect against diclofenac-induced kidney injury in rats.
  45. Probiotics-sensing mechanism in neurons that initiates gut mitochondrial surveillance for pathogen defense.
  46. Anoikis and Mitophagy-Related Gene Signature for Predicting the Survival and Tumor Cell Progression in Colon Cancer.
  1. Int J Biochem Cell Biol. 2024 Nov 26. pii: S1357-2725(24)00197-3. [Epub ahead of print] 106704
    Unveiling a novel signalling pathway involving NRF2 and PGAM5 in regulating the mitochondrial unfolded protein response in stressed cardiomyocytes.
    Rahme Nese Safakli, Stephen Gray, Nadia Bernardi, Ioannis Smyrnias.
      The mitochondrial unfolded protein response (UPRmt) is a conserved signalling pathway that initiates a specific transcriptional programme to maintain mitochondrial and cellular homeostasis under stress. Previous studies have demonstrated that UPRmt activation has protective effects in the pressure-overloaded human heart, suggesting that robust UPRmt stimulation could serve as an intervention strategy for cardiovascular diseases. However, the precise mechanisms of UPRmt regulation remain unclear. In this study, we present evidence that the NRF2 transcription factor is involved in UPRmt activation in cardiomyocytes during conditions of mitochondrial stress. Silencing NRF2 partially reduces UPRmt activation, highlighting its essential role in this pathway. However, constitutive activation of NRF2 via inhibition of its cytosolic regulator KEAP1 does not increase levels of UPRmt activation markers, suggesting an alternative regulatory mechanism independent of the canonical KEAP1-NRF2 axis. Further analysis revealed that NRF2 likely affects UPRmt activation through its interaction with PGAM5 at the mitochondrial membrane. Disruption of PGAM5 in cardiomyocytes subjected to mitochondrial stress reduces the interaction between PGAM5 and NRF2, enhancing nuclear translocation of NRF2 and significantly upregulating the UPRmt in an NRF2-dependent manner. This NRF2-regulated UPRmt amplification improves mitochondrial respiration, reflecting an enhanced capacity for cardiomyocytes to meet elevated energetic demands during mitochondrial stress. Our findings highlight the therapeutic potential of targeting the NRF2-PGAM5-KEAP1 signalling complex to amplify the UPRmt in cardiomyocytes for cardiovascular and other diseases associated with mitochondrial dysfunction. Future studies should aim to elucidate the mechanisms via which NRF2 enhances the protective effects of UPRmt, thereby contributing to more targeted therapeutic approaches.
    Keywords:  cardiomyocytes; cardioprotection; mitochondria; stress; unfolded protein response
    DOI:  https://doi.org/10.1016/j.biocel.2024.106704
  2. Free Radic Biol Med. 2024 Nov 23. pii: S0891-5849(24)01077-3. [Epub ahead of print]
    Altered Mitochondrial Unfolded Protein Response and Protein Quality Control promote oxidative distress in Down Syndrome brain.
    Simona Lanzillotta, Daniel Esteve, Chiara Lanzillotta, Antonella Tramutola, Ana Lloret, Elena Forte, Vito Pesce, Anna Picca, Fabio Di Domenico, Marzia Perluigi, Eugenio Barone.
      Down Syndrome (DS) is a genetic disorder caused by the presence of an extra copy of chromosome 21, and leading to various developmental and cognitive defects. A critical feature of DS is the occurrence of oxidative distress particularly in the brain, which exacerbates neurodevelopmental processes. Mitochondria play a crucial role in cell energy metabolism and their impairment is one of the major causes of oxidative distress in several pathologies. Hence, this study investigates mitochondrial proteostasis by the mean of the mitochondrial Unfolded Protein Response (UPRmt) and the mitochondrial protein quality control (MQC) mechanisms in the context of DS, focusing on their implications in redox homeostasis in brain development. We analyzed key UPRmt markers and mitochondrial function in the frontal cortex isolated fromTs2Cje mice, a model for DS, across different developmental stages. Our results demonstrate significant alterations in UPRmt markers, particularly at postnatal day 0 (P0) and 1 month (1M). These changes indicate early UPRmt activation, primarily driven by the ATF5/GRP75 axis, although compromised by reduced levels of other components. Impaired UPRmt correlates with decreased mitochondrial activity, evidenced by reduced oxygen consumption rates and altered expression of OXPHOS complexes. Additionally, elevated oxidative stress markers such as 3-nitrotyrosine (3-NT), 4-hydroxynonenal (HNE), and protein carbonyls (PC) were observed, linking mitochondrial dysfunction to increased oxidative damage. Defects of MQC, including disrupted biogenesis, increased fission, and the activation of mitophagy were evident mostly at P0 and 1M consistent with UPRmt activation. Principal Component Analysis revealed distinct phenotypic differences between Ts2Cje and control mice, driven by these molecular alterations. Our findings underscore the critical role of UPRmt and MQC in DS brain development, highlighting potential therapeutic targets to mitigate mitochondrial dysfunction and oxidative distress, thereby alleviating some of the neurodevelopmental and cognitive impairments associated with DS.
    Keywords:  Down Syndrome; UPRmt; brain development; mitochondrial metabolism; oxidative stress
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.043
  3. Hum Mol Genet. 2024 Nov 26. pii: ddae149. [Epub ahead of print]
    Retraction of: Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.
      
    DOI:  https://doi.org/10.1093/hmg/ddae149
  4. Proc Natl Acad Sci U S A. 2024 Dec 03. 121(49): e2410486121
    ER-tethered stress sensor CREBH regulates mitochondrial unfolded protein response to maintain energy homeostasis.
    Hyunbae Kim, Qi Chen, Donghong Ju, Neeraja Purandare, Xuequn Chen, Lobelia Samavati, Li Li, Ren Zhang, Lawrence I Grossman, Kezhong Zhang.
      The Mitochondrial Unfolded Protein Response (UPRmt), a mitochondria-originated stress response to altered mitochondrial proteostasis, plays important roles in various pathophysiological processes. In this study, we revealed that the endoplasmic reticulum (ER)-tethered stress sensor CREBH regulates UPRmt to maintain mitochondrial homeostasis and function in the liver. CREBH is enriched in and required for hepatic Mitochondria-Associated Membrane (MAM) expansion induced by energy demands. Under a fasting challenge or during the circadian cycle, CREBH is activated to promote expression of the genes encoding the key enzymes, chaperones, and regulators of UPRmt in the liver. Activated CREBH, cooperating with peroxisome proliferator-activated receptor α (PPARα), activates expression of Activating Transcription Factor (ATF) 5 and ATF4, two major UPRmt transcriptional regulators, independent of the ER-originated UPR (UPRER) pathways. Hepatic CREBH deficiency leads to accumulation of mitochondrial unfolded proteins, decreased mitochondrial membrane potential, and elevated cellular redox state. Dysregulation of mitochondrial function caused by CREBH deficiency coincides with increased hepatic mitochondrial oxidative phosphorylation (OXPHOS) but decreased glycolysis. CREBH knockout mice display defects in fatty acid oxidation and increased reliance on carbohydrate oxidation for energy production. In summary, our studies uncover that hepatic UPRmt is activated through CREBH under physiological challenges, highlighting a molecular link between ER and mitochondria in maintaining mitochondrial proteostasis and energy homeostasis under stress conditions.
    Keywords:  ER-mitochondria contact; cell metabolism; michondrial UPR; transcriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1073/pnas.2410486121
  5. Plants (Basel). 2024 Nov 05. pii: 3116. [Epub ahead of print]13(22):
    Heat Shock Factor HSFA6b Mediates Mitochondrial Unfolded Protein Response in Arabidopsis thaliana.
    Guolong Yu, Zhuoran Huang, Chaocheng Guo, Jiahao Li, Xinyuan Wang, Yudong Wang, Xu Wang.
      Mitochondria are important organelles in eukaryotes and are involved in various metabolic processes. Mitochondrial proteotoxic stress triggers the mitochondrial unfolded protein response (UPRmt) to restore mitochondrial protein homeostasis and maintain normal life activities. However, the regulatory mechanism of plant UPRmt remains to be revealed in Arabidopsis. Based on the fact that UPRmt activates heat shock protein (HSP) genes, we identified the heat shock transcription factor HSFA6b as a key regulator mediating UPRmt through reverse genetics. HSFA6b responded to mitochondrial proteotoxic stress and regulated mitochondrial heat shock proteins' genes' (mtHSPs) expression. HSFA6b translocated to the nuclear after treatment with doxycycline (Dox)-a mitochondrial ribosome translation inhibitor. HSFA6b binds to the mtHSPs promoters and activates mtHSPs expression. The HSFA6b mutation blocked the UPRmt signals to promote root growth under mitochondrial proteotoxic stress and accelerated leaf senescence during development. Our study reveals a novel signal-regulating mechanism in the UPRmt pathways and provides new insights regarding the regulation of plant growth and development and stress resistance by the UPRmt pathways.
    Keywords:  heat shock factor; heat shock protein; mitochondria; mitochondrial proteotoxic stress; mitochondrial unfolded protein response UPRmt
    DOI:  https://doi.org/10.3390/plants13223116
  6. J Transl Med. 2024 Nov 27. 22(1): 1071
    Procyanidin C1 ameliorates acidic pH stress induced nucleus pulposus degeneration through SIRT3/FOXO3-mediated mitochondrial dynamics.
    Wenbin Hua, Lin Xie, Chenpeng Dong, Guoyu Yang, Shouyuan Chi, Zhiqiang Xu, Cao Yang, Huiwen Wang, Xinghuo Wu.
      Intervertebral disc degeneration (IVDD) is a common cause of low back pain. Procyanidin C1 (PCC1) has been demonstrated to exert a protective effect on nucleus pulposus (NP) cells, and therefore, plays a critical role in the prevention and therapy of IVDD. Clarifying the pathophysiological characteristics and molecular mechanisms of IVDD may be helpful in establishing novel preventive and therapeutic strategies. This study aimed to investigate the probable mechanisms underlying the protection against acidic pH stress induced human NP cell injury. In vitro, acidic pH stress induced degeneration, mitochondrial dynamics imbalance, mitophagy, and mitochondria-mediated apoptosis in NP cells, all of which were ameliorated by PCC1. Autophagy inhibition partially eliminated the protective effects of PCC1 on mitochondrial homeostasis in NP cells. Moreover, PCC1 activated the sirtuin 3 (SIRT3)/forkhead box O3 (FOXO3) signaling pathway, a pivotal signaling pathway involved in the regulation of mitochondrial homeostasis in NP cells. In vivo, PCC1 ameliorated IVDD in a rat model and preserved the extracellular matrix of NP cells. Consequently, the protective effects of PCC1 on NP cells may inhibit IVDD progression via regulation of the SIRT3/FOXO3 signaling pathway. Therefore, regulation of the SIRT3/FOXO3 signaling pathway may be a novel preventive and therapeutic strategy for IVDD.
    Keywords:  Acidic pH stress; Intervertebral disc degeneration; Nucleus pulposus cells; Procyanidin C1; SIRT3/FOXO3 signaling
    DOI:  https://doi.org/10.1186/s12967-024-05805-4
  7. mBio. 2024 Nov 29. e0303624
    The dynamin-related protein PfDyn2 is essential for both apicoplast and mitochondrial fission in Plasmodium falciparum.
    Alexander A Morano, Wei Xu, Francesca M Navarro, Neeta Shadija, Jeffrey D Dvorin, Hangjun Ke.
      Dynamins, or dynamin-related proteins (DRPs), are large mechano-sensitive GTPases that mediate membrane dynamics or organellar fission/fusion events. Plasmodium falciparum encodes three dynamin-like proteins whose functions are poorly understood. Here, we demonstrate that one of these dynamin-related proteins, PfDyn2, is required to divide both the apicoplast and the mitochondrion, a striking divergence from the biology of related parasites. Using super-resolution and ultrastructure expansion microscopy (U-ExM), we show that PfDyn2 is expressed in dividing schizonts, and that it localizes to both the apicoplast and the mitochondrion. Our use of long-term, live-cell microscopy allows for the visualization of apicoplast and mitochondrial division in live parasites at super resolution for the first time, and demonstrates that in PfDyn2-deficient parasites, while the apicoplast and mitochondrion increase in size and complexity, they do not undergo fission. We also show that these organellar fission defects prevent successful individualization of the schizont mass and the formation of new daughter cells, or merozoites because the basal complex, the cytokinetic ring of Plasmodium, cannot fully contract in PfDyn2-deficient parasites, a phenotype secondary to physical blockage by undivided organelles occluding the ring. PfDyn2's singular role in mediating both apicoplast and mitochondrial fission has not been observed in other organisms possessing two endosymbiotic organelles, including other Apicomplexans, thus reflecting a unique, potentially exploitable method of organellar division in P. falciparum.IMPORTANCEPlasmodium falciparum remains a significant global pathogen, causing over 200 million infections and over 600,000 deaths per year. One significant obstacle to the control of malaria is increasing resistance to first-line artemisinin-based antimalarials. Another is a lack of basic knowledge about the cell biology of the parasite. Along with the mitochondrion, Plasmodium contains a second organelle descended from an endosymbiotic event, the apicoplast. Both organelles are common targets for antimalarials, but because many proteins involved in organellar fission are not conserved in Plasmodium, until now, the mechanisms underlying apicoplast and mitochondrial division have been unknown. In this study, we demonstrate that PfDyn2, a dynamin-related protein (DRP), is required for the division of both organelles. We also show that defects in organellar division hinder segmentation of the schizont and formation of invasive merozoites by preventing full contraction of the basal complex. By demonstrating its necessity for the proper division of both the apicoplast and the mitochondria, this study highlights PfDyn2 as a potential target for new antimalarials.
    Keywords:  PfDyn2; Plasmodium falciparum; apicoplast; apicoplast fission; basal complex; dynamin; dynamin-related protein; malaria; mitochondria; mitochondrial fission; residual body; schizogony
    DOI:  https://doi.org/10.1128/mbio.03036-24
  8. Free Radic Biol Med. 2024 Nov 27. pii: S0891-5849(24)01079-7. [Epub ahead of print]
    Zinc Ions Facilitate Metabolic Bioenergetic Recovery Post Spinal Cord Injury by Activating Microglial Mitophagy through the STAT3-FOXO3a-SOD2 Pathway.
    Yang Cui, Mingyu Bai, Shuang Gao, Haosen Zhao, Xifan Mei.
      Spinal cord injury (SCI) is a devastating condition of the central nervous system (CNS) with high global rates of disability and mortality, and no effective cure currently available. Microglia play a critical role in the progression of SCI, and enhancing their metabolic function may facilitate tissue repair and recovery. Mitochondrial dysfunction is a key feature of metabolic impairment, with the regulation of autophagy being essential for maintaining mitochondrial homeostasis and cell survival. The transcription factor Forkhead box O3a (FOXO3a) is integral to cellular metabolism, mitochondrial dysfunction, and oxidative stress responses, yet its role in post-SCI microglial metabolism remains underexplored. In this study, single-cell RNA sequencing reveals the crucial involvement of the FOXO signaling pathway in zinc ion-mediated enhancement of microglial metabolism. Mechanistically, oxidative stress-induced reactive oxygen species (ROS) accumulation exacerbates metabolic dysfunction by promoting excessive mitochondrial fission and impairing mitophagy. Importantly, zinc ions induce the nuclear translocation of FOXO3a, leading to its activation as a transcription factor. This activation enhances mitochondrial autophagy and fusion processes, thereby restoring microglial metabolic capacity. Our findings suggest that the zinc ion regulation of the STAT3-FOXO3a-SOD2 axis is pivotal in modulating mitochondrial gene expression, which governs microglial energy homeostasis and improves the spinal cord microenvironment, potentially enhancing neuronal survival. These insights highlight a promising therapeutic target for SCI.
    Keywords:  Microglia; Mitophagy; Oxidative stress; Spinal cord injury; Zinc
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.11.045
  9. Eur Heart J. 2024 Nov 27. pii: ehae782. [Epub ahead of print]
    Enhanced Parkin-mediated mitophagy mitigates adverse left ventricular remodelling after myocardial infarction: role of PR-364.
    Lizhuo Ai, Juliana de Freitas Germano, Chengqun Huang, Marianne Aniag, Savannah Sawaged, Jon Sin, Reetu Thakur, Deepika Rai, Christopher Rainville, David E Sterner, Yang Song, Honit Piplani, Suresh Kumar, Tauseef R Butt, Robert M Mentzer, Aleksandr Stotland, Roberta A Gottlieb, Jennifer E Van Eyk.
       BACKGROUND AND AIMS: Almost 30% of survivors of myocardial infarction (MI) develop heart failure (HF), in part due to damage caused by the accumulation of dysfunctional mitochondria. Organelle quality control through Parkin-mediated mitochondrial autophagy (mitophagy) is known to play a role in mediating protection against HF damage post-ischaemic injury and remodelling of the subsequent deteriorated myocardium.
    METHODS: This study has shown that a single i.p. dose (2 h post-MI) of the selective small molecule Parkin activator PR-364 reduced mortality, preserved cardiac ejection fraction, and mitigated the progression of HF. To reveal the mechanism of PR-364, a multi-omic strategy was deployed in combination with classical functional assays using in vivo MI and in vitro cardiomyocyte models.
    RESULTS: In vitro cell data indicated that Parkin activation by PR-364 increased mitophagy and mitochondrial biogenesis, enhanced adenosine triphosphate production via improved citric acid cycle, altered accumulation of calcium localization to the mitochondria, and initiated translational reprogramming with increased expression of mitochondrial translational proteins. In mice, PR-364 administered post-MI resulted in widespread proteome changes, indicating an up-regulation of mitochondrial metabolism and mitochondrial translation in the surviving myocardium.
    CONCLUSIONS: This study demonstrates the therapeutic potential of targeting Parkin-mediated mitophagy using PR-364 to protect surviving cardiac tissue post-MI from progression to HF.
    Keywords:  Heart failure; Mitochondrial function; Multi-omics; Myocardial infarction; Parkin-dependent mitophagy; Proteomics; Translational reprogramming
    DOI:  https://doi.org/10.1093/eurheartj/ehae782
  10. Aging Cell. 2024 Nov 28. e14440
    Piezo1 exacerbates inflammation-induced cartilaginous endplate degeneration by activating mitochondrial fission via the Ca2+/CaMKII/Drp1 axis.
    Zhidi Lin, Guangyu Xu, Xiao Lu, Hongli Wang, Feizhou Lu, Xinlei Xia, Jian Song, Jianyuan Jiang, Xiaosheng Ma, Fei Zou.
      Mitochondrial homeostasis plays a crucial role in degenerative joint diseases, including cartilaginous endplate (CEP) degeneration. To date, research into mitochondrial dynamics in IVDD is at an early stage. Since Piezo1 is a novel Ca2+-permeable channel, we asked whether Piezo1 could modulate mitochondrial fission through Ca2+ signalling during CEP degeneration. In vitro and in vivo models of inflammation-induced CEP degeneration were established with lipopolysaccharide (LPS). We found increased expression of Piezo1 in degenerated CEP tissues and LPS-treated CEP cells. The Piezo1 activator Yoda1 exacerbated CEP cell senescence and apoptosis by triggering Ca2+ influx. Yoda1 also induced mitochondrial fragmentation and dysfunction. In contrast, the Piezo1 inhibitor GsMTx4 exerted cytoprotective effects in LPS-treated CEP cells. Additionally, the CaMKII inhibitor KN-93 reversed Yoda1-induced mitochondrial fission and restored mitochondrial function. Mechanistically, the phosphorylation and mitochondrial translocation of Drp1 were regulated by the Ca2+/CaMKII signalling. The Drp1 inhibitor Mdivi-1 suppressed mitochondrial fission, then reduced mitochondrial dysfunction and CEP cell death. Moreover, knockdown of Piezo1 by siRNA hindered CaMKII and Drp1 activation, facilitating the redistribution of mitochondrial Drp1 to the cytosol in LPS-treated CEP cells. Piezo1 silencing improved mitochondrial morphology and function, thereby rescuing CEP cell senescence and apoptosis under inflammatory conditions. Finally, subendplate injection of GsMTx4 or AAV-shPiezo1 alleviated CEP degeneration in a rat model. Thus, Piezo1 may exacerbate inflammation-induced CEP degeneration by triggering mitochondrial fission and dysfunction via the Ca2+/CaMKII/Drp1 axis.
    Keywords:  Drp1; Piezo1; apoptosis; cartilaginous endplate degeneration; mitochondrial fission; senescence
    DOI:  https://doi.org/10.1111/acel.14440
  11. Cell Rep. 2024 Nov 23. pii: S2211-1247(24)01352-4. [Epub ahead of print]43(12): 115001
    AMPK regulates Bcl2-L-13-mediated mitophagy induction for cardioprotection.
    Tomokazu Murakawa, Jumpei Ito, Mara-Camelia Rusu, Manabu Taneike, Shigemiki Omiya, Javier Moncayo-Arlandi, Chiaki Nakanishi, Ryuta Sugihara, Hiroki Nishida, Kentaro Mine, Roland Fleck, Min Zhang, Kazuhiko Nishida, Ajay M Shah, Osamu Yamaguchi, Yasushi Sakata, Kinya Otsu.
      The accumulation of damaged mitochondria in the heart is associated with heart failure. Mitophagy is an autophagic degradation system that specifically targets damaged mitochondria. We have reported previously that Bcl2-like protein 13 (Bcl2-L-13) mediates mitophagy and mitochondrial fission in mammalian cells. However, the in vivo function of Bcl2-L-13 remains unclear. Here, we demonstrate that Bcl2-L-13-deficient mice and knockin mice, in which the phosphorylation site (Ser272) on Bcl2-L-13 was changed to Ala, showed left ventricular dysfunction in response to pressure overload. Attenuation of mitochondrial fission and mitophagy led to impairment of ATP production in these mouse hearts. In addition, we identified AMPKα2 as the kinase responsible for the phosphorylation of Bcl2-L-13 at Ser272. These results indicate that Bcl2-L-13 and its phosphorylation play an important role in maintaining cardiac function. Furthermore, the amplitude of stress-stimulated mitophagic activity could be modulated by AMPKα2.
    Keywords:  Bcl2-L-13; CP: Cell biology; heart failure; mitochondria; mitophagy
    DOI:  https://doi.org/10.1016/j.celrep.2024.115001
  12. Antioxidants (Basel). 2024 Nov 01. pii: 1343. [Epub ahead of print]13(11):
    Mitochondrial Quality Control in Alzheimer's Disease: Insights from Caenorhabditis elegans Models.
    Upasana Ganguly, Trae Carroll, Keith Nehrke, Gail V W Johnson.
      Alzheimer's disease (AD) is a complex neurodegenerative disorder that is classically defined by the extracellular deposition of senile plaques rich in amyloid-beta (Aβ) protein and the intracellular accumulation of neurofibrillary tangles (NFTs) that are rich in aberrantly modified tau protein. In addition to aggregative and proteostatic abnormalities, neurons affected by AD also frequently possess dysfunctional mitochondria and disrupted mitochondrial maintenance, such as the inability to eliminate damaged mitochondria via mitophagy. Decades have been spent interrogating the etiopathogenesis of AD, and contributions from model organism research have aided in developing a more fundamental understanding of molecular dysfunction caused by Aβ and toxic tau aggregates. The soil nematode C. elegans is a genetic model organism that has been widely used for interrogating neurodegenerative mechanisms including AD. In this review, we discuss the advantages and limitations of the many C. elegans AD models, with a special focus and discussion on how mitochondrial quality control pathways (namely mitophagy) may contribute to AD development. We also summarize evidence on how targeting mitophagy has been therapeutically beneficial in AD. Lastly, we delineate possible mechanisms that can work alone or in concert to ultimately lead to mitophagy impairment in neurons and may contribute to AD etiopathology.
    Keywords:  Alzheimer’s disease; Caenorhabditis elegans; aging; mitochondria; mitochondria quality control; mitophagy; model organism; neurodegeneration
    DOI:  https://doi.org/10.3390/antiox13111343
  13. Biochem Pharmacol. 2024 Nov 26. pii: S0006-2952(24)00670-1. [Epub ahead of print] 116669
    Mitochondria-targeting therapeutic strategies for chronic kidney disease.
    Annie Sun, Carol A Pollock, Chunling Huang.
      Chronic kidney disease (CKD) is a multifactorial health issue characterised by kidney impairment that has significant morbidity and mortality in the global population. Current treatments for CKD fail to prevent progression to end-stage kidney disease, where management is limited to renal replacement therapy or kidney transplantation. Mitochondrial dysfunction has been implicated in the pathogenesis of CKD and can be broadly categorised into abnormalities related to excessive oxidative stress, reduced mitochondrial biogenesis, excess mitochondrial fission and dysregulated mitophagy. Mitochondria-targeting therapeutic strategies target many of the outlined mechanisms of mitochondrial dysfunction, and an overview of recent evidence for mitochondria-targeting therapeutic strategies is explored in this review, including naturally derived compounds and novel approaches such as fusion proteins. Mitochondria-targeting therapeutic strategies using these approaches show the potential to stabilise or improve renal function, and clinical studies are needed to further confirm the safety and efficacy in human contexts.
    Keywords:  Chronic kidney disease; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial dysfunction; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bcp.2024.116669
  14. Adv Sci (Weinh). 2024 Nov 25. e2407757
    Self-Healing COCu-Tac Hydrogel Enhances iNSCs Transplantation for Spinal Cord Injury by Promoting Mitophagy via the FKBP52/AKT Pathway.
    Zhenming Tian, Han-Jian Hu, Chun Cheung Chan, Tian Hu, Chaoyang Cai, Hong Li, Limin Rong, Gang-Biao Jiang, Bin Liu.
      In the realm of neural regeneration post-spinal cord injury, hydrogel scaffolds carrying induced neural stem cells (iNSCs) have demonstrated significant potential. However, challenges such as graft rejection and dysfunction caused by mitochondrial damage persist after transplantation, presenting formidable barriers. Tacrolimus, known for its dual role as an immunosuppressant and promoter of neural regeneration, holds the potential for enhancing iNSC transplantation. However, systemic administration of tacrolimus often comes with severe side effects. This study pioneers the development of a self-healing hydrogel with sustained-release tacrolimus (COCu-Tac), tailored specifically for iNSC transplantation after spinal cord injury. This research reveals that the sustained release of tacrolimus enhances axonal growth and improves mitochondrial quality control in iNSCs and neurons. Further analysis shows that tacrolimus targets FKBP52 rather than FKBP51, enhancing mitophagy via the FKBP52/AKT pathway. This advanced system demonstrates significant efficacy in promoting neural regeneration and restoring motor function following spinal cord injury.
    Keywords:  FKBP52; induced neural stem cells; mitophagy; self‐healing hydrogel; spinal cord injury
    DOI:  https://doi.org/10.1002/advs.202407757
  15. Redox Biol. 2024 Nov 23. pii: S2213-2317(24)00413-0. [Epub ahead of print]78 103435
    YAP1 preserves tubular mitochondrial quality control to mitigate diabetic kidney disease.
    Siyang Ye, Meng Zhang, Xunhua Zheng, Suchun Li, Yuting Fan, Yiqin Wang, Huajing Peng, Sixiu Chen, Jiayi Yang, Li Tan, Manhuai Zhang, Peichen Xie, Xiaoyan Li, Ning Luo, Zhipeng Wang, Leigang Jin, Xiaoping Wu, Yong Pan, Jinjin Fan, Yi Zhou, Sydney C W Tang, Bin Li, Wei Chen.
      Renal tubule cells act as a primary site of injury in diabetic kidney disease (DKD), with dysfunctional mitochondrial quality control (MQC) closely associated with progressive kidney dysfunction in this context. Our investigation delves into the observed inactivation of yes-associated protein 1 (YAP1) and consequential dysregulation of MQC within renal tubule cells among DKD subjects through bioinformatic analysis of transcriptomics data from the Gene Expression Omnibus (GEO) dataset. Receiver operating characteristic curve analysis unequivocally underscores the robust diagnostic accuracy of YAP1 and MQC-related genes for DKD. Furthermore, we observed YAP1 inactivation, accompanied by perturbed MQC, within cultured tubule cells exposed to high glucose (HG) and palmitic acid (PA). This pattern was also evident in the tubulointerstitial compartment of kidney sections from biopsy-approved DKD patients. Additionally, renal tubule cell-specific Yap1 deletion exacerbated kidney injury in diabetic mice. Mechanistically, Yap1 deletion disrupted MQC, leading to mitochondrial aberrations in mitobiogenesis and mitophagy within tubule cells, ultimately culminating in histologic tubular injury. Notably, Yap1 deletion-induced renal tubule injury promoted the secretion of C-X-C motif chemokine ligand 1 (CXCL1), potentially augmenting M1 macrophage infiltration within the renal microenvironment. These multifaceted events were significantly ameliorated by administrating the YAP1 activator XMU-MP-1 in DKD mice. Consistently, bioinformatic analysis of transcriptomics data from the GEO dataset revealed a noteworthy upregulation of tubule cells-derived chemokine CXCL1 associated with macrophage infiltration among DKD patients. Crucially, overexpression of YAP1 via adenovirus transfection sustained mitochondrial membrane potential, mtDNA copy number, oxygen consumption rate, and activity of mitochondrial respiratory chain complex, but attenuated mitochondrial ROS production, thereby maintaining MQC and subsequently suppressing CXCL1 generation within cultured tubule cells exposed to HG and PA. Collectively, our study establishes a pivotal role of tubule YAP1 inactivation-mediated MQC dysfunction in driving DKD progression, at least in part, facilitated by promoting M1 macrophage polarization through a paracrine-dependent mechanism.
    Keywords:  Chemokine; Diabetic kidney disease; Hippo signaling pathway; Macrophage; Mitochondria; Yes-associated protein 1
    DOI:  https://doi.org/10.1016/j.redox.2024.103435
  16. Mol Neurobiol. 2024 Nov 28.
    P2Y6R Inhibition Induces Microglial M2 Polarization by Promoting PINK1/Parkin-Dependent Mitophagy After Spinal Cord Injury.
    Jiezhao Lin, Yuanfang Sun, Haoran Huang, Cheng Yu, Wenhao Kuang, Yihan Wang, Lixin Zhu.
      Secondary injury presents a significant hurdle to neural regeneration following spinal cord injury (SCI), primarily driven by inflammation in which microglial cells play a crucial role. Despite the growing interest in mitophagy, studies on its occurrence post-spinal cord injury, particularly within microglial cells, are scarce. While P2Y6R has been implicated in inflammation regulation in various neurological conditions, its specific role in SCI remains uncertain. Our study revealed an upregulation of P2Y6R expression following SCI notably in microglial cells. Treatment with the P2Y6R-specific inhibitor, MRS2578, in mice facilitated M2 polarization of microglial cells and alleviated secondary damage, ultimately enhancing neural regeneration and functional recovery. In an in vitro BV2 inflammation model, our findings indicate that P2Y6R inhibition induced M2 polarization of BV2 cells and reduced neuroinflammation through PINK/Parkin-dependent mitophagy activation. In summary, our results underscore the potential of P2Y6R inhibition in promoting mitophagy-induced M2 polarization of microglial cells, thereby ameliorating secondary injury following spinal cord injury.
    Keywords:  M2 polarization; Microglial; Mitophagy; P2Y6R; Spinal cord injury
    DOI:  https://doi.org/10.1007/s12035-024-04631-5
  17. Cell Mol Biol Lett. 2024 Nov 27. 29(1): 145
    KPNB1-ATF4 induces BNIP3-dependent mitophagy to drive odontoblastic differentiation in dental pulp stem cells.
    Zeying Zhang, Di Yang, Xiaoyuan Yan, Qiujing Qiu, Jiajie Guo, Lihong Qiu.
       BACKGROUND: Differentiating dental pulp stem cells (DPSCs) into odontoblasts is a critical process for tooth self-repair and dentine‒pulp engineering strategies in the clinic. However, the mechanism underlying the regulation of DPSC odontoblastic differentiation remains largely unknown. Here, we demonstrated that BCL-2 interacting protein 3 (BNIP3)-dependent mitophagy is associated with importin subunit beta-1 (KPNB1)-activating transcription factor 4 (ATF4), which promotes DPSC odontoblastic differentiation.
    METHODS: The key genes involved in DPSC odontogenic differentiation were identified via bioinformatics. Stable silencing or overexpression of BNIP3 was performed to investigate its impact on DPSC differentiation in vitro (n ≥ 3). To explore the role of BNIP3 in vivo, tooth root fragments loaded with the hydrogel-transfected DPSC complex were implanted into nude mice (n ≥ 6). Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) polymerase chain reaction (PCR) were conducted to explore the binding site of ATF4 to the BNIP3 promoter (n ≥ 3). Mitochondrial function experiments were performed to investigate the impact of ATF4-BNIP3 on mitochondria (n ≥ 3). Immunoprecipitation (IP) mass spectrometry (MS) was used to investigate the interaction between ATF4 and its binding protein, KPNB1. Plasmids containing wild-type (WT)/mutant (MUT)-nuclear localization signal (NLS) forms of ATF4 were constructed to determine the specific amino acid residues recognized by KPNB1 and their effects on DPSC odontoblastic differentiation (n ≥ 3).
    RESULTS: Compared with those in the control group, the levels of autophagy and mitophagy, especially BNIP3-dependent mitophagy, were greater in the DPSC odontoblastic differentiation group (P < 0.05). Genetic silencing or overexpression of BNIP3 demonstrated that BNIP3 expression was positively correlated with the transition of DPSCs into odontoblasts both in vitro and in vivo (P < 0.05). ATF4 regulates the expression of BNIP3 by directly binding to approximately -1292 to -1279 bp and approximately -1185 to -1172 bp within the BNIP3 promoter region, which is associated with mitophagy and mitochondrial reactive oxygen species (mtROS) levels (P < 0.05). Moreover, ATF4 increased mitophagy, mitochondrial function, and cell differentiation potential via BNIP3 (P < 0.05). Mechanistically, KPNB1 is a novel interacting protein of ATF4 that specifically recognizes amino acids (aa) 280-299 within ATF4 to control its translocation into the nucleus and subsequent transcription and differentiation processes (P < 0.05).
    CONCLUSIONS: We reported that the critical role of KPNB1/ATF4/BNIP3 axis-dependent mitophagy could provide new cues for the regeneration of the dental pulp‒dentin complex in DPSCs.
    Keywords:  ATF4; BNIP3; Dental pulp stem cell; KPNB1; Mitophagy; Odontoblastic differentiation
    DOI:  https://doi.org/10.1186/s11658-024-00664-9
  18. Nutrients. 2024 Nov 14. pii: 3878. [Epub ahead of print]16(22):
    Nano-Selenium Modulates NF-κB/NLRP3 Pathway and Mitochondrial Dynamics to Attenuate Microplastic-Induced Liver Injury.
    Qi Shen, Yunjie Liu, Jiakui Li, Donghai Zhou.
       BACKGROUND: Microplastics (PS-MPs) are a new type of pollutant with definite hepatotoxicity. Selenium, on the other hand, has natural, protective effects on the liver.
    OBJECTIVES/METHODS: The purpose of this experiment is to find out whether nano-selenium (SeNP) can alleviate liver damage caused by microplastics. Initially, we established through in vitro experiments that SeNP has the ability to enhance the growth of healthy mouse liver cells, while microplastics exhibit a harmful impact on normal mouse hepatocyte cell suspensions, leading to a decrease in cell count. Subsequently, through in vivo experiments on male ICR mice, we ascertained that SeNPs alleviated the detrimental impacts of PS-MPs on mouse liver.
    RESULTS: SeNPs hinder the signaling pathway of NF-κB/NLRP3 inflammatory vesicles, which is crucial for reducing inflammation induced by PS-MPs. In terms of their mechanism, SeNPs hinder the abnormalities in mitochondrial fission, biogenesis, and fusion caused by PS-MPs and additionally enhance mitochondrial respiration. This enhancement is crucial in averting disorders in energy metabolism and inflammation.
    CONCLUSIONS: To summarize, the use of SeNPs hindered inflammation by regulating mitochondrial dynamics, thus relieving liver damage caused by PS-MPs in mice. The anticipated outcomes offer new research directions that can be referenced in terms of inflammatory injuries caused by PS-MPs.
    Keywords:  NF-κB/NLRP3 signaling pathway; inflammation; microplastics; mitochondrial dynamics; nano-selenium
    DOI:  https://doi.org/10.3390/nu16223878
  19. Ageing Res Rev. 2024 Nov 26. pii: S1568-1637(24)00421-5. [Epub ahead of print] 102603
    The Mitochondrial Integrated Stress Response: A novel approach to anti-aging and pro-longevity.
    Xiaoding Wang, Guangyu Zhang.
      The ISR is a cellular signaling pathway that responds to various physiological changes and types of stimulation. The mitochondrial integrated stress response (ISRmt) is a stress response specific to mitochondria which is initiated by eIF2α phosphorylation and is responsive to mitochondrial stressors. The ISRmt triggers diverse metabolic responses reliant on activating transcription factor 4 (ATF4). The preliminary phases of ISRmt can provoke an adaptive stress response that antagonizes age-related diseases and promotes longevity. In this review, we provide an overview of the molecular mechanisms of the ISRmt, with a particular focus on its potential as a therapeutic target for age-related disease and the promotion of longevity.
    Keywords:  FGF21; Mitochondrial integrated stress response; aging; longevity
    DOI:  https://doi.org/10.1016/j.arr.2024.102603
  20. Biol Direct. 2024 Nov 29. 19(1): 126
    Soft X-ray tomography analysis of mitochondria dynamics in Saccharomyces cerevisiae.
    Wei-Ling Huang, Chang-Lin Chen, Zi-Jing Lin, Chia-Chun Hsieh, Mo Da-Sang Hua, Chih-Chan Cheng, Tzu-Hao Cheng, Lee-Jene Lai, Chuang-Rung Chang.
       BACKGROUND: Mitochondria are highly dynamic organelles that constantly undergo processes of fission and fusion. The changes in mitochondrial dynamics shape the organellar morphology and influence cellular activity regulation. Soft X-ray tomography (SXT) allows for three-dimensional imaging of cellular structures while they remain in their natural, hydrated state, which omits the need for cell fixation and sectioning. Synchrotron facilities globally primarily use flat grids as sample carriers for SXT analysis, focusing on adherent cells. To investigate mitochondrial morphology and structure in hydrated yeast cells using SXT, it is necessary to establish a method that employs the flat grid system for examining cells in suspension.
    RESULTS: We developed a procedure to adhere suspended yeast cells to a flat grid for SXT analysis. Using this protocol, we obtained images of wild-type yeast cells, strains with mitochondrial dynamics defects, and mutant cells possessing distinctive mitochondria. The SXT images align well with the results from fluorescent microscopy. Optimized organellar visualization was achieved by constructing three-dimensional models of entire yeast cells.
    CONCLUSIONS: In this study, we characterized the mitochondrial network in yeast cells using SXT. The optimized sample preparation procedure was effective for suspended cells like yeast, utilizing a flat grid system to analyze mitochondrial structure through SXT. The findings corresponded with the mitochondrial morphology observed under fluorescence microscopy, both in regular and disrupted dynamic equilibrium. With the acquired image of unique mitochondria in Δhap2 cells, our results revealed that intricate details of organelles, such as mitochondria and vacuoles in yeast cells, can be characterized using SXT. Therefore, this optimized system supports the expanded application of SXT for studying organellar structure and morphology in suspended cells.
    Keywords:  Mitochondria; Soft X-ray tomography; Yeast
    DOI:  https://doi.org/10.1186/s13062-024-00570-2
  21. Dev Comp Immunol. 2024 Nov 27. pii: S0145-305X(24)00167-8. [Epub ahead of print] 105295
    CgANT2 regulates mitophagy of oyster haemocyte response against bacterial stimulation.
    Wei Wu, Xiaoqian Lv, Jiejie Sun, Zihan Wang, Miren Dong, Lingling Wang, Linsheng Song.
      Adenine nucleotide translocator (ANT) is a major molecule in the inner membrane of mitochondria that plays an important role in regulating mitophagy. In the present study, a conserved ANT2 homologue (designated as CgANT2) was identified and functionally characterized in oyster Crassostrea gigas. There were three typical Mito_carr tandem repeats in CgANT2. The mRNA expression levels of CgANT2 in haemocytes increased significantly at 24 and 72 h after Vibrio splendidus stimulation. Its protein was abundantly expressed in granulocytes and was observed to be colocalized with mitochondria. When CgANT2 expression was suppressed by injection with its dsRNA, there was an increased mitochondrial reactive oxygen species (mtROS) production and mitochondrial permeability transition pore (mPTP) opening, while the mRNA expression levels of mitophagy-related genes (CgPINK1 and CgParkin) and the percentage of mitophagy in haemocytes all decreased significantly. These results indicated that CgANT2 regulated mtROS production and mPTP opening, thereby inducing mitophagy in the oyster haemocyte response against V. splendidus stimulation.
    Keywords:  Crassostrea gigas; adenine nucleotide translocator 2; haemocyte mitophagy; immune response; mtROS production
    DOI:  https://doi.org/10.1016/j.dci.2024.105295
  22. Pharmacol Res. 2024 Nov 26. pii: S1043-6618(24)00467-5. [Epub ahead of print] 107522
    Erratum to "Cardiovascular disease: Mitochondrial dynamics and mitophagy crosstalk mechanisms with novel programmed cell death and macrophage polarisation" [Pharmacol Res 206 (2024) 107258].
    Dandan Liu, Hewei Qin, Yang Gao, Mengyan Sun, Mengnan Wang.
      
    DOI:  https://doi.org/10.1016/j.phrs.2024.107522
  23. Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Nov 23. pii: S1388-1981(24)00132-X. [Epub ahead of print]1870(2): 159582
    Dysregulated mitochondrial fission and neurodegeneration proteomic signature in ACSF3-deficient cells.
    Khaled Alatibi, Kathrin Sumser, Maria Elpida Christopoulou, Martin J Hug, Sara Tucci.
      
    Keywords:  ACSF3; Energy metabolism; Mitochondrial dynamics; Neurodegeneration
    DOI:  https://doi.org/10.1016/j.bbalip.2024.159582
  24. Exp Cell Res. 2024 Nov 22. pii: S0014-4827(24)00436-1. [Epub ahead of print] 114345
    Fbxo11 maintains mitochondrial function and prevents podocyte injury in adriamycin-induced nephropathy by mediating the ubiquitin degradation of Fosl2.
    Yanhua Jin, Huan Wang, Yu Xin, Yanning Zhang.
      Mitochondrial dysfunction is a pivotal factor in the onset of podocyte damage, which is a central component in the pathogenesis of nephrotic syndrome (NS). However, the precise mechanisms underlying the changes in podocyte mitochondria remain elusive. Our study aims to clarify the potential mechanisms involved in the role of F-box protein 11 (Fbxo11) in NS, specifically concentrating on its impact on mitochondrial function. A mouse model was established by tail vein injection of adriamycin (ADR, 10 mg/kg) and was infected with lentivirus overexpressing Fbxo11. Mouse podocytes (MPC-5) were infected with lenti-Fbxo11-OE, followed by treatment with 0.4 μg/mL of ADR. We identified the decreased expression of Fbxo11 in mouse kidney tissues and MPC-5 cells induced by ADR. Lenti-Fbxo11-OE intervention relieved ADR-induced glomerular lesion, podocyte injury, and mitochondrial dysfunction. In vitro, overexpression of Fbxo11 in mouse podocytes improved mitochondrial function and reduced podocyte damage, thereby inhibiting podocyte apoptosis. Mechanistically, Fbxo11 decreased the protein expression of Fosl2 through ubiquitin-dependent proteasomal degradation. Rescue experiments revealed that overexpression of Fosl2 abolished the protective effects of Fbxo11 overexpression on mitochondrial damage and podocyte injury. Importantly, the regulatory effects of the Fbxo11/Fosl2 axis were reversed when treated with the mitochondrial fission inhibitor mdivi-1. Taken together, our results demonstrated that Fbxo11-mediated ubiquitin degradation of Fosl2 is critical for maintaining mitochondrial function and preventing podocyte injury during NS.
    Keywords:  Fbxo11; Fosl2; adriamycin; mitochondrial dysfunction; nephrotic syndrome; podocyte injury
    DOI:  https://doi.org/10.1016/j.yexcr.2024.114345
  25. Research (Wash D C). 2024 ;7 0539
    STAT2/SLC27A3/PINK1-Mediated Mitophagy Remodeling Lipid Metabolism Contributes to Pazopanib Resistance in Clear Cell Renal Cell Carcinoma.
    Dingheng Lu, Yuxiao Li, Xinyang Niu, Jiazhu Sun, Weitao Zhan, Yuchen Shi, Kai Yu, Suyuelin Huang, Xiaoyan Liu, Liping Xie, Xueyou Ma, Ben Liu.
      Background: Clear cell renal cell carcinoma (ccRCC) is a prevalent malignant tumor of the urinary system. While tyrosine kinase inhibitors (TKIs) are currently the first-line treatments for advanced/metastatic ccRCC, patients often develop resistance after TKI therapy. Lipid metabolic reprogramming, a hallmark of tumor progression, contributes to acquired drug resistance in various malignant tumors. Mitophagy, a process that maintains mitochondrial homeostasis, aids tumor cells in adapting to microenvironmental changes and consequently developing drug resistance. Solute carrier family 27 member 3 (SLC27A3), highly expressed in lipid-rich tumors like ccRCC, has been associated with poor prognosis. However, the impact of SLC27A3 and the transcription factor complex containing STAT2 on lipid metabolic reprogramming, mitophagy in ccRCC, and their role in TKI resistance remain unexplored. Methods: 786-O to pazopanib resistance was induced by gradient increase of concentration, and the genes related to lipid metabolism were screened by RNA sequencing. Bioinformatics was used to analyze the differential expression of SLC27A3 and its effect on patient prognosis, and to predict the activated pathway in pazopanib-resistant cells. Lipid droplets (LDs) were detected by Red Oil O and BODIPY probe. Micro-targeted lipidomic of acyl-coenzyme A (CoA) and lipid metabolomics were performed to screen potential metabolites of SLC27A3. The differential expression of SLC27A3 was detected in clinical samples. The differential expression of SLC27A3 and its effect on drug resistance of ccRCC tumor were detected in vitro and in vivo. Mitophagy was detected by electron microscopy, Mtphagy probe, and Western blot. The mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels were detected by JC-1 and DCF probes. The binding site of the transcription factor complex to the SLC27A3 promoter was detected by dual-luciferase reporter gene assay. Results: SLC27A3, highly expressed in lipid-rich tumors such as ccRCC and glioblastoma, predicts poor prognosis. SLC27A3 expression level also increased in pazopanib-resistant 786-O cells (786-O-PR) with more LD accumulation compared to parental cells. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis from RNA sequencing showed that PINK1/Parkin-mediated mitophagy pathway was enriched in 786-O-PR. Knockdown of SLC27A3 markedly suppressed LD accumulation and mitophagy, and overcame pazopanib resistance in vitro and in vivo. Moreover, SLC27A3 functions as an acyl-CoA ligase catalyzing the formation of acyl-CoA, which refers to fatty acid oxidation accompanied by ROS production and synthesis of lipid. Overproduced acyl-CoA oxidation in mitochondria resulted in MMP decrease and amounts of ROS production, subsequently triggering PINK1/Parkin-mediated mitophagy. Moreover, mitophagy inhibition led to more ROS accumulation and cell death, indicating that mitophagy can keep ROS at an appropriate level by negative feedback. Mitophagy, simultaneously, prevented fatty acid oxidation in mitochondria by consuming CPT1A, forcing synthesis of triglycerides and cholesterol esters stored in LDs by transforming acyl-CoA, to support ccRCC progression. Besides, we found that STAT2 expression was positively correlated to SLC27A3. Transcriptional factor complex containing STAT2 could bind to the promoter of SLC27A3 mRNA to promote SLC27A3 transcription proved by dual-luciferase reporter assay, which also regulated LD metabolism and activated mitophagy during pazopanib resistance. Conclusion: SLC27A3 is up-regulated in pazopanib-resistant ccRCC and predicts poor prognosis. High expression of SLC27A3 produces excessive metabolites of various long-chain fatty acyl-CoA (12:0-, 16:0-, 17:0-, 20:3-CoA) to enter mitochondria for β-oxidation and produce amounts of ROS activating mitophagy. Subsequent mitophagy/ROS negative feedback controls ROS homeostasis and consumes CPT1A protein within mitochondria to suppress fatty acid β-oxidation, forcing acyl-CoA storage in LDs, mediating pazopanib resistance in ccRCC. Furthermore, STAT2 was identified as a core component of a potential upstream transcriptional factor complex for SLC27A3. Our findings shed new light on the underlying mechanism of SLC27A3 in ccRCC TKI resistance, which may provide a novel therapeutic target for the management of ccRCC.
    DOI:  https://doi.org/10.34133/research.0539
  26. Biomolecules. 2024 Oct 28. pii: 1370. [Epub ahead of print]14(11):
    Use of Caenorhabditis elegans to Unravel the Tripartite Interaction of Kynurenine Pathway, UPRmt and Microbiome in Parkinson's Disease.
    Charles Viau, Alyssa Nouar, Jianguo Xia.
      The model organism Caenorhabditis elegans and its relationship with the gut microbiome are gaining traction, especially for the study of neurodegenerative diseases such as Parkinson's Disease (PD). Gut microbes are known to be able to alter kynurenine metabolites in the host, directly influencing innate immunity in C. elegans. While the mitochondrial unfolded protein response (UPRmt) was first characterized in C. elegans in 2007, its relevance in host-microbiome interactions has only become apparent in recent years. In this review, we provide novel insights into the current understanding of the microbiome-gut-brain axis with a focus on tripartite interactions between the UPRmt, kynurenine pathway, and microbiome in C. elegans, and explore their relationships for PD remediations.
    Keywords:  C. elegans; Parkinson’s disease; UPRmt; kynurenine; microbiome
    DOI:  https://doi.org/10.3390/biom14111370
  27. Int J Clin Oncol. 2024 Nov 27.
    Prediction of prognosis and immune response in lung adenocarcinoma based on mitophagy and lactate-related gene signatures.
    Wenjie Jiang, Fan Zhang, Zhen Tang, Shuonan Xu, Yukun Zhang, Lina Liu, Daixing Zhong, Yingxiang Liu.
       BACKGROUND: Lung adenocarcinoma (LUAD) causes leading death worldwide. Mitophagy and lactate metabolism accumulation are distinctive features of LUAD. We aimed to identify lactate-related genes (LRGs) signatures based on mitophagy for predicting prognosis and immune response in LUAD.
    METHODS: The gene expression and clinical data were downloaded from TCGA and GEO database. First, the subtype analysis was analyzed based on 29 mitophagy genes. Survival, immune, and function differences between the different subtypes were analyzed. Then, based on mitophagy genes and 14 LRGs, the best LRGs were screened to construct a risk score model and combined with clinical factors to establish a nomogram for predicting patient survival. Finally, the expression level and molecular function of the key candidate gene OGDH were verified by in vitro experiments.
    RESULTS: All the LUAD samples were divided into 2 subtypes: sub1 and sub2. The sub2 possessed worse survival. Immune score, immune checkpoint genes, and human leucocyte antigen genes in sub1 were higher than in sub2. Six optimal mitophagy-related LRGs were used to construct a risk score model. A high-risk score indicates poorer survival, higher tumor mutation burden, and higher drug sensitivity. The nomogram was robust in predicting LUAD survival. The experiments in vitro showed that knockdown of OGDH inhibited the proliferation, migration and invasion in LUAD cells.
    CONCLUSIONS: A nomogram based on the construction of the mitophagy-related lactate genes predicts prognosis and immune response in LUAD. These results could help with risk stratification and targeted therapy for LUAD.
    Keywords:  Immune microenvironment; Lactate; Lung adenocarcinoma; Mitophagy; Nomogram
    DOI:  https://doi.org/10.1007/s10147-024-02664-3
  28. Autism Res. 2024 Nov 29.
    Analysis of mitochondrial DNA replisome in autism spectrum disorder: Exploring the role of replisome genes.
    Valentina Rojas, Carlos Carrasco-Gallardo, Lidia Tenorio, Margrethe A Olesen, Victor Tapia, Manuel Carrasco, Patricio Araos, Rodrigo A Quintanilla, Lina M Ruiz.
      Autism spectrum disorder (ASD) is a neurodevelopmental condition often associated with mitochondrial dysfunction, including increased mitochondrial DNA (mtDNA) copy number and impaired energy production. This study investigates the role of the mitochondrial replisome-specifically, the genes TFAM, TWNK, POLG, and TOP1MT-in mtDNA replication and its potential contribution to ASD pathophysiology. We analyzed samples from the oral mucosa of children with ASD and typically developing (TD) controls, assessing mtDNA copy number, gene expression, and protein levels. Our findings revealed a significant increase in mtDNA copy number in the oral mucosa of ASD children, along with partially deleted mtDNA molecules. However, there were no significant changes in the expression of TFAM, TWNK, POLG, or MT-TL1 genes between ASD and TD samples. Additionally, TFAM protein levels, including monomeric, dimeric, and trimeric forms, did not differ significantly. We also observed increased oxidative stress and inflammatory markers in the oral mucosa of ASD children, suggesting that mitochondrial alterations may be linked to inflammation and oxidative damage in ASD. To further investigate the functional impact of TFAM, we overexpressed it in human HEK293 cells and cortical neurons (CN1.4). TFAM overexpression led to increased mtDNA copy number, cell proliferation, and ATP production in HEK293 cells, but did not significantly alter mitochondrial gene expression, protein oxidation, or mtDNA integrity. In CN1.4 neurons, TFAM overexpression increased mitochondrial membrane potential and length, indicating potential changes in mitochondrial dynamics. Overall, our study suggests that while mtDNA alterations are present in ASD, they are not directly driven by changes in mitochondrial replisome gene expression. These findings highlight the complexity of mitochondrial dysfunction in ASD and suggest the need for further investigation into the underlying molecular mechanisms.
    Keywords:  ASD; MT‐TL1; POLG; TFAM overexpression; TOPMT1; TWNK; autism; mitochondrial DNA; mtDNA replisome; TFAM
    DOI:  https://doi.org/10.1002/aur.3277
  29. J Agric Food Chem. 2024 Nov 25.
    Myricetin Alleviates Silica-Mediated Lung Fibrosis via PPARγ-PGC-1α Loop and Suppressing Mitochondrial Senescence in Epithelial Cells.
    Weixi Xie, Lang Deng, Xiaohua Zhang, Xiaoting Huang, JinFeng Ding, Wei Liu, Si-Yuan Tang.
       OBJECTIVE: Long-term inhalation of silica dust particles leads to lung tissue fibrosis, resulting in impaired gas exchange and increased mortality. Silica inhalation triggers the aging of epithelial cells (AECs), which is a key contributor to the development of pulmonary fibrosis. Myricetin, a flavonoid compound extracted from Myrica genus plants, possesses various biological activities, including antioxidant and immunomodulatory effects. However, the mechanisms underlying myricetin's ability to counter senescence and fibrosis need to be further studied.
    EXPERIMENTAL APPROACH: In vivo, the antifibrotic and anti-senescence effects of myricetin were evaluated using a silica-induced pulmonary fibrosis mouse model. To further elucidate the mechanisms by which myricetin counteracts silica-induced senescence, in vitro experiments were conducted using AECs.
    RESULTS: Our studies revealed that myricetin treatment alleviated silica-induced mortality, improved lung function, and reduced the severity of pulmonary fibrosis in mice. Immunofluorescence analysis suggests its potential in mitigating senescence of AECs. Under laboratory conditions, myricetin intervened in the cellular senescence pathway induced by silica dust by modulating mitochondrial function. It acted through the PPARγ-PGC1α axis, effectively reducing silica-induced mitochondrial oxidative stress in AECs, promoting mitophagy, and maintaining mitochondrial dynamics. However, the efficacy of myricetin was reversed under PPARγ siRNA intervention. Additionally, myricetin exhibited an enhancing effect on PPARγ and autophagy in animal models. Treatment with PPARγ and PGC-1α siRNA elucidated the role of myricetin in promoting the formation of a positive feedback loop between PPARγ and PGC-1α. Additionally, the PPARγ inhibitor GW9662 verified the in vivo effects of myricetin.
    CONCLUSIONS: Myricetin activates PPARγ, forming a PPARγ-PGC-1α loop, which promotes mitophagy and maintains mitochondrial dynamics. This alleviates epithelial cell senescence induced by silica exposure, consequently mitigating silica-induced pulmonary fibrosis in mice.
    Keywords:  PGC-1α; mitochondria; myricetin; pparγ; senescence; silicosis
    DOI:  https://doi.org/10.1021/acs.jafc.4c04887
  30. J Craniofac Surg. 2024 Nov 25.
    FSTL1 Can Be a Promising Target in TMJ Osteoarthritis via Regulating Chondrocyte Mitophagy and Apoptosis.
    Fangjie Li, Weixiang Qian, Jiayao Wang, Minghua Gao.
       BACKGROUND: Previous studies have shown that follistatin-like protein 1 (FSTL1) is elevated in the synovial fluid of osteoarthritis and whether it is associated with disease development progress in cartilage degeneration is still unclear. The experiment was performed to explore the effect and mechanism of FSTL1 on chondrocyte degeneration and its further impaction in osteoarthritis as well as its treatment method.
    METHODS: The patients who were diagnosed with temporomandibular joint (TMJ) disc displacement and osteoarthritis (OA) group was divided into 2 groups, anterior disc displacement (ADD) without bone resorption and ADD with bone resorption group according to the radiologic examination. The ELISA kit was used to determine the expression level of FSTL1 in patients TMJ environment. The function of FSTL1 in promoting chondrocyte degeneration was tested by quantitative reverse transcription polymerase chain reaction (Rt-qPCR) and western blot. The chondrocyte apoptosis and mitophagy were further test by flow cytometry and mitosox staining by upregulating and downregulating of FSTL1. In the end, the effectiveness of regulating FSTL1 in OA procedure was further validated by hematoxylin-eosin (HE), safranin O, and immunohistochemical (IHC) staining in vivo.
    RESULTS: There were 56 samples collected from the patients were included into this study. According to the ELISA results, FSTL1 expression levels of ADD without bone resorption groups were significantly lower than that in ADD with bone resorption group. Furthermore, the rate of cell apoptosis cells and the mitophagy procedure were highly activated when FSTL1 was upregulated. The morphology analysis of mitochondria showed significant changes when FSTL1 was highly upregulated in vitro. The in vivo and in vitro experiments showed that suppressing FSTL1 could alleviate the cartilage degeneration in TMJ OA progression.
    CONCLUSIONS: To sum up, upregulated expression level of FSTL1 in synovial fluid promoted the progression of TMJ OA by upregulating accelerating the chondrocyte apoptosis and mitophagy, and suppressing the FSTL1 in TMJ can rescue the OA progression. Therefore, it may be a promising result to consider the FSTL1 as a therapeutic target in the future.
    DOI:  https://doi.org/10.1097/SCS.0000000000010906
  31. Life (Basel). 2024 Nov 19. pii: 1507. [Epub ahead of print]14(11):
    Comparison of the Mitophagy and Apoptosis Related Gene Expressions in Waste Embryo Culture Medium of Female Infertility Types.
    Duygu Kütük, Çağrı Öner, Murat Başar, Berkay Akcay, İbrahim Orçun Olcay, Ertuğrul Çolak, Belgin Selam, Mehmet Cincik.
      Mitochondria is an important organelle for the oocyte-to-embryo transition in the early embryonic development period. The oocyte uses mitochondria functionally and its mitochondrial DNA (mtDNA) content as the main energy source in the embryo development at the preimplantation stage. The aim of this study is to compare mitophagic, apoptotic and humanin gene expressions from the culture medium fluid in which embryos are developed and monitored among normoresponder (NOR), polycystic ovary syndrome (PCOS), young and older patients with poor ovarian reserve (POR). The study groups consisted of infertile patients who applied to the Bahçeci Umut IVF Center as NOR (Control), PCOS, POR-Advanced (POR-A) and POR-Young (POR-Y). After the isolation of total RNA from the collected samples, MFN1, MFN2, PINK1, PARKIN, SMN1, SMN2, p53 and Humanin gene expressions were determined by Real Time-PCR. The average age of only the POR-A was determined to be higher than the NOR (p < 0.001). The MFN1, SMN2 (p < 0.05), Humanin and p53 gene expressions (p < 0.001) increased, while PINK1 gene expression decreased (p < 0.05), in the POR-Y compared to the NOR. A decrease in MFN2, PARKIN (p < 0.05) and PINK1 gene expressions was determined in the PCOS compared to the NOR (p < 0.001). Furthermore, a decrease was observed in MFN2, PINK1 (p < 0.001) and Humanin gene expressions compared to the NOR (p < 0.05). The current data are the first in the literature determining the apoptotic and mitophagic status of the oocyte. The current results prove that waste embryo culture fluid may provide a non-invasive profile for important cellular parameters such as mitochondrial dysfunction in female infertility. The evaluation of significant cellular parameters can be performed much earlier without any intervention into the embryo.
    Keywords:  apoptosis; humanin; infertility; mitophagy; waste embryo culture medium
    DOI:  https://doi.org/10.3390/life14111507
  32. Comp Biochem Physiol C Toxicol Pharmacol. 2024 Nov 23. pii: S1532-0456(24)00232-1. [Epub ahead of print]288 110064
    MEHP induced mitochondrial damage by promoting ROS production in CIK cells, leading to apoptosis, autophagy, cell cycle arrest.
    Lu Li, Wan Li, Yufeng Liu, Bing Han, Yanbo Yu, Hongjin Lin.
      Although Mono (2-ethylhexyl) phthalate (MEHP) is a metabolite of Di (2-ethylhexyl) phthalate (DEHP), it has been confirmed to exhibit stronger biological toxicity than DEHP. Mitochondrial dynamic homeostasis and normal mitochondrial function regulate numerous physiological and pathological processes. However, it remains unclear whether MEHP triggers apoptosis, autophagy, and cell cycle arrest in grass carp kidney (CIK) cells by causing mitochondrial damage. Here, we established a MEHP dose-dependent exposure models in CIK cells and treated them with NAC. The results demonstrated that MEHP promoted ROS production and decreased antioxidant enzyme activities in CIK cells in a concentration-dependent manner. MEHP destroyed mitochondrial homeostasis and mitochondrial function in CIK cells, manifested by decreasing mitochondrial membrane potential (MMP), down-regulating gene expression of fusion division genes including MFN1, MFN2, CLPP, DRP1, OPA1, and MFF, and reducing OXPHOS complex enzyme protein level including COXI, COXII, COXIII, COXIV, and COXV. In addition, MEHP treatment not only can increase the level of Cyt-c, Atg12, Atg13, Atg14, Beclin1, ULK1, LC3-II, Caspase3, Caspase9, and Bax, but also can decrease the level of Bcl2, p62, CyclinB, CyclinD, and CyclinE in a concentration-dependent manner, which resulted in apoptosis, autophagy and cell cycle arrest. Furthermore, MEHP dose-dependently nduced downregulation gene expression of immunoglobulins and antimicrobial peptides (Hepcidin, β-defensin, LEAP2). However, NAC treatment could significantly reverse the above changes and alleviate CIK cells damage caused by exposure to MEHP. This study has expanded our understanding about molecular mechanisms of MEHP toxicity in aquatic animals and provided a reference for comparative medicine research.
    Keywords:  Apoptosis; Autophagy; Cell cycle arrest; MEHP; Mitochondrial damage; ROS
    DOI:  https://doi.org/10.1016/j.cbpc.2024.110064
  33. Int Immunopharmacol. 2024 Nov 22. pii: S1567-5769(24)02134-9. [Epub ahead of print]144 113612
    Luteolin ameliorates periodontitis by modulating mitochondrial dynamics and macrophage polarization via the JAK2/STAT3 pathway.
    SiJia Ma, Hongbing He, Xiaobin Ren, Rongkun Chen, Ruoyu Zhao, Keyu Dong, Chenxi Wei.
       BACKGROUND: Periodontal disease (PD) is a chronic inflammatory condition affecting oral and systemic health. Luteolin (LUT), a natural flavonoid, has shown anti-inflammatory effects, but its therapeutic potential and mechanisms in PD remain unclear.
    OBJECTIVE: This study aimed to investigate the effects of LUT on PD, focusing on its impact on mitochondrial dynamics, macrophage polarization, and the JAK2/STAT3 signaling pathway.
    METHODS: A combination of network pharmacology analysis and in vivo and in vitro experiments was employed. The efficacy of LUT was evaluated using a ligature-induced rat PD model and LPS-stimulated THP-1-derived macrophages. Key assessments included micro-CT for bone loss, flow cytometry for macrophage polarization, and Western blot for pathway analysis.
    RESULTS: LUT significantly reduced alveolar bone loss and enhanced M2 macrophage polarization, as indicated by increased CD206 and Arg1 expression. Additionally, it improved mitochondrial function by reducing ROS and restoring membrane potential, decreasing mitochondrial fission, and promoting mitochondrial fusion. Mechanistically, LUT inhibited JAK2/STAT3 phosphorylation, promoting anti-inflammatory effects.
    CONCLUSION: These findings suggest that LUT ameliorates periodontal inflammation and bone loss by modulating mitochondrial dynamics, promoting M2 macrophage polarization, and suppressing the JAK2/STAT3 signaling pathway. This highlights LUT as a promising multitarget candidate for PD treatment.
    Keywords:  JAK2/STAT3 signaling; Luteolin; Macrophage polarization; Mitochondrial dynamics; Periodontal disease
    DOI:  https://doi.org/10.1016/j.intimp.2024.113612
  34. Invest Ophthalmol Vis Sci. 2024 Nov 04. 65(13): 55
    cRGD-Conjugated Bilirubin Nanoparticles Alleviate Dry Eye Disease Via Activating the PINK1-Mediated Mitophagy.
    Yang Huang, Lijun Wang, Haiying Jin.
       Purpose: The purpose of this study was to evaluate the cytoprotective effect and the mechanism of cRGD-conjugated bilirubin nanoparticles (cNPs@BR) in dry eye disease (DED).
    Methods: The binding capacity and cellular uptake of cNPs@BR in human corneal epithelial cells (HCECs) were assessed by immunofluorescence. The anti-inflammation and anti-oxidative stress effects of cNPs@BR were determined by flow cytometry, immunofluorescence, Western blot, chromatin immunoprecipitation (ChIP), and ELISA assay in LPS-stimulated RAW264.7 cells and hypertonic HCECs. The function of ocular surface barrier, tear production, and the number of goblet cells after cNPs@BR treatment were further assessed by fluorescein sodium staining, phenol red cotton threads, quantitative PCR (qPCR), hematoxylin and eosin (H&E) staining, and Periodic Acid-Schiff (PAS) staining in a 0.2% BAC-induced DED mouse model. Furthermore, the mechanism of cNPs@BR in treating DED was explored by RNA sequencing and RNA interference.
    Results: The cRGD peptide prolonged the retention time of nanoparticles on HCECs and enhanced the cellular uptake efficiency. In both cell models, 20 µM cNPs@BR pretreatment ameliorated oxidative stress by decreasing the intracellular reactive oxygen species (ROS) levels and the expression of NOX4 and 4-HNE, while promoting HO-1 and nuclear Nrf2 levels. Moreover, cNPs@BR alleviated the inflammatory response by inhibiting NF-κB p65 nuclear translocation and decreasing the expression of iNOS and the secretion of IL-1β, IL-6, and TNF-α. In addition, cNPs@BR protected ocular surface epithelium against oxidative stress and inflammation and restored conjunctival goblet cells in the mouse model of DED by activating PINK1-mediated mitophagy.
    Conclusions: The cNPs@BR suppressed oxidative stress and inflammatory response in the ocular surface epithelium and restored goblet cells by activating PINK1-mediated mitophagy.
    DOI:  https://doi.org/10.1167/iovs.65.13.55
  35. Nucleic Acids Res. 2024 Nov 28. pii: gkae1144. [Epub ahead of print]
    DNA sequence and lesion-dependent mitochondrial transcription factor A (TFAM)-DNA-binding modulates DNA repair activities and products.
    Kathleen Urrutia, Yu Hsuan Chen, Jin Tang, Ta I Hung, Guodong Zhang, Wenyan Xu, Wenxin Zhao, Dylan Tonthat, Chia-En A Chang, Linlin Zhao.
      Mitochondrial DNA (mtDNA) is indispensable for mitochondrial function and is maintained by DNA repair, turnover, mitochondrial dynamics and mitophagy, along with the inherent redundancy of mtDNA. Base excision repair (BER) is a major DNA repair mechanism in mammalian mitochondria. Mitochondrial BER enzymes are implicated in mtDNA-mediated immune response and inflammation. mtDNA is organized into mitochondrial nucleoids by mitochondrial transcription factor A (TFAM). The regulation of DNA repair activities by TFAM-DNA interactions remains understudied. Here, we demonstrate the modulation of DNA repair enzymes by TFAM concentrations, DNA sequences and DNA modifications. Unlike previously reported inhibitory effects, we observed that human uracil-DNA glycosylase 1 (UNG1) and AP endonuclease I (APE1) have optimal activities at specific TFAM/DNA molar ratios. High TFAM/DNA ratios inhibited other enzymes, OGG1 and AAG. In addition, TFAM reduces the accumulation of certain repair intermediates. Molecular dynamics simulations and DNA-binding experiments demonstrate that the presence of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in certain sequence motifs enhances TFAM-DNA binding, partially explaining the inhibition of OGG1 activity. Bioinformatic analysis of published 8-oxodG, dU, and TFAM-footprint maps reveals a correlation between 8-oxodG and TFAM locations in mtDNA. Collectively, these results highlight the complex regulation of mtDNA repair by DNA sequence, TFAM concentrations, lesions and repair enzymes.
    DOI:  https://doi.org/10.1093/nar/gkae1144
  36. Redox Biol. 2024 Nov 19. pii: S2213-2317(24)00415-4. [Epub ahead of print]78 103437
    Antrodia cinnamomea triterpenoids attenuate cardiac hypertrophy via the SNW1/RXR/ALDH2 axis.
    Yinghua Ma, Yunxia Wang, Gulinigaer Anwaier, Nuerbiye Tuerdi, Yangchang Wu, Yinyue Huang, Boyang Qin, Haoyue Ma, Qiao Zhang, Dalei Wu, Kewu Zeng, Rong Qi.
      Aldehyde dehydrogenase 2 (ALDH2), a pivotal enzyme in the metabolism of toxic aldehydes produced by oxidative stress, has been demonstrated to play a cardioprotective role in cardiovascular diseases. Antrodia cinnamomea triterpenoids (ACT) is a medicinal mushroom with anti-inflammatory and antioxidant properties, and our previous study found that ACT can exert anti-fatty liver effects by regulating ALDH2. This study aimed to elucidate the impact of ACT and its monomer on cardiac hypertrophy and investigate the relationship between its pharmacological mechanism and ALDH2. Through examining cardiac morphology and expression levels of hypertrophic biomarkers, ACT significantly reduced myocardial hypertrophy induced by angiotensin II (Ang II) and transverse aortic constriction (TAC)surgery in wild-type mice, but not in ALDH2 knockout mice. In vitro, ACT and its monomeric dehydrosulphurenic acid (DSA) inhibited the hypertrophic phenotype of Ang II-stimulated neonatal cardiac myocytes (NRCMs) in an ALDH2-dependent manner. Regarding the pharmacological mechanism, it was observed that ACT and DSA restored ALDH2 expression and activity in myocardial tissues of WT-Ang II/TAC mice and Ang II-induced NRCMs. Furthermore, it inhibited oxidative stress and improved mitochondrial quality control (MQC) homeostasis in an ALDH2-dependent manner. We screened SNW1, a transcriptional coactivator, as a DSA-binding protein by "target fishing" and cellular enthusiasm transfer assay techniques and validated that SNW1 promoted ALDH2 transcription and translation levels through synergistic interaction with the transcription factor RXR. In conclusion, the findings demonstrate that ACT/DSA upregulates ALDH2 expression via regulating SNW1/RXR, thereby inhibiting oxidative stress and maintaining MQC homeostasis, and then protects against cardiac hypertrophy.
    Keywords:  Acetaldehyde dehydrogenase 2; Antrodia cinnamomea triterpenoids; Cardiac hypertrophy; Dehydrosulphurenic acid; Oxidative stress and mitochondrial quality control; SNW domain containing 1
    DOI:  https://doi.org/10.1016/j.redox.2024.103437
  37. Biochim Biophys Acta Mol Basis Dis. 2024 Nov 22. pii: S0925-4439(24)00576-3. [Epub ahead of print]1871(2): 167582
    MMP8-mediated vascular remodeling in pulmonary hypertension.
    Xiaodong Deng, Yong You, Sheng Lv, Yi Liu.
      Pulmonary arterial hypertension (PAH) is a vascular remodeling disease that impacts the cardiopulmonary system. Due to the currently limited understanding of vascular remodeling, a cure for PAH remains elusive. This study highlights the critical role of the STAT1 (signal transducer and activator of transcription 1)/MMP8 (matrix metallopeptidase 8)/DRP1 (dynamin-related protein 1) axis in vascular remodeling and the pathogenesis of pulmonary hypertension. Notably, MMP8 is significantly elevated in pulmonary arterial endothelial cells and its levels correlate with the severity of the disease. MMP8 binds to and activates DRP1, inducing mitochondrial fragmentation and promoting a malignant phenotype of endothelial cells under hypoxic conditions. Moreover, MMP8 is tightly regulated by STAT1. The knockout of MMP8 attenuates chronic pulmonary vascular remodeling, and drugs targeting MMP8 alleviate pulmonary hypertension and enhance cardiac function. This study offers fresh insights into hypoxia-induced vascular remodeling, laying a theoretical foundation for countering vascular remodeling by directly regulating the STAT1/MMP8/DRP1 axis.
    Keywords:  DRP1; Hypoxia; MMP8; Mitochondria fission; PAH
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167582
  38. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2024 Oct;36(10): 1117-1120
    [Research progress on the role of mitochondrial dynamics disorder in sepsis-associated acute kidney injury].
    Zhu Li, Lili Tang, Jie Zhang, Dongrui He, Jianglu Tan, Xiaoyue Li.
      Sepsis is a life-threatening organ dysfunction caused by the host's uncontrolled response to infection, and is one of the main causes of death in critically ill patients. Sepsis-associated acute kidney injury (SA-AKI) is associated with the poor prognosis of sepsis patients, and its pathogenesis is complex and still unclear to this day. Mitochondrial dynamics is crucial for maintaining the normal morphology, quantity, number and function of mitochondria, which is a new research hotspot in recent years. Mitochondrial dynamics disorder is involved in the occurrence and development of SA-AKI by regulating renal tubular dysfunction, which is expected to become new therapeutic targets. Deeply exploring the role of mitochondrial dynamic disorders in the pathogenesis of SA-AKI will help to find more effective treatment methods, thereby improving the success rate of rescue in SA-AKI patients.
    DOI:  https://doi.org/10.3760/cma.j.cn121430-20230802-00573
  39. Nat Commun. 2024 Nov 23. 15(1): 10163
    The nutrient-sensing Rag-GTPase complex in B cells controls humoral immunity via TFEB/TFE3-dependent mitochondrial fitness.
    Xingxing Zhu, Yue Wu, Yanfeng Li, Xian Zhou, Jens O Watzlawik, Yin Maggie Chen, Ariel L Raybuck, Daniel D Billadeau, Virginia Smith Shapiro, Wolfdieter Springer, Jie Sun, Mark R Boothby, Hu Zeng.
      Germinal center (GC) formation, which is an integrant part of humoral immunity, involves energy-consuming metabolic reprogramming. Rag-GTPases are known to signal amino acid availability to cellular pathways that regulate nutrient distribution such as the mechanistic target of rapamycin complex 1 (mTORC1) pathway and the transcription factors TFEB and TFE3. However, the contribution of these factors to humoral immunity remains undefined. Here, we show that B cell-intrinsic Rag-GTPases are critical for the development and activation of B cells. RagA/RagB deficient B cells fail to form GCs, produce antibodies, and to generate plasmablasts during both T-dependent (TD) and T-independent (TI) humoral immune responses. Deletion of RagA/RagB in GC B cells leads to abnormal dark zone (DZ) to light zone (LZ) ratio and reduced affinity maturation. Mechanistically, the Rag-GTPase complex constrains TFEB/TFE3 activity to prevent mitophagy dysregulation and maintain mitochondrial fitness in B cells, which are independent of canonical mTORC1 activation. TFEB/TFE3 deletion restores B cell development, GC formation in Peyer's patches and TI humoral immunity, but not TD humoral immunity in the absence of Rag-GTPases. Collectively, our data establish the Rag GTPase-TFEB/TFE3 pathway as a likely mTORC1 independent mechanism to coordinating nutrient sensing and mitochondrial metabolism in B cells.
    DOI:  https://doi.org/10.1038/s41467-024-54344-5
  40. Biomedicines. 2024 Oct 31. pii: 2497. [Epub ahead of print]12(11):
    Neuroprotective Effects of Ascorbic Acid, Vanillic Acid, and Ferulic Acid in Dopaminergic Neurons of Zebrafish.
    Fatemeh Hedayatikatouli, Michael Kalyn, Dana Elsaid, Herman Aishi Mbesha, Marc Ekker.
      Background/Objectives: Parkinson's disease (PD) is a debilitating neurodegenerative disease that targets the nigrostriatal dopaminergic (DAnergic) system residing in the human midbrain and is currently incurable. The aim of this study is to investigate the neuroprotective effects of ascorbic acid, vanillic acid, and ferulic acid in a zebrafish model of PD induced by MPTP by assessing the impact of these compounds on DAnergic neurons, focusing on gene expression, mitochondrial dynamics, and cellular stress responses. Methods/Results: Following exposure and qPCR and immunohistochemical analyses, ascorbic acid enhanced DAnergic function, indicated by an upregulation of the dopamine transporter (dat) gene and increased eGFP+ DAnergic cells, suggesting improved dopamine reuptake and neuroprotection. Ascorbic acid also positively affected mitochondrial dynamics and stress response pathways, countering MPTP-induced dysregulation. Vanillic acid only had modest, if any, neuroprotective effects on DAnergic neurons following MPTP administration. Ferulic acid exhibited the largest neuroprotective effects through the modulation of gene expression related to DAnergic neurons and mitochondrial dynamics. Conclusions: These findings suggest that ascorbic acid and ferulic acid can act as potential protective interventions for DAnergic neuron health, demonstrating various beneficial effects at the molecular and cellular levels. However, further investigation is needed to translate these results into clinical applications. This study enhances the understanding of neuroprotective strategies in neurodegenerative diseases, emphasizing the importance of considering interactions between physiological systems.
    Keywords:  Parkinson’s disease; behavior; dopamine; mitochondrial dynamics; neurodegeneration; neuroprotection; zebrafish
    DOI:  https://doi.org/10.3390/biomedicines12112497
  41. Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2024 Oct;36(10): 1075-1081
    [Sulforaphane regulates mitochondrial homeostasis through adenosine monophosphate-activated protein kinase signaling to treat acute carbon monoxide poisoning induced brain injury in rats].
    Aochun Yue, Huiping Song, Xudong Zhou, Wei Han, Qin Li.
       OBJECTIVE: To explore the neuroprotective effect and molecular mechanism of sulforaphane (SFN) on acute carbon monoxide poisoning (ACOP) in rats.
    METHODS: A total of 135 healthy adult male Sprague-Dawley (SD) rats were randomly divided into normal control group, ACOP model group, and SFN intervention group, with 45 rats in each group. The ACOP animal model was reproduced using carbon monoxide (CO) inhalation in a hyperbaric oxygen chamber, while the normal control group was allowed to breathe fresh air freely. The rats in the SFN intervention group received intraperitoneal injection of SFN at a dose of 20 mg/kg once daily starting 2 hours after CO poisoning and continuing until euthanasia. The normal control group and the ACOP model group received equivalent volume of saline injection. Three rats from each group were sacrificed 1 day after intervention to observe the changes in the ultrastructure of neuronal mitochondria in brain tissues under transmission electron microscopy. Six rats from each group were evaluated for cognitive function using neurobehavioral test 7 days after intervention. Brain tissues of 6 rats in each group were collected 1, 3, and 7 days after intervention, and the expressions of phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK), mitofusin 2 (MFN2), and dynamin-related protein 1 (DRP1) were detected using immunohistochemistry staining and Western blotting. Linear regression analysis was performed to assess the correlations between the expression levels of above proteins.
    RESULTS: In the normal control group, the rats did not exhibit any abnormalities in cognitive function or the ultrastructure of neuronal mitochondria in brain tissues. ACOP induced cognitive impairment and ultrastructural injury to neuronal mitochondria in rats. However, SFN significantly improved cognitive function in poisoned rats and mitigated the extent of neuronal mitochondrial damage. Over poisoning time, the expression levels of p-AMPK and MFN2 in the brain tissues of ACOP rats were gradually decreased, while the expression level of DRP1 was gradually increased. Compared with the normal control group, the ACOP model group showed significant differences in the expressions of p-AMPK, MFN2, and DRP1. After SFN intervention, the expression levels of above proteins were significantly reversed. Compared with the ACOP model group, the SFN intervention group exhibited a marked increase in the expressions of p-AMPK and MFN2 [p-AMPK positive expression (A value): 0.226±0.003 vs. 0.177±0.033, p-AMPK protein (p-AMPK/GAPDH): 1.41±0.05 vs. 0.89±0.05, MFN2 positive expression (A value): 0.241±0.004 vs. 0.165±0.007, MFN2 protein (MFN2/GAPDH): 1.33±0.04 vs. 0.79±0.03, all P < 0.05], along with a significant decrease in DRP1 expression [DRP1 positive expression (A value): 0.103±0.002 vs. 0.214±0.011, DRP1 protein (DRP1/GAPDH): 1.00±0.03 vs. 1.50±0.03, both P < 0.05]. Linear regression analysis revealed a strong negative linear correlation between DRP1 protein expression and MFN2, p-AMPK protein expressions (R2 values were 0.977 and 0.971, both P < 0.01), and a positive linear correlation between p-AMPK protein expression and MFN2 protein expression (R2 = 0.985, P < 0.01).
    CONCLUSIONS: SFN can help maintain neuronal mitochondrial homeostasis by activating the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway, thereby alleviating neuronal injury caused by ACOP.
    DOI:  https://doi.org/10.3760/cma.j.cn121430-20230326-00217
  42. bioRxiv. 2024 Nov 13. pii: 2024.11.12.623337. [Epub ahead of print]
    Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation.
    Wenqian Chen, Jie Yang, Gabriel C Lander.
      The human ClpXP complex (hClpXP) plays a central role in mitochondrial protein quality control by degrading misfolded or unneeded proteins. While bacterial ClpXP complexes have been extensively characterized, the molecular determinants underlying hClpXP assembly and regulation are not as well understood. We determined cryo-electron microscopy (cryo-EM) structures of hClpP in isolation and in complex with hClpX, revealing how hClpX binding promotes rearrangement of an asymmetric hClpP heptamer to assemble as a symmetric tetradecamer. Our hClpXP structure also highlights the stabilizing role of a previously uncharacterized eukaryotic ClpX sequence, referred to as the E-loop, and its importance in ATPase activity and hexamer assembly. We further show that peptide interaction with the hClpP proteolytic active site promotes the complex to adopt a proteolytically competent conformation. Together, these findings advance our understanding of the molecular mechanisms defining hClpXP activation and function.
    DOI:  https://doi.org/10.1101/2024.11.12.623337
  43. J Alzheimers Dis. 2024 Nov 25. 13872877241295403
    Exacerbated mitochondrial dynamic abnormalities without evident tau pathology in rapidly progressive Alzheimer's disease.
    Yanbin Xiyang, Ju Gao, Mao Ding, Xiaojia Ren, Brian S Appleby, James B Leverenz, Masaru Miyagi, Jagan A Pillai, George Perry, Xinglong Wang.
       BACKGROUND: Rapidly progressive Alzheimer's disease (rpAD) is a clinical subtype distinguished by its rapid cognitive decline and shorter disease duration. rpAD, like typical AD (tAD), is characterized by underlying neuropathology of amyloid plaques and neurofibrillary tangles. There is early evidence that the composition of amyloid plaques could vary between the rpAD and tAD. Differences in tau pathology between rpAD and tAD are also of interest. Additionally, mitochondrial dysfunction is a key early-stage change in tAD but has not yet been evaluated in rpAD.
    OBJECTIVE: To deepen our understanding of the underlying pathophysiological processes specific to rpAD, we explore potential changes in tau pathology and mitochondrial dysfunction in rpAD compared to tAD.
    METHODS: We performed immunohistochemical and immunoblot analyses of tau, phosphorylated tau, and key regulators of mitochondrial dynamics and bioenergetics in postmortem human temporal cortex tissues obtained from patients diagnosed with tAD or rpAD, and tissues from age-matched normal subjects.
    RESULTS: tAD was characterized by significant tau phosphorylation at the PHF1 epitope. Unexpectedly, rpAD showed milder PHF1 tau phosphorylation, similar to that of age-matched controls. Despite these differences in tau pathology, both tAD and rpAD exhibited a significant decrease in the key regulators of mitochondrial dynamics and bioenergetics compared to controls. However, the decline in mitochondrial dynamics regulators was more pronounced in rpAD.
    CONCLUSIONS: These findings suggest divergent pathological processes between tAD and rpAD, specifically in terms of tau pathology and mitochondrial dynamic abnormalities, which underscore the necessity for different approaches to understand and potentially treat various AD subtypes.
    Keywords:  Alzheimer's disease; amyloid plaque; mitochondrial dynamics; mitochondrial dysfunction; neurofibrillary tangles; rapidly progressive Alzheimer's disease; tau
    DOI:  https://doi.org/10.1177/13872877241295403
  44. Naunyn Schmiedebergs Arch Pharmacol. 2024 Nov 23.
    Activation of sirtuin 3 and maintenance of mitochondrial homeostasis by artemisinin protect against diclofenac-induced kidney injury in rats.
    Doaa Hellal, Sarah Ragab Abd El-Khalik, Heba M Arakeep, Doaa A Radwan, Hend S Abo Safia, Eman A E Farrag.
      Nonsteroidal anti-inflammatory drug (NSAID)-induced kidney injury is one of the most common causes of renal failure. The exact pathogenesis of NSAID induced kidney injury is not fully known and the treatment is still challenging. Artemisinin (ART) gains more attention by its potent biological activities in addition to its antimalarial effect. In our research, we evaluated the preventive and therapeutic effects of ART in Diclofenac (DIC) induced kidney injury through its effect on mitochondria and regulation of sirtuin 3 (SIRT3). Thirty adult male Sprague Dawley rats were divided into five groups: control, ART, DIC, DIC + ART prophylactic, and DIC followed + ART therapeutic groups. At the end of the study, animals were scarified and the following parameters were evaluated: serum urea and creatinine, renal malondialdehyde (MDA), superoxide dismutase (SOD) and nitrate. SIRT3 was detected by western blotting and real-time PCR. Mitochondrial related markers (PGC-1α, Drp1, and mitochondrial ATP) were detected by immunoassay. Caspase-3 and LC3 II expression in kidney tissues were demonstrated by immune-histochemical staining. The kidney specimens were stained for H&E and PAS special stain. Electron microscopy was done to detect mitochondrial morphology. ART improved renal function test, oxidative stress, SIRT3 level, mitochondrial function, LC3 II expression and decrease caspase-3. Histopathological examination confirmed ART alleviation as determined by light or electron microscopy. ART can modulate biochemical and pathological changes in DIC-induced kidney injury and can be considered a new possible therapeutic approach for DIC-induced kidney injury through its effect on SIR3 and maintenance of mitochondrial homeostasis.
    Keywords:  Artemisinin; DIC-induced kidney injury; Mitochondria; SIRT3
    DOI:  https://doi.org/10.1007/s00210-024-03620-8
  45. Cell Rep. 2024 Nov 26. pii: S2211-1247(24)01372-X. [Epub ahead of print]43(12): 115021
    Probiotics-sensing mechanism in neurons that initiates gut mitochondrial surveillance for pathogen defense.
    Huimin Liu, Panpan Chen, Xubo Yang, FanRui Hao, Guojing Tian, Zhao Shan, Bin Qi.
      Animals constantly face microbial challenges, and microbe-mediated infection protection is crucial for host survival. Identifying specific bacteria and their interactions with host intracellular surveillance systems is important but challenging. Here, we develop a "probiotics" screening system that identifies Escherichia coli mutants, such as ΔymcB, which protect hosts from Pseudomonas aeruginosa PA14 infection by activating the mitochondrial unfolded protein response (UPRmt). Genetic screening reveals that MDSS-1, a neuronal transmembrane protein, is crucial for sensing ΔymcB and triggering intestinal UPRmt. MDSS-1 functions as a potential receptor in ASE neurons, detecting ΔymcB and transmitting signals through neuropeptides, GPCRs, Wnt signaling, and endopeptidase inhibitors to activate intestinal UPRmt and enhance protection. Constitutive activation of MDSS-1 in ASE neurons is sufficient to induce UPRmt and confer infection resistance. This study uncovers a neuron-intestine communication mechanism, where ASE neurons detect bacteria and modulate the intestinal mitochondrial surveillance system for host adaptation to pathogens.
    Keywords:  C. elegans; CP: Microbiology; CP: Neuroscience; UPR(mt); cell-non-autonomous; infection; mitochondrial surveillance; pathogen; probiotics
    DOI:  https://doi.org/10.1016/j.celrep.2024.115021
  46. Crit Rev Immunol. 2025 ;45(1): 1-13
    Anoikis and Mitophagy-Related Gene Signature for Predicting the Survival and Tumor Cell Progression in Colon Cancer.
    Jian Shen, Minzhe Li.
      Anoikis is a specialized form of programmed cell death and is also related mitophagy process. We aimed to identify an anoikis and mitophagy-related genes (AMRGs) prognostic model and explore the role of SPHK1 in colon cancer (CC). Bioinformatic methods were used to screen the AMRGs. Based on these genes, all the samples were divided into different subtypes. Furthermore, LASSO was conducted to optimize the AMRGs. Based on the optimal genes, a prognostic risk score model was established and evaluated. Finally, the effects of downregulated SPHK1 on the CC cell proliferation, migration, invasion, and anoikis were investigated. Based on the AMRGs, all the CC samples were divided into subtype 1 and subtype 2. An AMRGs signature containing three key genes (SPHK1, CDC25C, and VPS37A) that exhibiting predicting ability in CC survival is confirmed. Subtype2 and low-risk groups exhibited better survival and higher immune cell infiltration. Moreover, downregulated SPHK1 is related to lower cell proliferation, migration, and invasion ability, as well as higher anoikis in CC cell line (P < 0.01). The AMRGs risk score model exhibits promising predicting ability on patients with CC. SPHK1 might inhibit CC cell growth, migration, and invasion through stimulating anoikis.
    DOI:  https://doi.org/10.1615/CritRevImmunol.2024053203
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