bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–10–06
sixty papers selected by
Gavin McStay, Liverpool John Moores University
  1. The role of PINK1-Parkin in mitochondrial quality control.
  2. Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.
  3. SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
  4. Biogenesis of mitochondrial β-barrel membrane proteins.
  5. Targeting DNM1L/DRP1-FIS1 axis inhibits high-grade glioma progression by impeding mitochondrial respiratory cristae remodeling.
  6. Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
  7. Reassessing kinetin's effect on PINK1 and mitophagy.
  8. Hypoxia-induced mitochondrial fission regulates the fate of bone marrow mesenchymal stem cells by maintaining HIF1α stabilization.
  9. KLF6 aggravates myocardial fibrosis by promoting mitochondrial division.
  10. Omega-3 Fatty Acids Modify Drp1 Expression and Activate the PINK1-Dependent Mitophagy Pathway in the Kidney and Heart of Adenine-Induced Uremic Rats.
  11. Impact of O -GlcNAcylation elevation on mitophagy and glia in the dentate gyrus.
  12. Study on the Role of Dihuang Yinzi in Regulating the AMPK/SIRT1/PGC-1α Pathway to Promote Mitochondrial Biogenesis and Improve Alzheimer's Disease.
  13. Targeting mitochondria with small molecules: A promising strategy for combating Parkinson's disease.
  14. Temporal alterations of the nascent proteome in response to mitochondrial stress.
  15. Preservation of Mitochondrial Function by SkQ1 in Skin Fibroblasts Derived from Patients with Leber's Hereditary Optic Neuropathy Is Associated with the PINK1/PRKN-Mediated Mitophagy.
  16. Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs).
  17. The role and possible mechanism of the ferroptosis-related SLC7A11/GSH/GPX4 pathway in myocardial ischemia-reperfusion injury.
  18. Enhancing Cardiomyocyte Resilience to Ischemia-Reperfusion Injury: The Therapeutic Potential of an Indole-Peptide-Tempo Conjugate (IPTC).
  19. NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.
  20. LncRNA PVT1 induces mitochondrial dysfunction of podocytes via TRIM56 in diabetic kidney disease.
  21. Mitochondria: the beating heart of the eukaryotic cell.
  22. Low-dose deoxynivalenol exposure triggers hepatic excessive ferritinophagy and mitophagy mitigated by hesperidin modulated O-GlcNAcylation.
  23. Hyperuricemia Facilitates Uric Acid-Mediated Vascular Endothelial Cell Damage by Inhibiting Mitophagy.
  24. ALCAT1-Mediated Pathological Cardiolipin Remodeling and PLSCR3-Mediated Cardiolipin Transferring Contribute to LPS-Induced Myocardial Injury.
  25. Gut Microbiota-Derived Trimethylamine Promotes Inflammation with a Potential Impact on Epigenetic and Mitochondrial Homeostasis in Caco-2 Cells.
  26. Orchestrating AMPK/mTOR signaling to initiate melittin-induced mitophagy: A neuroprotective strategy against Parkinson's disease.
  27. Effect of Spermidine on Endothelial Function in Systemic Lupus Erythematosus Mice.
  28. Impact of Mitophagy-Related Genes on the Diagnosis and Development of Esophageal Squamous Cell Carcinoma via Single-Cell RNA-seq Analysis and Machine Learning Algorithms.
  29. Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
  30. Upregulation of GRP78 is accompanied by decreased antioxidant response and mitophagy promotion in streptozotocin-induced type 1 diabetes in rats.
  31. AGR2 knockdown induces ER stress and mitochondria fission to facilitate pancreatic cancer cell death.
  32. ATM1, an essential conserved transporter in Apicomplexa, bridges mitochondrial and cytosolic [Fe-S] biogenesis.
  33. Dioscin improves fatty liver hemorrhagic syndrome by promoting ERα-AMPK mediated mitophagy in laying hens.
  34. TSG Extends the Longevity of Caenorhabditis elegans by Targeting the DAF-16/SKN-1/SIR-2.1-Mediated Mitochondrial Quality Control Process.
  35. CREB1 regulates RECQL4 to inhibit mitophagy and promote esophageal cancer metastasis.
  36. A snapshot of the Physcomitrella N-terminome reveals N-terminal methylation of organellar proteins.
  37. Spinster homolog 2/S1P signaling ameliorates macrophage inflammatory response to bacterial infections by balancing PGE2 production.
  38. Myeloid PGC1β attenuates high-fat-diet induced inflammation via mitochondrial fission/mtDNA/Nlrp3 pathway.
  39. Melatonin protects RPE cells from necroptosis and NLRP3 activation via promoting SERCA2-related intracellular Ca2+ homeostasis.
  40. Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling.
  41. ROCK inhibitor enhances mitochondrial transfer via tunneling nanotubes in retinal pigment epithelium.
  42. Naringenin Nanocrystals Mitigate Rotenone Neurotoxicity in SH-SY5Y Cell Line by Modulating Mitophagy and Oxidative Stress.
  43. Exosomes-mediated delivery of miR-486-3p alleviates neuroinflammation via SIRT2-mediated inhibition of mitophagy after subarachnoid hemorrhage.
  44. Commentary on "Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke".
  45. Aminocarb Exposure Induces Cytotoxicity and Endoplasmic Reticulum Stress-Mediated Apoptosis in Mouse Sustentacular Sertoli Cells: Implications for Male Infertility and Environmental Health.
  46. β-asarone Protects Against Age-related Motor Decline via Activation of SKN-1/Nrf2 and Subsequent Induction of GST-4.
  47. Maintaining mitochondrial DNA copy number mitigates ROS-induced oocyte decline and female reproductive aging.
  48. [Aberrant mitochondrial dynamics in myeloid neoplasms].
  49. Differential Mobility Spectrometry-Based Cardiolipin Analysis.
  50. Mapping the research of mitochondria and Parkinson's disease: a bibliometric analysis.
  51. Morusin, a novel inhibitor of ACLY, induces mitochondrial apoptosis in hepatocellular carcinoma cells through ROS-mediated mitophagy.
  52. Matrix stiffness regulates mitochondria-lysosome contacts to modulate the mitochondrial network, alleviate the senescence of MSCs.
  53. Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.
  54. Gypenosides alleviate oxidative stress in the hippocampus, promote mitophagy, and mitigate depressive-like behaviors induced by CUMS via SIRT1.
  55. Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome.
  56. Comparative evaluation of cigarette smoke and a heated tobacco product on microglial toxicity, oxidative stress and inflammatory response.
  57. Modifications of Mitochondrial Network Morphology Affect the MAVS-Dependent Immune Response in L929 Murine Fibroblasts during Ectromelia Virus Infection.
  58. Correction for Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
  59. Analyses of single-cell and bulk RNA sequencing combined with machine learning reveal the expression patterns of disrupted mitophagy in schizophrenia.
  60. Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.
  1. Nat Cell Biol. 2024 Oct 02.
    The role of PINK1-Parkin in mitochondrial quality control.
    Derek P Narendra, Richard J Youle.
      Mitophagy mediated by the recessive Parkinson's disease genes PINK1 and Parkin responds to mitochondrial damage to preserve mitochondrial function. In the pathway, PINK1 is the damage sensor, probing the integrity of the mitochondrial import pathway, and activating Parkin when import is blocked. Parkin is the effector, selectively marking damaged mitochondria with ubiquitin for mitophagy and other quality-control processes. This selective mitochondrial quality-control pathway may be especially critical for dopamine neurons affected in Parkinson's disease, in which the mitochondrial network is widely distributed throughout a highly branched axonal arbor. Here we review the current understanding of the role of PINK1-Parkin in the quality control of mitophagy, including sensing of mitochondrial distress by PINK1, activation of Parkin by PINK1 to induce mitophagy, and the physiological relevance of the PINK1-Parkin pathway.
    DOI:  https://doi.org/10.1038/s41556-024-01513-9
  2. Cell Death Dis. 2024 Sep 30. 15(9): 707
    Reciprocal regulation of oxidative stress and mitochondrial fission augments parvalbumin downregulation through CDK5-DRP1- and GPx1-NF-κB signaling pathways.
    Su Hyeon Wang, Duk-Shin Lee, Tae-Hyun Kim, Ji-Eun Kim, Tae-Cheon Kang.
      Loss of parvalbumin (PV) expressing neurons (PV neurons) is relevant to the underlying mechanisms of the pathogenesis of neurological and psychiatric diseases associated with the dysregulation of neuronal excitatory networks and brain metabolism. Although PV modulates mitochondrial morphology, volume and dynamics, it is largely unknown whether mitochondrial dynamics affect PV expression and what the molecular events are responsible for PV neuronal degeneration. In the present study, L-buthionine sulfoximine (BSO, an inhibitor of glutathione synthesis) did not degenerate PV neurons under physiological condition. However, BSO-induced oxidative stress decreased PV expression and facilitated cyclin-dependent kinase 5 (CDK5) tyrosine (Y) 15 phosphorylation, dynamin-related protein 1 (DRP1)-mediated mitochondrial fission and glutathione peroxidase-1 (GPx1) downregulation in PV neurons. Co-treatment of roscovitine (a CDK5 inhibitor) or mitochondrial division inhibitor-1 (Mdivi-1, an inhibitor of mitochondrial fission) attenuated BSO-induced PV downregulation. WY14643 (an inducer of mitochondrial fission) reduced PV expression without affecting CDK5 Y15 phosphorylation. Following status epilepticus (SE), CDK5 Y15 phosphorylation and mitochondrial fission were augmented in PV neurons. These were accompanied by reduced GPx1-mediated inhibition of NF-κB p65 serine (S) 536 phosphorylation. N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.
    DOI:  https://doi.org/10.1038/s41419-024-07050-5
  3. Sci Adv. 2024 Oct 04. 10(40): eadq6223
    SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
    Richard Seager, Nitheyaa Shree Ramesh, Stephen Cross, Chun Guo, Kevin A Wilkinson, Jeremy M Henley.
      Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys151, MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.
    DOI:  https://doi.org/10.1126/sciadv.adq6223
  4. FEBS Open Bio. 2024 Oct;14(10): 1595-1609
    Biogenesis of mitochondrial β-barrel membrane proteins.
    Iniyan Ganesan, Jon V Busto, Nikolaus Pfanner, Nils Wiedemann.
      β-barrel membrane proteins in the mitochondrial outer membrane are crucial for mediating the metabolite exchange between the cytosol and the mitochondrial intermembrane space. In addition, the β-barrel membrane protein subunit Tom40 of the translocase of the outer membrane (TOM) is essential for the import of the vast majority of mitochondrial proteins encoded in the nucleus. The sorting and assembly machinery (SAM) in the outer membrane is required for the membrane insertion of mitochondrial β-barrel proteins. The core subunit Sam50, which has been conserved from bacteria to humans, is itself a β-barrel protein. The β-strands of β-barrel precursor proteins are assembled at the Sam50 lateral gate forming a Sam50-preprotein hybrid barrel. The assembled precursor β-barrel is finally released into the outer mitochondrial membrane by displacement of the nascent β-barrel, termed the β-barrel switching mechanism. SAM forms supercomplexes with TOM and forms a mitochondrial outer-to-inner membrane contact site with the mitochondrial contact site and cristae organizing system (MICOS) of the inner membrane. SAM shares subunits with the ER-mitochondria encounter structure (ERMES), which forms a membrane contact site between the mitochondrial outer membrane and the endoplasmic reticulum. Therefore, β-barrel membrane protein biogenesis is closely connected to general mitochondrial protein and lipid biogenesis and plays a central role in mitochondrial maintenance.
    Keywords:  Mco6; Mdm10; SAM; Sam35; Sam37; Sam50; mitochondria; outer membrane; sorting and assembly machinery; β‐barrel protein
    DOI:  https://doi.org/10.1002/2211-5463.13905
  5. J Exp Clin Cancer Res. 2024 Sep 30. 43(1): 273
    Targeting DNM1L/DRP1-FIS1 axis inhibits high-grade glioma progression by impeding mitochondrial respiratory cristae remodeling.
    Xiaodong Li, Jingjing Tie, Yuze Sun, Chengrong Gong, Shizhou Deng, Xiyu Chen, Shujiao Li, Yaoliang Wang, Zhenhua Wang, Feifei Wu, Hui Liu, Yousheng Wu, Guopeng Zhang, Qingdong Guo, Yanling Yang, Yayun Wang.
       BACKGROUND: The dynamics of mitochondrial respiratory cristae (MRC) and its impact on oxidative phosphorylation (OXPHOS) play a crucial role in driving the progression of high-grade glioma (HGG). However, the underlying mechanism remains unclear.
    METHODS: In the present study, we employed machine learning-based transmission electron microscopy analysis of 7141 mitochondria from 54 resected glioma patients. Additionally, we conducted bioinformatics analysis and multiplex immunohistochemical (mIHC) staining of clinical glioma microarrays to identify key molecules involved in glioma. Subsequently, we modulated the expression levels of mitochondrial dynamic-1-like protein (DNM1L/DRP1), and its two receptors, mitochondrial fission protein 1 (FIS1) and mitochondrial fission factor (MFF), via lentiviral transfection to further investigate the central role of these molecules in the dynamics of glioblastoma (GBM) cells and glioma stem cells (GSCs). We then evaluated the potential impact of DNM1L/DRP1, FIS1, and MFF on the proliferation and progression of GBM cells and GSCs using a combination of CCK-8 assay, Transwell assay, Wound Healing assay, tumor spheroid formation assay and cell derived xenograft assay employing NOD/ShiLtJGpt-Prkdcem26Cd52Il2rgem26Cd22/Gpt (NCG) mouse model. Subsequently, we validated the ability of the DNM1L/DRP1-FIS1 axis to remodel MRC structure through mitophagy by utilizing Seahorse XF analysis technology, mitochondrial function detection, MRC abundance detection and monitoring dynamic changes in mitophagy.
    RESULTS: Our findings revealed that compared to low-grade glioma (LGG), HGG exhibited more integrated MRC structures. Further research revealed that DNM1L/DRP1, FIS1, and MFF played pivotal roles in governing mitochondrial fission and remodeling MRC in HGG. The subsequent validation demonstrated that DNM1L/DRP1 exerts a positive regulatory effect on FIS1, whereas the interaction between MFF and FIS1 demonstrates a competitive inhibition relationship. The down-regulation of the DNM1L/DRP1-FIS1 axis significantly impaired mitophagy, thereby hindering the remodeling of MRC and inhibiting OXPHOS function in glioma, ultimately leading to the inhibition of its aggressive progression. In contrast, MFF exerts a contrasting effect on MRC integrity, OXPHOS activity, and glioma progression.
    CONCLUSIONS: This study highlights that the DNM1L/DRP1-FIS1 axis stabilizes MRC structures through mitophagy in HGG cells while driving their OXPHOS activity ultimately leading to robust disease progression. The inhibition of the DNM1L/DRP1-FIS1 axis hinders MRC remodeling and suppresses GBM progression. We propose that down-regulation of the DNM1L/DRP1-FIS1 axis could be a potential therapeutic strategy for treating HGG.
    Keywords:  DNM1L/DRP1; FIS1; Glioma; Mitochondrial respiratory cristae; Mitophagy; OXPHOS
    DOI:  https://doi.org/10.1186/s13046-024-03194-6
  6. Int J Mol Sci. 2024 Sep 20. pii: 10116. [Epub ahead of print]25(18):
    Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
    Chong Zhao, Yonghao Wu, Shuaiqi Zhu, Haiying Liu, Shuai Xu.
      Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.
    Keywords:  irisin; mitochondrial quality control; musculoskeletal health; myokine; osteoporosis; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms251810116
  7. Autophagy. 2024 Sep 29. 1-2
    Reassessing kinetin's effect on PINK1 and mitophagy.
    Zhong Yan Gan, David Komander, Sylvie Callegari.
      Substantial evidence indicates that a decline in mitochondrial health contributes to the development of Parkinson disease. Accordingly, therapeutic stimulation of mitophagy, the autophagic turnover of dysfunctional mitochondria, is a promising approach to treat Parkinson disease. An attractive target in such a setting is PINK1, a protein kinase that initiates the mitophagy cascade. Previous reports suggest that PINK1 kinase activity can be enhanced by kinetin triphosphate (KTP), an enlarged ATP analog that acts as an alternate phosphate donor for PINK1 during phosphorylation. However, the mechanism of how KTP could exert such an effect on PINK1 was unclear. In a recent study, we demonstrate that contrary to previous thinking, KTP cannot be used by PINK1. Nucleotide-bound PINK1 structures indicate that KTP would clash with the back of PINK1's ATP binding pocket, and enlarging this pocket by mutagenesis is required to enable PINK1 to use KTP. Strikingly, mutation shifts PINK1's nucleotide preference from ATP to KTP. Similar results could be demonstrated in cells with kinetin, a membrane-permeable precursor of KTP. These results overturn the previously accepted mechanism of how kinetin enhances mitophagy and indicate that kinetin and its derivatives instead function through a currently unidentified mechanism.
    Keywords:  Mitophagy; PINK1; parkin; parkinson’s disease; protein kinase; ubiquitin
    DOI:  https://doi.org/10.1080/15548627.2024.2395144
  8. Free Radic Biol Med. 2024 Oct 02. pii: S0891-5849(24)00957-2. [Epub ahead of print]
    Hypoxia-induced mitochondrial fission regulates the fate of bone marrow mesenchymal stem cells by maintaining HIF1α stabilization.
    Xiaoyong Wu, Kanbin Wang, Hongyu Chen, Binhao Cao, Yibo Wang, Zhongxiang Wang, Chengxin Dai, Minjun Yao, Xiaoxiao Ji, Xiaowen Jiang, Weijun Zhang, Zhijun Pan, Deting Xue.
      For mesenchymal stem cells derived from bone marrow, a controlled reduction in ambient oxygen concentration has been recognized as a facilitator of osteogenic differentiation and the formation of calcium nodules. However, the specific molecular mechanisms underlying this phenotype remain unclear. The aim of this study was to elucidate the impact of hypoxia on the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and to explore the involvement of mitophagy and the regulation of mitochondrial dynamics mediated by the mitochondrial dynamic regulatory factor FUN14 domain-containing 1 (FUNDC1). Our findings suggest that FUNDC1 is required for promoting osteogenic differentiation in BMSCs under hypoxic conditions. However, this effect was not dependent on FUNDC1-mediated mitophagy but rather on FUNDC1-mediated regulation of mitochondrial fission. At the mechanistic level, FUNDC1 binds more DNM1L and less OPA1 under hypoxic conditions, leading to an upsurge in mitochondrial division. This heightened mitochondrial division culminates in the increased translocation of Parkin to mitochondria, diminishing its interactions with HIF1α in the cytoplasm and consequently facilitating HIF1α deubiquitination and stabilization. In summary, FUNDC1-regulated mitochondrial division in hypoxic culture emerges as a critical determinant for the translocation of Parkin to mitochondria, ultimately maintaining HIF1α stabilization and promoting osteogenic differentiation.
    Keywords:  BMSCs; FUNDC1; Hypoxia; Ubiquitination; mitochondria fission; osteogenesis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.256
  9. Pak J Pharm Sci. 2024 May;37(3): 669-679
    KLF6 aggravates myocardial fibrosis by promoting mitochondrial division.
    Tingting Zhang, Hongyao Ge, Qiuhang Song, Gaoshan Yang, Aiying Li.
      The dysregulation of mitochondrial dynamics in cardiac fibroblasts (CFs) is closely linked to myocardial fibrosis, which can induce cardiac dysfunction and even lead to heart failure. As an essential multifunctional zinc-finger transcriptional factor of cardiovascular remodeling, the role of KLF6 mediating the link between mitochondrial fission and myocardial fibrosis remains unclear. Next, we want to explore whether the effect of KLF6 on mitochondrial fission might influence cardiac fibroblasts, we established a model of Transforming growth factor β1 (TGF-β1) and Isoprenaline (ISO)-induced myocardial fibrosis. Here, we found that KLF6 up-regulation in CFs is correlated with myocardial fibrosis. While knockdown of KLF6 suppresses mitochondrial fission and the Keap1/Nrf2 pathway molecules, which alleviates myocardial fibrosis induced by TGF-β1. Our findings not only clarified the regulation mechanism of mitochondrial fission by KLF6 but also provided a potential therapeutic target for cardiovascular disease.
  10. Biomedicines. 2024 Sep 15. pii: 2107. [Epub ahead of print]12(9):
    Omega-3 Fatty Acids Modify Drp1 Expression and Activate the PINK1-Dependent Mitophagy Pathway in the Kidney and Heart of Adenine-Induced Uremic Rats.
    Dong Ho Choi, Su Mi Lee, Bin Na Park, Mi Hwa Lee, Dong Eun Yang, Young Ki Son, Seong Eun Kim, Won Suk An.
      Mitochondrial homeostasis is controlled by biogenesis, dynamics, and mitophagy. Mitochondrial dysfunction plays a central role in cardiovascular and renal disease and omega-3 fatty acids (FAs) are beneficial for cardiovascular disease. We investigated whether omega-3 fatty acids (FAs) regulate mitochondrial biogenesis, dynamics, and mitophagy in the kidney and heart of adenine-induced uremic rats. Eighteen male Sprague Dawley rats were divided into normal control, adenine control, and adenine with omega-3 FA groups. Using Western blot analysis, the kidney and heart expression of mitochondrial homeostasis-related molecules, including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), dynamin-related protein 1 (Drp1), and phosphatase and tensin homolog-induced putative kinase 1 (PINK1) were investigated. Compared to normal, serum creatinine and heart weight/body weight in adenine control were increased and slightly improved in the omega-3 FA group. Compared to the normal controls, the expression of PGC-1α and PINK1 in the kidney and heart of the adenine group was downregulated, which was reversed after omega-3 FA supplementation. Drp1 was upregulated in the kidney but downregulated in the heart in the adenine group. Drp1 expression in the heart recovered in the omega-3 FA group. Mitochondrial DNA (mtDNA) was decreased in the kidney and heart of the adenine control group but the mtDNA of the heart was recovered in the omega-3 FA group. Drp1, which is related to mitochondrial fission, may function oppositely in the uremic kidney and heart. Omega-3 FAs may be beneficial for mitochondrial homeostasis by activating mitochondrial biogenesis and PINK1-dependent mitophagy in the kidney and heart of uremic rats.
    Keywords:  biogenesis; chronic kidney disease; dynamics; fatty acid; mitochondria; omega-3
    DOI:  https://doi.org/10.3390/biomedicines12092107
  11. bioRxiv. 2024 Sep 20. pii: 2024.09.19.613771. [Epub ahead of print]
    Impact of O -GlcNAcylation elevation on mitophagy and glia in the dentate gyrus.
    Joshua Kramer, John C Chatham, Martin E Young, Victor Darley-Usmar, Jianhua Zhang.
      O -GlcNAcylation is a dynamic and reversible protein post-translational modification of serine or threonine residues which modulates the activity of transcriptional and signaling pathways and controls cellular responses to metabolic and inflammatory stressors. We and others have shown that O -GlcNAcylation has the potential to regulate autophagy and mitophagy to play a critical role in mitochondrial quality control, but this has not been assessed in vivo in the brain. This is important since mitochondrial dysfunction contributes to the development of neurodegenerative disease. We used mito-QC reporter mice to assess mitophagy in diverse cells in the dentate gyrus in response to pharmacological inhibition of OGA with thiamet G which leads to elevation of protein O -GlcNAcylation. We demonstrate that mitophagy occurs predominantly in the GFAP positive astrocytes and is significantly decreased in response to elevated O -GlcNAcylation. Furthermore, with increased O -GlcNAcylation, the levels of astrocyte makers GFAP and S100B, and microglial cell marker IBA1 were decreased in the dentate gyrus, while the levels of microglial cell marker TMEM119 were increased, indicating significant changes in glia homeostasis. These results provide strong evidence of the regulation of mitophagy and glia signatures by the O -GlcNAc pathway.
    DOI:  https://doi.org/10.1101/2024.09.19.613771
  12. J Ethnopharmacol. 2024 Sep 26. pii: S0378-8741(24)01158-9. [Epub ahead of print] 118859
    Study on the Role of Dihuang Yinzi in Regulating the AMPK/SIRT1/PGC-1α Pathway to Promote Mitochondrial Biogenesis and Improve Alzheimer's Disease.
    Chao Zhu, Zheng Zhang, Yousong Zhu, Yuzhong Du, Cheng Han, Qiong Zhao, Qinqing Li, Jiangqi Hou, Junlong Zhang, Wenbin He, Yali Qin.
       ETHNOPHARMACOLOGICAL RELEVANCE: Dihuang Yinzi (DHYZ) is a classic prescription in traditional Chinese medicine. Its therapeutic effect on Alzheimer's disease (AD) has been widely validated. However, the underlying molecular mechanisms of DHYZ in AD treatment remain unclear and require further research.
    AIM OF THE STUDY: Elucidating DHYZ's promotion of mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α pathway improves neuronal loss, mitochondrial damage, and memory deficits in AD.
    MATERIALS AND METHODS: Administering DHYZ by gavage to SAMP8 mice, after completing behavioral tests, the effects of DHYZ on hippocampal neuron loss and mitochondrial structural damage in AD model mice were assessed using Nissl staining and transmission electron microscopy. Western blot was used to detect the expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, mitochondrial fusion protein MFN2, and mitochondrial fission proteins DRP1 and FIS1. At the same time, immunofluorescence(IF) was employed to measure the relative fluorescence intensity of mitochondrial fusion protein MFN1. After determining the optimal dose of DYHZ for treating AD, we conducted mechanistic studies. By intraperitoneally injecting SAMP8 mice with the AMPK inhibitor (Compound C) to inhibit AMPK protein expression and subsequently treating them with DHYZ, the impact of DHYZ on hippocampal neurons in AD model mice was evaluated using Nissl and hematoxylin-eosin staining. Western blot was used to detect the protein expression of AMPK, p-AMPK, SIRT1, PGC-1α, NRF1, and TFAM. In contrast, IF was used to measure the relative fluorescence intensity of PGC-1α, NRF1, and TFAM proteins in the hippocampal CA1 region.
    RESULTS: DHYZ significantly improved AD model mice's cognitive impairment and memory deficits and mitigated hippocampal neuron loss and degeneration. Additionally, it ameliorated mitochondrial morphological structures. DHYZ upregulated the protein expression of mitochondrial biogenesis-related proteins PGC-1α, CREB, and mitochondrial fusion proteins MFN1 and MFN2 while inhibiting the expression of mitochondrial fission proteins DRP1 and FIS1. Further studies revealed that DHYZ could upregulate the expression of the AMPK/SIRT1/PGC-1α pathway proteins and their downstream proteins NRF1 and TFAM.
    CONCLUSION: DHYZ promotes mitochondrial biogenesis by activating the AMPK/SIRT1/PGC-1α signaling pathway, thereby improving memory deficits, neuronal loss, and mitochondrial dysfunction in AD.
    Keywords:  Alzheimer's disease; Dihuang Yinzi; Mitochondria; Mitochondrial biogenesis; Mitochondrial dynamics; Mitochondrial homeostasis
    DOI:  https://doi.org/10.1016/j.jep.2024.118859
  13. Mitochondrion. 2024 Sep 30. pii: S1567-7249(24)00129-6. [Epub ahead of print] 101971
    Targeting mitochondria with small molecules: A promising strategy for combating Parkinson's disease.
    Chinmay Pal.
      Parkinson's disease (PD), a neurodegenerative disorder, is one of the most significant challenges confronting modern societies, affecting millions of patients globally each year. The pathophysiology of PD is significantly influenced by mitochondrial dysfunction, as evident by the contribution of altered mitochondrial dynamics, bioenergetics, and increased oxidative stress to neuronal death. This review examines the potential use of small molecules that target mitochondria as a therapeutic approach for treating PD. Progress in mitochondrial biology has revealed various mitochondrial targets that can be modulated to restore function and mitigate neurodegeneration. Small molecules that promote mitochondrial biogenesis, enhance mitochondrial dynamics, decrease oxidative stress, and prevent the opening of the mitochondrial permeability transition pore (mPTP) have shown promise in preclinical models. Additionally, targeting mitochondrial quality control mechanisms, such as mitophagy, provides another therapeutic approach. This review explores recent research on small molecules targeting mitochondria, examines their mechanisms of action, and assesses their potential efficacy and safety profiles. By highlighting the most promising candidates and addressing the challenges and future directions in this field, this review aims to offer a comprehensive overview of current and future prospects for mitochondrial-targeted therapies in PD. Ultimately, treating mitochondrial dysfunction holds significant promise for developing disease-modifying PD medications, giving patients hope for better outcomes and improved quality of life.
    Keywords:  Mitochondrial dysfunction; Oxidative Stress; Parkinson’s disease; Reactive oxygen species; Small molecule
    DOI:  https://doi.org/10.1016/j.mito.2024.101971
  14. Cell Rep. 2024 Oct 02. pii: S2211-1247(24)01154-9. [Epub ahead of print]43(10): 114803
    Temporal alterations of the nascent proteome in response to mitochondrial stress.
    Tomasz M Stępkowski, Vanessa Linke, Dorota Stadnik, Maciej Zakrzewski, Anna E Zawada, Remigiusz A Serwa, Agnieszka Chacinska.
      Under stress, protein synthesis is attenuated to preserve energy and mitigate challenges to protein homeostasis. Here, we describe, with high temporal resolution, the dynamic landscape of changes in the abundance of proteins synthesized upon stress from transient mitochondrial inner membrane depolarization. This nascent proteome was altered when global translation was attenuated by stress and began to normalize as translation was recovering. This transition was associated with a transient desynchronization of cytosolic and mitochondrial translation and recovery of cytosolic and mitochondrial ribosomal proteins. Further, the elongation factor EEF1A1 was downregulated upon mitochondrial stress, and its silencing mimicked the stress-induced nascent proteome remodeling, including alterations in the nascent respiratory chain proteins. Unexpectedly, the stress-induced alterations in the nascent proteome were independent of physiological protein abundance and turnover. In summary, we provide insights into the physiological and pathological consequences of mitochondrial function and dysfunction.
    Keywords:  CP: Cell biology; CP: Metabolism; EEF1A; EEF1A1; cellular stress; elongation factor; mass spectrometry; mitochondria; nascent chain; protein synthesis; proteomics; translation
    DOI:  https://doi.org/10.1016/j.celrep.2024.114803
  15. Biomedicines. 2024 Sep 04. pii: 2020. [Epub ahead of print]12(9):
    Preservation of Mitochondrial Function by SkQ1 in Skin Fibroblasts Derived from Patients with Leber's Hereditary Optic Neuropathy Is Associated with the PINK1/PRKN-Mediated Mitophagy.
    Jin Xu, Yan Li, Shun Yao, Xiuxiu Jin, Mingzhu Yang, Qingge Guo, Ruiqi Qiu, Bo Lei.
      Increased or altered mitochondrial ROS production in the retinal ganglion cells is regarded as the chief culprit of the disease-causing Leber's hereditary optic neuropathy (LHON). SkQ1 is a rechargeable mitochondria-targeted antioxidant with high specificity and efficiency. SkQ1 has already been used to treat LHON patients, and a phase 2a randomized clinical trial of SkQ1 has demonstrated improvements in eyesight. However, the underlying mechanism of SkQ1 in LHON remains unclear. This study aimed to assess the effects and molecular mechanism of SkQ1 in the preservation of mitochondrial function using skin fibroblasts derived from LHON patients. Our study found that SkQ1 could reduce ROS production and stabilize the mitochondrial membrane. Mechanistically, through network pharmacology and molecular docking, we identified the key targets of SkQ1 as SOD2 and PINK1, which play crucial roles in redox and mitophagy. SkQ1 interacted with PINK1 and downregulated its expression to balance mitochondrial homeostasis. Collectively, the findings of our study reveal that by regulating PINK1/PRKN-mediated mitophagy, SkQ1 preserves mitochondrial function in LHON fibroblasts. The data indicate that SkQ1 may be a novel therapeutic intervention to prevent the progression of LHON.
    Keywords:  Leber’s hereditary optic neuropathy; ROS; SkQ1; mitochondria function; mitophagy
    DOI:  https://doi.org/10.3390/biomedicines12092020
  16. Biomolecules. 2024 Sep 01. pii: 1096. [Epub ahead of print]14(9):
    Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs).
    Kumudesh Mishra, Or Kakhlon.
      Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control, generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades, thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSDs.
    Keywords:  autophagy and mitophagy; glycogen storage disorders; mitochondrial dysfunction; myopathy; oxidative stress; reactive oxygen species
    DOI:  https://doi.org/10.3390/biom14091096
  17. BMC Cardiovasc Disord. 2024 Oct 01. 24(1): 531
    The role and possible mechanism of the ferroptosis-related SLC7A11/GSH/GPX4 pathway in myocardial ischemia-reperfusion injury.
    Bingxin Chen, Ping Fan, Xue Song, Mingjun Duan.
       BACKGROUND: Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy.
    METHODS: A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot.
    RESULTS: The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury.
    CONCLUSIONS: Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation.
    Keywords:  Ferroptosis; GPX4 enzyme; Lipid peroxidation; Membrane potential; Mitophagy; Myocardial ischemia-reperfusion injury; SLC7A11; The SLC7A11/GSH/GPX4 pathway
    DOI:  https://doi.org/10.1186/s12872-024-04220-3
  18. ACS Omega. 2024 Sep 24. 9(38): 39401-39418
    Enhancing Cardiomyocyte Resilience to Ischemia-Reperfusion Injury: The Therapeutic Potential of an Indole-Peptide-Tempo Conjugate (IPTC).
    Shanshan Hou, Xin Yan, Xiang Gao, Steffen Jockusch, K Michael Gibson, Zhiying Shan, Lanrong Bi.
      Ischemia/reperfusion (I/R) injury leads to apoptosis and extensive cellular and mitochondrial damage, triggered by the early generation and subsequent accumulation of mitochondrial reactive oxygen species (mtROS). This condition not only contributes to the pathology of I/R injury itself but is also implicated in a variety of other diseases, especially within the cardiovascular domain. Addressing mitochondrial oxidative stress thus emerges as a critical therapeutic target. In this context, our study introduces an indole-peptide-tempo conjugate (IPTC), a compound designed with dual functionalities: antioxidative properties and the ability to modulate autophagy. Our findings reveal that IPTC effectively shields H9C2 cardiomyocytes against hypoxia/reoxygenation (H/R) damage, primarily through counteracting mtROS overproduction linked to impaired mitophagy and mitochondrial dysfunction. We propose that IPTC operates by simultaneously reducing mtROS levels and inducing mitophagy, highlighting its potential as a novel therapeutic strategy for mitigating mitochondrial oxidative damage and, by extension, easing I/R injury and potentially other related cardiovascular conditions.
    DOI:  https://doi.org/10.1021/acsomega.4c02725
  19. Gene. 2024 Oct 01. pii: S0378-1119(24)00857-6. [Epub ahead of print] 148976
    NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.
    Run Yan, Liting Chen, Zimu Cai, Jiyao Tang, Yanlin Zhu, Yanping Li, Xuemin Wang, Yu Ruan, Qi Han.
      Mitochondria are essential for cell metabolism and survival as they produce the majority of cellular ATP through oxidative phosphorylation as well as regulate critical processes such as cell proliferation and apoptosis. NIPSNAP family of proteins are predominantly mitochondrial matrix proteins. However, the molecular and cellular functions of the NIPSNAPs, particularly NIPSNAP3A, have remained elusive. Here, we demonstrated that NIPSNAP3A knockdown in HeLa cells inhibited their proliferation and migration and attenuated apoptosis induced by Actinomycin D (Act-D). These findings suggested a complex relationship between cellular processes and mitochondrial functions, mediated by NIPSNAP3A. Further investigations revealed that NIPSNAP3A knockdown not only inhibited mitochondrial fission through reduction of DRP1-S616, but also suppressed cytochrome c release in apoptosis. Collectively, our findings highlight the critical role of NIPSNAP3A in coordinating cellular processes, likely through its influence on mitochondrial dynamics.
    Keywords:  Apoptosis; Drp1; Fission; Mitochodnria; NIPSNAP3A; Proliferation
    DOI:  https://doi.org/10.1016/j.gene.2024.148976
  20. Cell Death Dis. 2024 Sep 30. 15(9): 697
    LncRNA PVT1 induces mitochondrial dysfunction of podocytes via TRIM56 in diabetic kidney disease.
    Zhimei Lv, Ziyang Wang, Jinxiu Hu, Hong Su, Bing Liu, Yating Lang, Qun Yu, Yue Liu, Xiaoting Fan, Meilin Yang, Ning Shen, Dongdong Zhang, Xia Zhang, Rong Wang.
      Mitochondrial dysfunction is a significant contributor to podocyte injury in diabetic kidney disease (DKD). While previous studies have shown that PVT1 might play a vital role in DKD, the precise molecular mechanisms are largely unknown. By analyzing the plasma and kidney tissues of DKD patients, we observed a significant upregulation of PVT1 expression, which exhibited a positive correlation with albumin/creatinine ratios and serum creatinine levels. Then, we generated mice with podocyte-specific deletion of PVT1 (Nphs2-Cre/Pvt1flox/flox) and confirmed that the deletion of PVT1 suppressed podocyte mitochondrial dysfunction and inflammation in addition to ameliorating diabetes-induced podocyte injury, glomerulopathy, and proteinuria. Subsequently, we cultured podocytes in vitro and observed that PVT1 expression was upregulated under hyperglycemic conditions. Mechanistically, we demonstrated that PVT1 was involved in mitochondrial dysfunction by interacting with TRIM56 post-transcriptionally to modulate the ubiquitination of AMPKα, leading to aberrant mitochondrial biogenesis and fission. Additionally, the release of mtDNA and mtROS from damaged mitochondria triggered inflammation in podocytes. Subsequently, we verified the important role of TRIM56 in vivo by constructing Nphs2-Cre/Trim56flox/flox mice, consistently with the results of Nphs2-Cre/Pvt1flox/flox mice. Together, our results revealed that upregulation of PVT1 could promote mitochondrial dysfunction and inflammation of podocyte by modulating TRIM56, highlighting a potential novel therapeutic target for DKD.
    DOI:  https://doi.org/10.1038/s41419-024-07107-5
  21. FEBS Open Bio. 2024 Oct;14(10): 1588-1590
    Mitochondria: the beating heart of the eukaryotic cell.
    Johannes M Herrmann.
      Mitochondria are essential organelles of eukaryotic cells. They consist of hundreds of proteins, which are synthesized in the cytosol and imported into mitochondria via different targeting routes. In addition, a small number of proteins are encoded by the organellar genome and synthesized by mitochondrial ribosomes. In this 'In the Limelight' special issue of FEBS Open Bio, five review articles describe these different biogenesis routes of mitochondrial proteins and provide a comprehensive overview of the structures and mechanisms by which mitochondrial proteins are synthesized and transported to their respective location within the organelle. These reviews, written by leading experts, provide a general overview, but also highlight current developments in the field of mitochondrial biogenesis.
    DOI:  https://doi.org/10.1002/2211-5463.13884
  22. J Hazard Mater. 2024 Sep 24. pii: S0304-3894(24)02531-7. [Epub ahead of print]480 135952
    Low-dose deoxynivalenol exposure triggers hepatic excessive ferritinophagy and mitophagy mitigated by hesperidin modulated O-GlcNAcylation.
    Hao Chen, Xintong Zhou, Jun Ma, Anshan Shan.
      The level and breadth of deoxynivalenol (DON) contamination in foods made with cereals have increased due to global warming. Consumption of DON-contaminated food and feed poses significant risks to human health and animal production. However, the mechanism by which prolonged exposure to low-dose DON leads to liver damage in animals and effective treatments remain unclear. Our investigation focused on the impact of varying DON exposure times on AML12 cells as well as the long-term liver damage caused by low-dose DON exposure in mice. In addition, this article investigated the unique role of hesperidin in mitigating hepatic ferroptosis induced by low-dose DON exposure. Our results imply that DON's suppression of O-GlcNAcylation exacerbated mitophagy by encouraging ferritinophagy and causing labile iron to aggregate within mitochondria. Furthermore, DON could increase NCOA4-mediated ferritinophagy by De-O-GlcNAcylation FTH to trigger ferroptosis-associated liver injury in mice. Notably, hesperidin alleviated the susceptibility to ferroptosis by increasing O-GlcNAcylation levels and effectively attenuated the liver injury induced by low-dose DON exposure. This finding provides a new strategy for dealing with liver injury caused by low-dose DON exposure.
    Keywords:  Deoxynivalenol; Ferritinophagy; Hesperidin; Mitophagy; O-GlcNAcylation
    DOI:  https://doi.org/10.1016/j.jhazmat.2024.135952
  23. Cell Biochem Biophys. 2024 Sep 28.
    Hyperuricemia Facilitates Uric Acid-Mediated Vascular Endothelial Cell Damage by Inhibiting Mitophagy.
    Gang Wu, Jun Liu, Guirong Ma, Qiuyu Wei, Xinghui Song.
      Hyperuricemia remains an elusive factor in the pathogenesis of vascular endothelial injury. This study elucidates the role of hydroxychloroquine (HCQ) in the context of uric acid (UA)-induced vascular endothelial cell damage. Human umbilical vein endothelial cells (HUVECs) were exposed to varying UA concentrations (6 mg/dL to 50 mg/dL) for 48 h, or to 50 mg/dL UA for different time points (6 to 72 h). We observed a concentration- and time-dependent inhibition of cell proliferation, particularly at 40 mg/dL and 50 mg/dL UA. The autophagy marker LC3 exhibited reduced fluorescence intensity post-UA treatment, along with decreased expression of LC3-II/LC3I, beclin1, and p62, indicating impaired autophagy. The mechanistic exploration revealed that HCQ, in conjunction with the mitochondrial autophagy inhibitor Cyclosporine A (CsA), exacerbated the inhibitory effects of UA on HUVEC autophagy. This was evidenced by a further reduction in mitochondrial autophagy-related proteins and diminished fluorescence of LC3-II/LC3-I and Parkin, culminating in suppressed cell proliferation and accelerated cell senescence and apoptosis. Conversely, the co-treatment with the mitochondrial autophagy inducer carbonyl cyanide m-chlorophenyl hydrazine (CCCP) and HCQ mitigated the detrimental effects of UA on HUVEC autophagy. This intervention led to increased expression of PINK1, Parkin, Bnip3, and Nix, along with enhanced fluorescence of LC3-II/LC3-I and Parkin, effectively inhibiting cell senescence and apoptosis while promoting cell proliferation. In conclusion, our findings underscore the pivotal role of HCQ in modulating UA-mediated vascular endothelial cell damage through the inhibition of mitophagy, providing novel insights into the therapeutic potential of targeting HCQ in the management of hyperuricemia-associated vascular complications.
    Keywords:  Human umbilical vein endothelial cells; Hydroxychloroquine; Hyperuricemia; Mitophagy
    DOI:  https://doi.org/10.1007/s12013-024-01512-5
  24. Biomedicines. 2024 Sep 03. pii: 2013. [Epub ahead of print]12(9):
    ALCAT1-Mediated Pathological Cardiolipin Remodeling and PLSCR3-Mediated Cardiolipin Transferring Contribute to LPS-Induced Myocardial Injury.
    Dong Han, Chenyang Wang, Xiaojing Feng, Li Hu, Beibei Wang, Xinyue Hu, Jing Wu.
      Cardiolipin (CL), a critical phospholipid situated within the mitochondrial membrane, plays a significant role in modulating intramitochondrial processes, especially in the context of certain cardiac pathologies; however, the exact effects of alterations in cardiolipin on septic cardiomyopathy (SCM) are still debated and the underlying mechanisms remain incompletely understood. This study highlights a notable increase in the expressions of ALCAT1 and PLSCR3 during the advanced stage of lipopolysaccharide (LPS)-induced SCM. This up-regulation potential contribution to mitochondrial dysfunction and cellular apoptosis-as indicated by the augmented oxidative stress and cytochrome c (Cytc) release-coupled with reduced mitophagy, decreased levels of the antiapoptotic protein B-cell lymphoma-2 (Bcl-2) and lowered cell viability. Additionally, the timing of LPS-induced apoptosis coincides with the decline in both autophagy and mitophagy at the late stages, implying that these processes may serve as protective factors against LPS-induced SCM in HL-1 cells. Together, these findings reveal the mechanism of LPS-induced CL changes in the center of SCM, with a particular emphasis on the importance of pathological remodeling and translocation of CL to mitochondrial function and apoptosis. Additionally, it highlights the protective effect of mitophagy in the early stage of SCM. This study complements previous research on the mechanism of CL changes in mediating SCM. These findings enhance our understanding of the role of CL in cardiac pathology and provide a new direction for future research.
    Keywords:  cardiolipin; pathological CL remodeling; septic cardiomyopathy; translocation of CL
    DOI:  https://doi.org/10.3390/biomedicines12092013
  25. Antioxidants (Basel). 2024 Aug 30. pii: 1061. [Epub ahead of print]13(9):
    Gut Microbiota-Derived Trimethylamine Promotes Inflammation with a Potential Impact on Epigenetic and Mitochondrial Homeostasis in Caco-2 Cells.
    Laura Bordoni, Irene Petracci, Giulia Feliziani, Gaia de Simone, Chiara Rucci, Rosita Gabbianelli.
      Trimethylamine (TMA), a byproduct of gut microbiota metabolism from dietary precursors, is not only the precursor of trimethylamine-N-oxide (TMAO) but may also affect gut health. An in vitro model of intestinal epithelium of Caco-2 cells was used to evaluate the impact of TMA on inflammation, paracellular permeability, epigenetics and mitochondrial functions. The expression levels of pro-inflammatory cytokines (IL-6, IL-1β) increased significantly after 24 h exposure to TMA 1 mM. TMA exposure was associated with an upregulation of SIRT1 (TMA 1 mM, 400 μM, 10 μM) and DNMT1 (TMA 1 mM, 400 µM) genes, while DNMT3A expression decreased (TMA 1 mM). In a cell-free model, TMA (from 0.1 µM to 1 mM) induced a dose-dependent reduction in Sirtuin enzyme activity. In Caco-2 cells, TMA reduced total ATP levels and significantly downregulated ND6 expression (TMA 1 mM). TMA excess (1 mM) reduced intracellular mitochondrial DNA copy numbers and increased the methylation of the light-strand promoter in the D-loop area of mtDNA. Also, TMA (1 mM, 400 µM, 10 µM) increased the permeability of Caco-2 epithelium, as evidenced by the reduced transepithelial electrical resistance values. Based on our preliminary results, TMA excess might promote inflammation in intestinal cells and disturb epigenetic and mitochondrial homeostasis.
    Keywords:  epigenetics; inflammation; mitochondria; nutrigenomics; trimethylamine
    DOI:  https://doi.org/10.3390/antiox13091061
  26. Int J Biol Macromol. 2024 Sep 27. pii: S0141-8130(24)06928-9. [Epub ahead of print]281(Pt 1): 136119
    Orchestrating AMPK/mTOR signaling to initiate melittin-induced mitophagy: A neuroprotective strategy against Parkinson's disease.
    Mingran Chen, Xue Wang, Shuangyan Bao, Dexiao Wang, Jie Zhao, Qian Wang, Chaojie Liu, Haiong Zhao, Chenggui Zhang.
      Apitherapy has a long history in treating Parkinson's disease (PD) in humans, with evidence suggesting that bee venom (BV) can mitigate Parkinson's symptoms. Central to BV's effects is melittin (MLT), a principal peptide whose neuroprotective mechanisms in PD are not fully understood. The study investigated the effects of MLT on an experimental PD model in mice and dopaminergic neuron cells, induced by MPTP or MPP+. We concentrate on the autophagic response elicited by MLT during PD pathogenesis. The findings showed that MLT was shown to protect against MPP+/MPTP cytotoxicity and preserve tyrosine hydroxylase (TH) levels, indicating neuronal safeguarding. Remarkably, MLT instigated mitophagy, enhancing mitochondrial homeostasis in MPP+-exposed SH-SY5Y cells. Further, MLT's promotion of mitophagy was confirmed to be AMPK/mTOR signaling-dependent. Validation using Bafilomycin A1, an autophagy inhibitor, confirmed MLT's neuroprotective role, with autophagy inhibition negating MLT's benefits and reducing TH preservation. These findings illuminate MLT's therapeutic potential, particularly its modulation of mitochondrial dysfunction in PD pathology. Our research advances the understanding of MLT's mechanistic action, emphasizing its role in mitochondrial autophagy and AMPK/mTOR signaling, offering a novel perspective beyond the symptomatic relief associated with BV.
    Keywords:  AMPK/mTOR signaling pathway; Dopaminergic neuron; Melittin; Mitophagy; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.ijbiomac.2024.136119
  27. Int J Mol Sci. 2024 Sep 14. pii: 9920. [Epub ahead of print]25(18):
    Effect of Spermidine on Endothelial Function in Systemic Lupus Erythematosus Mice.
    Hyoseon Kim, Michael P Massett.
      Endothelial dysfunction is common in Systemic Lupus Erythematosus (SLE), even in the absence of cardiovascular disease. Evidence suggests that impaired mitophagy contributes to SLE. Mitochondrial dysfunction is also associated with impaired endothelial function. Spermidine, a natural polyamine, stimulates mitophagy by the PINK1-parkin pathway and counters age-associated endothelial dysfunction. However, the effect of spermidine on mitophagy and vascular function in SLE has not been explored. To address this gap, 9-week-old female lupus-prone (MRL/lpr) and healthy control (MRL/MpJ) mice were randomly assigned to spermidine treatment (lpr_Spermidine and MpJ_Spermidine) for 8 weeks or as control (lpr_Control and MpJ_Control). lpr_Control mice exhibited impaired endothelial function (e.g., decreased relaxation to acetylcholine), increased markers of inflammation, and lower protein content of parkin, a mitophagy marker, in the thoracic aorta. Spermidine treatment prevented endothelial dysfunction in MRL-lpr mice. Furthermore, aortas from lpr_Spermidine mice had lower levels of inflammatory markers and higher levels of parkin. Lupus phenotypes were not affected by spermidine. Collectively, these results demonstrate the beneficial effects of spermidine treatment on endothelial function, inflammation, and mitophagy in SLE mice. These results support future studies of the beneficial effects of spermidine on endothelial dysfunction and cardiovascular disease risk in SLE.
    Keywords:  MRL/MpJ-Faslpr/J; PINK1–parkin; autoantibodies; mitophagy; thoracic aorta; vascular; vascular cell adhesion molecule 1 (Vcam1)
    DOI:  https://doi.org/10.3390/ijms25189920
  28. J Microbiol Biotechnol. 2024 Sep 23. 34(11): 1-14
    Impact of Mitophagy-Related Genes on the Diagnosis and Development of Esophageal Squamous Cell Carcinoma via Single-Cell RNA-seq Analysis and Machine Learning Algorithms.
    Xuzhi Mo, Feng Ji, Jianguang Chen, Chengcheng Yi, Fang Wang.
      As a treatment for esophageal squamous cell carcinoma (ESCC), which is common and fatal, mitophagy is a conserved cellular mechanism that selectively removes damaged mitochondria and is crucial for cellular homeostasis. While tumor development and resistance to anticancer therapies are related to ESCC, their role in ESCC remains unclear. Here, we investigated the relationship between mitophagy-related genes (MRGs) and ESCC to provide novel insights into the role of mitophagy in ESCC prognosis and diagnosis prediction. First, we identified MRGs from the GeneCards database and examined them at both the single-cell and transcriptome levels. Key genes were selected and a prognostic model was constructed using least absolute shrinkage and selection operator analysis. External validation was performed using the GSE53624 dataset and Kaplan-Meier survival analysis was performed to identify PYCARD as a gene significantly associated with survival in ESCC. We then examined the effect of PYCARD on ESCC cell proliferation and migration and identified 169 MRGs at the single-cell and transcriptome levels, as well as the high-risk groups associated with cancer-related pathways. Thirteen key genes were selected for model construction via multiple machine learning algorithms. PYCARD, which is upregulated in patients with ESCC, was negatively correlated with prognosis and its knockdown inhibited ESCC cell proliferation and migration. Our ESCC prediction model based on mitophagy-related genes demonstrated promising results and provides more options for the management and clinical treatment of ESCC patients. Moreover, targeting or regulating PYCARD levels might offer new therapeutic strategies for ESCC patients in clinical settings.
    Keywords:  ESCC; machine learning; mitophagy-related genes; prediction model; single-cell RNA-seq
    DOI:  https://doi.org/10.4014/jmb.2407.07052
  29. EMBO J. 2024 Oct 04.
    Longitudinal autophagy profiling of the mammalian brain reveals sustained mitophagy throughout healthy aging.
    Anna Rappe, Helena A Vihinen, Fumi Suomi, Antti J Hassinen, Homa Ehsan, Eija S Jokitalo, Thomas G McWilliams.
      Mitophagy neutralizes mitochondrial damage, thereby preventing cellular dysfunction and apoptosis. Defects in mitophagy have been strongly implicated in age-related neurodegenerative disorders such as Parkinson's and Alzheimer's disease. While mitophagy decreases throughout the lifespan of short-lived model organisms, it remains unknown whether such a decline occurs in the aging mammalian brain-a question of fundamental importance for understanding cell type- and region-specific susceptibility to neurodegeneration. Here, we define the longitudinal dynamics of basal mitophagy and macroautophagy across neuronal and non-neuronal cell types within the intact aging mouse brain in vivo. Quantitative profiling of reporter mouse cohorts from young to geriatric ages reveals cell- and tissue-specific alterations in mitophagy and macroautophagy between distinct subregions and cell populations, including dopaminergic neurons, cerebellar Purkinje cells, astrocytes, microglia and interneurons. We also find that healthy aging is hallmarked by the dynamic accumulation of differentially acidified lysosomes in several neural cell subsets. Our findings argue against any widespread age-related decline in mitophagic activity, instead demonstrating dynamic fluctuations in mitophagy across the aging trajectory, with strong implications for ongoing theragnostic development.
    Keywords:  Aging; Autophagy; Brain; Mitochondria; Mitophagy
    DOI:  https://doi.org/10.1038/s44318-024-00241-y
  30. Biochim Biophys Acta Mol Basis Dis. 2024 Sep 29. pii: S0925-4439(24)00525-8. [Epub ahead of print] 167531
    Upregulation of GRP78 is accompanied by decreased antioxidant response and mitophagy promotion in streptozotocin-induced type 1 diabetes in rats.
    O Kaniuka, A Deregowska, Yu Bandura, M Sabadashka, D Chala, O Kulachkovskyi, H Kubis, J Adamczyk-Grochala, N Sybirna.
      Endoplasmic reticulum stress, oxidative stress, and mitochondrial dysfunction are interconnected processes involved in the pathogenesis of diabetes mellitus (DM). In the present study, we demonstrate a distinct unfolded protein response (UPR) signaling pathways in two mammalian models of DM: β-TC-6 cell line and streptozotocin-induced type 1 diabetes model in rats. However, a feature common to both systems was the upregulation of the GRP78 protein. Moreover, in vivo studies showed the disruption of the antioxidant system and an escalation of mitophagy against the background of a depletion of the level of ATP in pancreatic cells. In conclusion, we suggest that glucotoxic conditions induced GRP78 upregulation, and next cause depletion of the antioxidant pool and disruption of the functioning of antioxidant defense enzymes and in consequence promote mitophagy in pancreatic cells. Therefore, GRP78 may be considered as a potential therapeutic factor in patients with diabetes.
    Keywords:  Diabetes mellitus; Endoplasmic reticulum stress; GRP78; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167531
  31. Biochim Biophys Acta Mol Cell Res. 2024 Sep 29. pii: S0167-4889(24)00197-6. [Epub ahead of print] 119854
    AGR2 knockdown induces ER stress and mitochondria fission to facilitate pancreatic cancer cell death.
    Philip Salu, Daniel Tuvin, Katie M Reindl.
      Anterior gradient 2 (AGR2) is often overexpressed in many human cancers, including pancreatic ductal adenocarcinoma (PDAC). Elevated AGR2 expression is known to play a critical role in tumor development, progression, and metastasis and positively correlates with poor patient survival. However, the relationship between AGR2 expression and tumor growth is not fully understood. Our study aims to investigate the impact of AGR2 knockdown on the survival of two pancreatic cancer cell lines, HPAF-II and PANC-1, that exhibit high AGR2 expression. This study revealed that the knockdown of AGR2 expression through an inducible shRNA-mediated approach reduced the proliferative ability and colony-forming potential of PDAC cells compared to scramble controls. Significantly, knocking down AGR2 led to the inhibition of multiple protein biosynthesis pathways and induced ER stress through unfolded protein response (UPR) activation. AGR2 knockdown induced ER stress and increased mitochondrial fission, while mitochondrial fusion remained unaffected. Ultimately, apoptotic cell death was heightened in AGR2 knockdown PDAC cells compared to the controls. Overall, these data reveal a new axis involving AGR2-ER stress-associated mitochondrial fission that could be targeted to improve PDAC patient outcomes.
    Keywords:  Anterior gradient 2 (AGR2); ER stress; Mitochondria dysfunction; Pancreatic ductal adenocarcinoma (PDAC); Unfolded protein response (UPR)
    DOI:  https://doi.org/10.1016/j.bbamcr.2024.119854
  32. PLoS Pathog. 2024 Sep 30. 20(9): e1012593
    ATM1, an essential conserved transporter in Apicomplexa, bridges mitochondrial and cytosolic [Fe-S] biogenesis.
    Deepti Shrivastava, Ernest Abboud, Jadhav Prasad Ramchandra, Akanksha Jha, Jean-Baptiste Marq, Animesh Chaurasia, Kalyan Mitra, Mohammad Sadik, Mohammad Imran Siddiqi, Dominique Soldati-Favre, Joachim Kloehn, Saman Habib.
      The Apicomplexa phylum encompasses numerous obligate intracellular parasites, some associated with severe implications for human health, including Plasmodium, Cryptosporidium, and Toxoplasma gondii. The iron-sulfur cluster [Fe-S] biogenesis ISC pathway, localized within the mitochondrion or mitosome of these parasites, is vital for parasite survival and development. Previous work on T. gondii and Plasmodium falciparum provided insights into the mechanisms of [Fe-S] biogenesis within this phylum, while the transporter linking mitochondria-generated [Fe-S] with the cytosolic [Fe-S] assembly (CIA) pathway remained elusive. This critical step is catalyzed by a well-conserved ABC transporter, termed ATM1 in yeast, ATM3 in plants and ABCB7 in mammals. Here, we identify and characterize this transporter in two clinically relevant Apicomplexa. We demonstrate that depletion of TgATM1 does not specifically impair mitochondrial metabolism. Instead, proteomic analyses reveal that TgATM1 expression levels inversely correlate with the abundance of proteins that participate in the transfer of [Fe-S] to cytosolic proteins at the outer mitochondrial membrane. Further insights into the role of TgATM1 are gained through functional complementation with the well-characterized yeast homolog. Biochemical characterization of PfATM1 confirms its role as a functional ABC transporter, modulated by oxidized glutathione (GSSG) and [4Fe-4S].
    DOI:  https://doi.org/10.1371/journal.ppat.1012593
  33. Phytomedicine. 2024 Sep 19. pii: S0944-7113(24)00713-X. [Epub ahead of print]135 156056
    Dioscin improves fatty liver hemorrhagic syndrome by promoting ERα-AMPK mediated mitophagy in laying hens.
    Yuxiao Xing, Benzeng Huang, Ziyi Cui, Quanwei Zhang, Haitian Ma.
       BACKGROUND: Mitochondria play a crucial role in upholding metabolic homeostasis. Mitochondrial damage closely associated with the pathogenesis of fatty liver hemorrhagic syndrome (FLHS), while mitophagy being among the most effective methods for eliminating the damaged mitochondria. Dioscin, a natural extract, can activate autophagy; however, its effects on FLHS regarding mitophagy regulation remain unelucidated.
    PURPOSE: We explored the impact of dioscin on FLHS induced by a high-energy and low-protein (HELP) diet in laying hens, mainly focused the protective effects of dioscin on mitochondrial injury.
    METHOD: To investigate the impact of dioscin on fatty liver syndrome in laying hens, we first induced the condition by feeding them a high-energy and low-protein diet. Then, we assessed lipid metabolism-related markers using oil red staining and a commercial detection kit. In addition, the role of dioscin on fatty liver syndrome in laying hens was confirmed by assessing the activation of hepatocyte fat deposition and hepatocyte apoptosis; and the mechanism of dioscin in FLHS was investigated through LMH cell experiment in vitro. Furthermore, CETSA and molecular docking were conducted for additional confirmation.
    RESULT: The results showed that dioscin alleviated mitochondrial damage, relieved the excessive deposition of hepatic lipid droplets and oxidative stress induced by HELP diet in laying hens. Furthermore, dioscin regulated the mitophagy by activating the estrogen receptor α (ERα)/adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling pathway, thus mitigating mitochondria injury and apoptosis in hepatocytes. In addition, we found that dioscin promoted the translocation of nuclear transcription factor into nucleus by activating ERα-AMPK signaling, facilitating autophagic flux in the liver of laying hens and LMH cells. Furthermore, cells pretreated with the lysosomal acidification inhibitor bafilomycin A1 blocked the inhibitory effect of dioscin on the apoptosis induced by palmitic acid (PA)-stimulation in LMH cells, suggesting that dioscin reduces PA-induced apoptosis by activating mitophagy. Moreover, dioscin-induced lysosomal acidification and mitochondrial biogenesis were reversed in PA-induced LMH cells pretreated with ERα-specific inhibitor methylpiperidino pyrazole.
    CONCLUSION: This study firstly demonstrated that dioscin alleviates fatty liver syndrome induced by HELP diet in laying hens. The findings from this study illustrated that dioscin plays a significant role in reducing mitochondrial damage and apoptosis, and these beneficial effects mainly achieve through promotion of ERα-AMPK signaling, which mediates autophagy within the liver of laying hens fed a HELP-diets. These findings provide a theoretical basis for considering dioscin as a possible treatment option for mitigating FLHS in egg-laying hens.
    Keywords:  Dioscin; Fatty liver hemorrhagic syndrome; Mitochondria injury; Mitochondrial apoptotic pathway; Mitophagy
    DOI:  https://doi.org/10.1016/j.phymed.2024.156056
  34. Antioxidants (Basel). 2024 Sep 04. pii: 1086. [Epub ahead of print]13(9):
    TSG Extends the Longevity of Caenorhabditis elegans by Targeting the DAF-16/SKN-1/SIR-2.1-Mediated Mitochondrial Quality Control Process.
    Menglu Sun, Congmin Wei, Yehui Gao, Xinyan Chen, Kaixin Zhong, Yingzi Li, Zhou Yang, Yihuai Gao, Hongbing Wang.
      The improvement of mitochondrial function is described as a strategy for alleviating oxidative stress and intervening in the aging process. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the major bioactive components isolated from Polygonum multiflorum Thunb, and it exhibits multiple activities, including antioxidant and anti-inflammatory effects. In this study, we found that 200 μM TSG significantly extended the mean lifespan of Caenorhabditis elegans by 16.48% and improved health status by delaying age-associated physiological decline in worms. The longevity prolongation effect of TSG depended on the regulation of the mitochondrial quality control process mediated by DAF-16/FOXO, SKN-1/Nrf2 and SIR-2.1/SIRT1 to improve mitochondrial function. Moreover, TSG treatment obviously alleviated the proteotoxicity of β-amyloid and tau proteins in worms. Our findings indicated that TSG is a promising natural product for preventing aging and treating aging-associated neurodegenerative diseases by regulating the mitochondrial quality control process to improve mitochondrial function.
    Keywords:  2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside; Caenorhabditis elegans; aging; mitochondrial function; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/antiox13091086
  35. J Clin Biochem Nutr. 2024 Sep;75(2): 102-110
    CREB1 regulates RECQL4 to inhibit mitophagy and promote esophageal cancer metastasis.
    Shiyi Zheng, Yi Zhang, Xiaozhou Gong, Zhangyu Teng, Jun Chen.
      Mitophagy plays a vital role in carcinogenesis and tumor progression. However, the research on the mechanism of mitophagy in esophageal cancer metastasis is limited. This study explored the regulatory mechanism of RECQL4 in mitophagy and affects esophageal cancer metastasis. The RECQL4 expression in esophageal cancer tissues and cells was examined by bioinformatics and qRT-PCR. Bioinformatics analysis was used to determine the upstream regulatory factor of RECQL4 and CREB1. Their binding relationship was evaluated by dual luciferase and Chromatin Immunoprecipitation assays. The effects of RECQL4 on esophageal cancer cells viability, metastasis, and mitophagy were examined using CCK-8, Transwell, immunofluorescence, and Western blot assays. The expression of RECQL4 was up-regulated in esophageal cancer tissues and cells. Overexpression of RECQL4 promoted the cells viability, invasion, migration, and epithelial-mesenchymal transition by inhibiting mitophagy. Bioinformatics analysis revealed a positive correlation between RECQL4 and CREB1, their binding relationship was validatied by dual luciferase and ChIP assays. CREB1 knockdown promoted mitophagy and prevented the metastasis of cancer cells, which could be countered by overexpressing RECQL4. In conclusion, CREB1 was found to transcriptionally activate RECQL4 to inhibit mitophagy, thereby promoting esophageal cancer metastasis. Targeting mitophagy could be an effective therapeutic approach for esophageal cancer.
    Keywords:  CREB1; RECQL4; esophageal cancer; metastasis; mitophagy
    DOI:  https://doi.org/10.3164/jcbn.23-118
  36. Plant Cell Rep. 2024 Oct 03. 43(10): 250
    A snapshot of the Physcomitrella N-terminome reveals N-terminal methylation of organellar proteins.
    Sebastian N W Hoernstein, Andreas Schlosser, Kathrin Fiedler, Nico van Gessel, Gabor L Igloi, Daniel Lang, Ralf Reski.
       KEY MESSAGE: Analysis of the N-terminome of Physcomitrella reveals N-terminal monomethylation of nuclear-encoded, mitochondria-localized proteins. Post- or co-translational N-terminal modifications of proteins influence their half-life as well as mediating protein sorting to organelles via cleavable N-terminal sequences that are recognized by the respective translocation machinery. Here, we provide an overview on the current modification state of the N-termini of over 4500 proteins from the model moss Physcomitrella (Physcomitrium patens) using a compilation of 24 N-terminomics datasets. Our data reveal distinct proteoforms and modification states and confirm predicted targeting peptide cleavage sites of 1,144 proteins localized to plastids and the thylakoid lumen, to mitochondria, and to the secretory pathway. In addition, we uncover extended N-terminal methylation of mitochondrial proteins. Moreover, we identified PpNTM1 (P. patens alpha N-terminal protein methyltransferase 1) as a candidate for protein methylation in plastids, mitochondria, and the cytosol. These data can now be used to optimize computational targeting predictors, for customized protein fusions and their targeted localization in biotechnology, and offer novel insights into potential dual targeting of proteins.
    Keywords:  AARE; N-terminus; Organelle; Proteases; Protein methylation; Protein modification; Protein targeting
    DOI:  https://doi.org/10.1007/s00299-024-03329-1
  37. Cell Commun Signal. 2024 Sep 30. 22(1): 463
    Spinster homolog 2/S1P signaling ameliorates macrophage inflammatory response to bacterial infections by balancing PGE2 production.
    Chao Fang, Pan Ren, Yejun He, Yitian Wang, Shuting Yao, Congying Zhao, Xueyong Li, Xi Zhang, Jinqing Li, Mingkai Li.
       BACKGROUND: Mitochondria play a crucial role in shaping the macrophage inflammatory response during bacterial infections. Spinster homolog 2 (Spns2), responsible for sphingosine-1-phosphate (S1P) secretion, acts as a key regulator of mitochondrial dynamics in macrophages. However, the link between Spns2/S1P signaling and mitochondrial functions remains unclear.
    METHODS: Peritoneal macrophages were isolated from both wild-type and Spns2 knockout rats, followed by non-targeted metabolomics and RNA sequencing analysis to identify the potential mediators through which Spns2/S1P signaling influences the mitochondrial functions in macrophages. Various agonists and antagonists were used to modulate the activation of Spns2/S1P signaling and its downstream pathways, with the underlying mechanisms elucidated through western blotting. Mitochondrial functions were assessed using flow cytometry and oxygen consumption assays, as well as morphological analysis. The impact on inflammatory response was validated through both in vitro and in vivo sepsis models, with the specific role of macrophage-expressed Spns2 in sepsis evaluated using Spns2flox/floxLyz2-Cre mice. Additionally, the regulation of mitochondrial functions by Spns2/S1P signaling was confirmed using THP-1 cells, a human monocyte-derived macrophage model.
    RESULTS: In this study, we unveil prostaglandin E2 (PGE2) as a pivotal mediator involved in Spns2/S1P-mitochondrial communication. Spns2/S1P signaling suppresses PGE2 production to support malate-aspartate shuttle activity. Conversely, excessive PGE2 resulting from Spns2 deficiency impairs mitochondrial respiration, leading to intracellular lactate accumulation and increased reactive oxygen species (ROS) generation through E-type prostanoid receptor 4 activation. The overactive lactate-ROS axis contributes to the early-phase hyperinflammation during infections. Prolonged exposure to elevated PGE2 due to Spns2 deficiency culminates in subsequent immunosuppression, underscoring the dual roles of PGE2 in inflammation throughout infections. The regulation of PGE2 production by Spns2/S1P signaling appears to depend on the coordinated activation of multiple S1P receptors rather than any single one.
    CONCLUSIONS: These findings emphasize PGE2 as a key effector of Spns2/S1P signaling on mitochondrial dynamics in macrophages, elucidating the mechanisms through which Spns2/S1P signaling balances both early hyperinflammation and subsequent immunosuppression during bacterial infections.
    Keywords:  Immunometabolism; Inflammatory response; Macrophages; Prostaglandin E2 ; Sphingosine-1-phosphate; Spinster homolog 2
    DOI:  https://doi.org/10.1186/s12964-024-01851-z
  38. Biochim Biophys Acta Mol Basis Dis. 2024 Oct 02. pii: S0925-4439(24)00522-2. [Epub ahead of print] 167528
    Myeloid PGC1β attenuates high-fat-diet induced inflammation via mitochondrial fission/mtDNA/Nlrp3 pathway.
    En Li, Jiajia Ji, Gaoyang Zong, Hao Liu, Yue Sun, Liangliang Wei, Zhihao Xia, Xiaoyu Yang, Dageng Huang, Yan Zhang.
      Peroxisome proliferator-activated receptor gamma coactivators 1β (PGC1β) is essential in mitochondrial oxidative phosphorylation and alternative macrophages activation. To determine the contribution of PGC1β in obesity induced inflammation, Ppargc1b (PGC1β coding gene) myeloid conditional knockout mice (cKO) were fed with high fat diet (HFD) to examine the following effects. We found that HFD-fed cKO mice gained more fat with increased serum triglyceride (TG), low density lipoprotein (LDL), adiponectin, and leptin. Adipogenesis was stimulated while lipolysis was retarded in HFD-fed cKO mice adipose. Gluconeogenesis, lipogenesis, and fatty acid uptake were provoked while lipolysis was inhibited in HFD-fed cKO liver. Serum alanine transaminase (ALT) level, indicating fatty liver, also increased. Inflammatory cytokine including tumor necrosis factor-α (TNF-α), IL-1β, and IL-6 was elevated in cKO mice, accompanied with glucose intolerant and insulin resistance. Energy expenditure was decreased in HFD-fed cKO mice. Further evidence showed that cKO macrophages were prone to repolarize into M1 inflammatory type in vitro. In addition to mitochondrial biogenesis and oxidative respiration, PGC1β also modulated mitochondrial fission and cytosolic mitochondrial DNA (mtDNA) release, contributing to NLR family pyrin domain containing 3 (Nlrp3) inflammasome priming and activation. Treatment of mitochondrial fission inhibitor abolished the increased mRNA levels of Nlrp3 and IL-1β induced by PGC1β depletion. Nlrp3 knockdown restored the induced IL-1β mRNA expression by PGC1β deficiency. Myeloid PGC1β regulated adipocyte adipogenesis and lipolysis. PGC1β loss-of-function and mtDNA abundance correlated with obesity and diabetes. These observations uncovered the protective role of PGC1β against obesity induced systemic inflammation. Enhancing myeloid PGC1β function may be a potential strategy for the intervention of obesity and related diseases.
    Keywords:  Inflammation; Macrophage; Mitochondria; PGC1β
    DOI:  https://doi.org/10.1016/j.bbadis.2024.167528
  39. Phytomedicine. 2024 Sep 22. pii: S0944-7113(24)00745-1. [Epub ahead of print]135 156088
    Melatonin protects RPE cells from necroptosis and NLRP3 activation via promoting SERCA2-related intracellular Ca2+ homeostasis.
    Chengda Ren, Chengyu Hu, Ming Hu, Yan Wu, Yang Yang, Fang Lu.
       BACKGROUND: Melatonin is an antioxidant that also has anti-inflammatory effects. It has been reported to delay the progression of age-related macular degeneration (AMD), however, the mechanism has not been fully recognized.
    PURPOSE: The aim of the present study was to investigate the effects of melatonin on sodium iodate (SI)-induced retinal degeneration and elucidate the specific mechanisms, then, provide novel targets in AMD treatment.
    METHODS: Retinal degeneration mouse model and in vitro retinal pigment epithelium (RPE) death model were established by SI treatment. Melatonin was administrated intraperitoneally at a concentration of 20, 40 or 80 mg/kg for in vivo study or treated at 48 h before SI treatment. To confirm the therapeutic effects of melatonin on mouse, the retinal structure and visual function were evaluated. The specific cell death rates were determined by CCK-8 assay, PI staining and protein level of RIPK3. The cytosolic or mitochondrial calcium levels were determined by Fluo-4AM or Rhod-2AM staining. Mitochondrial functions including mitochondrial dynamics, mitochondrial membrane potential, or mitochondrial permeability pore opening were evaluated. The proteins involved in endoplasmic reticulum (ER) stress were measured by western blot assay while the genes expression in calcium signaling pathway were measured by RT-qPCR.
    RESULTS: We show that melatonin protects RPE cells from necroptosis and NLRP3 inflammasome activation induced by SI. Mechanistically, melatonin suppresses ER stress and intracellular calcium overload triggered by SI through restoring the function of SERCA2. Silencing of SERCA2 or blocking of melatonin receptors inhibit the protective effects of melatonin. Melatonin reduces mitochondrial Ca2+ levels and restores mitochondrial membrane potential. Constant mitochondrial Ca2+ overload directly promote cell necroptosis through mitochondrial fission. Inhibition of mitochondrial fission by Mdivi-1 prevent necroptosis induced by SI without altering the level of mitochondrial Ca2+.
    CONCLUSIONS: The results confirmed that melatonin protects RPE cells from SI-induced injury by regulates MT2/SERCA2/Ca2+ axis. This study highlighted the potential of melatonin in the treatment of AMD and elucidated the mechanism and signaling pathway that mediate the protective effects.
    Keywords:  Calcium signaling; ER-stress; Inflammation; Melatonin; Necroptosis; Retinal degeneration
    DOI:  https://doi.org/10.1016/j.phymed.2024.156088
  40. Redox Biol. 2024 Sep 24. pii: S2213-2317(24)00349-5. [Epub ahead of print]77 103371
    Interplay of ROS, mitochondrial quality, and exercise in aging: Potential role of spatially discrete signaling.
    Siobhan M Craige, Rebecca K Mammel, Niloufar Amiri, Orion S Willoughby, Joshua C Drake.
      
    Keywords:  Energetic stress; Mitochondrial adaptation to exercise; Mitochondrial quality control and aging; Reactive oxygen species (ROS); Spatially discrete signaling; Stress resilience
    DOI:  https://doi.org/10.1016/j.redox.2024.103371
  41. Theranostics. 2024 ;14(15): 5762-5777
    ROCK inhibitor enhances mitochondrial transfer via tunneling nanotubes in retinal pigment epithelium.
    Jing Yuan, Fangxuan Chen, Dan Jiang, Zehua Xu, Hang Zhang, Zi-Bing Jin.
      Rationale: Tunnel nanotube (TNT)-mediated mitochondrial transport is crucial for the development and maintenance of multicellular organisms. Despite numerous studies highlighting the significance of this process in both physiological and pathological contexts, knowledge of the underlying mechanisms is still limited. This research focused on the role of the ROCK inhibitor Y-27632 in modulating TNT formation and mitochondrial transport in retinal pigment epithelial (RPE) cells. Methods: Two types of ARPE19 cells (a retinal pigment epithelial cell line) with distinct mitochondrial fluorescently labeled, were co-cultured and treated with ROCK inhibitor Y-27632. The formation of nanotubes and transport of mitochondria were assessed through cytoskeletal staining and live cell imaging. Mitochondrial dysfunction was induced by light damage to establish a model, while mitochondrial function was evaluated through measurement of oxygen consumption rate. The effects of Y-27632 on cytoskeletal and mitochondrial dynamics were further elucidated through detailed analysis. Results: Y-27632 treatment led to an increase in nanotube formation and enhanced mitochondrial transfer among ARPE19 cells, even following exposure to light-induced damage. Our analysis of cytoskeletal and mitochondrial distribution changes suggests that Y-27632 promotes nanotube-mediated mitochondrial transport by influencing cytoskeletal remodeling and mitochondrial movement. Conclusions: These results suggest that Y-27632 has the ability to enhance mitochondrial transfer via tunneling nanotubes in retinal pigment epithelium, and similarly predict that ROCK inhibitor can fulfill its therapeutic potential through promoting mitochondrial transport in the retinal pigment epithelium in the future.
    Keywords:  ARPE19; Y-27632; cytoskeletal remodeling; light damage; mitochondrial transfer; nanotubes
    DOI:  https://doi.org/10.7150/thno.96508
  42. AAPS PharmSciTech. 2024 Sep 30. 25(7): 227
    Naringenin Nanocrystals Mitigate Rotenone Neurotoxicity in SH-SY5Y Cell Line by Modulating Mitophagy and Oxidative Stress.
    Vaibhavi Giradkar, Akshada Mhaske, Rahul Shukla.
      Naringenin, a potent antioxidant with anti-apoptotic effects, holds potential in counteracting rotenone-induced neurotoxicity, a model for Parkinson's disease, by reducing oxidative stress and supporting mitochondrial function. Rotenone disrupts ATP production in SH-SY5Y cells through mitochondrial complex-I inhibition, leading to increased reactive oxygen species (ROS) and cellular damage. However, the therapeutic use of naringenin is limited by its poor solubility, low bioavailability, and stability concerns. Nano crystallization of naringenin (NCs), significantly improved its solubility, dissolution rates, and stability for targeted drug delivery. The developed NAR-NC and HSA-NAR-NC formulations exhibit particle sizes of 95.23 nm and 147.89 nm, with zeta potentials of -20.6 mV and -28.5 mV, respectively. These nanocrystals also maintain high drug content and show stability over time, confirming their pharmaceutical viability. In studies using the SH-SY5Y cell line, these modified nanocrystals effectively preserved mitochondrial membrane potential, sustained ATP production, and regulated ROS levels, counteracting the neurotoxic effects of rotenone. Naringenin nanocrystals offer a promising solution for improving the stability and bioavailability of naringenin, with potential therapeutic applications in neurodegenerative diseases.
    Keywords:  Mitochondrial oxidative stress; nanocrystals; neuroprotective ; reactive oxygen species; rotenone neurotoxicity
    DOI:  https://doi.org/10.1208/s12249-024-02936-1
  43. Stroke Vasc Neurol. 2024 Oct 02. pii: svn-2024-003509. [Epub ahead of print]
    Exosomes-mediated delivery of miR-486-3p alleviates neuroinflammation via SIRT2-mediated inhibition of mitophagy after subarachnoid hemorrhage.
    Bin Sheng, Sen Gao, XiangXin Chen, Yang Liu, Niansheng Lai, Jin Dong, Jiaqing Sun, Yan Zhou, Lingyun Wu, Chun-Hua Hang, Wei Li.
       BACKGROUND: Neuroinflammation participates in the pathogenesis of subarachnoid haemorrhage (SAH); however, no effective treatments exist. MicroRNAs regulate several aspects of neuronal dysfunction. In a previous study, we found that exosomal miR-486-3p is involved in the pathophysiology of SAH. Targeted delivery of miR-486-3p without blood-brain barrier (BBB) restriction to alleviate SAH is a promising neuroinflammation approach.
    METHODS: In this study, we modified exosomes (Exo) to form an RVG-miR-486-3p-Exo (Exo/miR) to achieve targeted delivery of miR-486-3p to the brain. Neurological scores, brain water content, BBB damage, flow cytometry and FJC staining were used to determine the effect of miR-486-3p on SAH. Western blot analysis, ELISA and RT-qPCR were used to measure relevant protein and mRNA levels. Immunofluorescence staining and laser confocal detection were used to measure the expression of mitochondria, lysosomes and autophagosomes, and transmission electron microscopy was used to observe the level of mitophagy in the brain tissue of mice after SAH.
    RESULTS: Tail vein injection of Exo/miR improved targeting of miR-486-3p to the brains of SAH mice. The injection reduced levels of neuroinflammation-related factors by changing the phenotype switching of microglia, inhibiting the expression of sirtuin 2 (SIRT2) and enhancing mitophagy. miR-486-3p treatment alleviated neurobehavioral disorders, brain oedema, BBB damage and neurodegeneration. Further research found that the mechanism was achieved by regulating the acetylation level of peroxisome proliferator-activated receptor γ coactivator l alpha (PGC-1α) after SIRT2 enters the nucleus.
    CONCLUSION: Exo/miR treatment attenuates neuroinflammation after SAH by inhibiting SIRT2 expression and stimulating mitophagy, suggesting potential clinical applications.
    Keywords:  Aneurysm; Brain; Hemorrhage; Stroke; Subarachnoid
    DOI:  https://doi.org/10.1136/svn-2024-003509
  44. Pharmacol Res. 2024 Sep 30. pii: S1043-6618(24)00385-2. [Epub ahead of print] 107440
    Commentary on "Orosomucoid 2 is an endogenous regulator of neuronal mitochondrial biogenesis and promotes functional recovery post-stroke".
    Raja Kannan.
      
    DOI:  https://doi.org/10.1016/j.phrs.2024.107440
  45. Biology (Basel). 2024 Sep 14. pii: 721. [Epub ahead of print]13(9):
    Aminocarb Exposure Induces Cytotoxicity and Endoplasmic Reticulum Stress-Mediated Apoptosis in Mouse Sustentacular Sertoli Cells: Implications for Male Infertility and Environmental Health.
    Sílvia Moreira, Ana D Martins, Marco G Alves, Luis Miguel Pastor, Vicente Seco-Rovira, Pedro F Oliveira, Maria de Lourdes Pereira.
      Exposure to pesticides, poses a significant threat to male fertility by compromising crucial cells involved in spermatogenesis. Aminocarb, is a widely used carbamate insecticide, although its detrimental effects on the male reproductive system, especially on sustentacular Sertoli cells, pivotal for spermatogenesis, remains poorly understood. In this study, we investigated the effects of escalating concentrations of aminocarb on a mouse Sertoli cell line, TM4. Assessments included cytotoxic analysis, mitochondrial biogenesis and membrane potential, expression of apoptotic proteins, caspase-3 activity, and oxidative stress evaluation. Our findings revealed a dose-dependent reduction in the proliferation and viability of TM4 cells following exposure to increasing concentrations of aminocarb. Notably, exposure to 5 μM of aminocarb induced depolarization of mitochondria membrane potential, and a significant decrease in the ratio of phosphorylated eIF2α to total eIF2α, suggesting heightened endoplasmic reticulum stress via the activation of the eIF2α pathway. Moreover, the same aminocarb concentration was demonstrated to increase both caspase-3 protein levels and activity, indicating an apoptotic induction. Collectively, our results demonstrate that aminocarb serves as an apoptotic inducer for mouse sustentacular Sertoli cells in vitro, suggesting its potential to modulate independent pathways of the apoptotic cascade. These findings underscore the deleterious impact of aminocarb on spermatogenic performance and male fertility, highlighting the urgent need for further investigation into its mechanisms of action and mitigation strategies to safeguard male fertility.
    Keywords:  ER stress; aminocarb; apoptosis; carbamates; male fertility; sertoli cells
    DOI:  https://doi.org/10.3390/biology13090721
  46. Pharmacol Res. 2024 Oct 02. pii: S1043-6618(24)00395-5. [Epub ahead of print] 107450
    β-asarone Protects Against Age-related Motor Decline via Activation of SKN-1/Nrf2 and Subsequent Induction of GST-4.
    Ming Lei, Jiayu Wu, Yanheng Tan, Yang Shi, Wuyan Yang, Haijun Tu, Weihong Tan.
      Decelerating motor decline is important for promoting healthy aging in the elderly population. Acorus tatarinowii Schott is a traditional Chinese medicine that contains β-asarone as a pharmacologically active constituent. We found that β-asarone can decelerate motor decline in various age groups of Caenorhabditis elegans, while concurrently prolonging their lifespan and modulating synaptic transmission. To understand the mechanisms of its efficacy in motor improvement, we investigated and discovered that mitochondrial fragmentation, a marker for aging, is delayed after β-asarone treatment. Moreover, their efficacy is blocked by dysfunctional mitochondria. Corresponding to their role in regulating mitochondrial homeostasis, we found that SKN-1/Nrf2 and GST-4 are critical in the β-asarone treatment, and they appear to be activated via the insulin/IGF-1 signaling pathway. Well-developed intestinal microvilli are required for this process. Our study demonstrates the efficacy and mechanism of β-asarone treatment in age-related motor decline, contributing to the discovery of drugs for achieving healthy aging.
    Keywords:  healthy aging; mitochondrial fragmentation; motor decline; synaptic transmission; β-asarone
    DOI:  https://doi.org/10.1016/j.phrs.2024.107450
  47. Commun Biol. 2024 Oct 01. 7(1): 1229
    Maintaining mitochondrial DNA copy number mitigates ROS-induced oocyte decline and female reproductive aging.
    Shiyun Long, Yunchao Zheng, Xiaoling Deng, Jing Guo, Zhe Xu, Karin Scharffetter-Kochanek, Yanmei Dou, Min Jiang.
      Oocytes play a crucial role in transmitting maternal mitochondrial DNA (mtDNA), essential for the continuation of species. However, the effects of mitochondrial reactive oxygen species (ROS) on mammalian oocyte maturation and mtDNA maintenance remain unclear. We investigated this by conditionally knocking out the Sod2 gene in primordial follicles, elevating mitochondrial matrix ROS levels from early oocyte stages. Our data indicates that reproductive aging in Sod2 conditional knockout females begins at 6 months, with oxidative stress impairing oocyte quality, particularly affecting OXPHOS complex II and mtDNA-encoded mRNA levels. Despite unchanged mtDNA mutation load, mtDNA copy numbers exhibited significant variations. Strikingly, reducing mtDNA copy numbers by reducing mtSSB protein, crucial for mtDNA replication, accelerated reproductive aging onset to three months, underscoring the critical role of mtDNA copy number maintenance under oxidative stress conditions. This research provides new insights into the relationship among mitochondrial ROS, mtDNA, and reproductive aging, offering potential strategies for delaying aging-related fertility decline.
    DOI:  https://doi.org/10.1038/s42003-024-06888-x
  48. Rinsho Ketsueki. 2024 ;65(9): 865-871
    [Aberrant mitochondrial dynamics in myeloid neoplasms].
    Yoshihiro Hayashi.
      Age-related clonal hematopoiesis and myeloid malignancies arise from hematopoietic stem cells and progenitors with genetic abnormalities. Advances in next-generation sequencing technology have led to the identification of a wide variety of genetic alterations involved in disease onset. However, it remains unclear how diverse genetic alterations, lacking disease specificity, lead to the development of myeloid malignancies and the progression of clonal hematopoiesis. Mitochondrial abnormalities and their roles in various pathological conditions such as aging, inflammation, neurological diseases, cardiac diseases, and cancer have recently been revealed, and have garnered attention as new therapeutic targets. This review focuses on regulation of mitochondrial dynamics and outlines the role of mitochondria in myeloid malignancies and clonal hematopoiesis.
    Keywords:  Clonal hematopoiesis; Mitochondrial dynamics; Myelodysplastic syndromes; Myeloid malignancies
    DOI:  https://doi.org/10.11406/rinketsu.65.865
  49. Methods Mol Biol. 2025 ;2855 373-385
    Differential Mobility Spectrometry-Based Cardiolipin Analysis.
    Fabien Riols, Michael Witting, Mark Haid.
      Cardiolipins (CL) are special lipids in many respects. First of all, CL are composed of four fatty acids linked by two phosphatidic acids, which provide CL a unique molecular structure. Secondly, in eukaryotic cells they are specific to a single organelle, mitochondria, where they are also synthetized. CL are one of the most abundant lipid classes in mitochondria, mainly localized in the inner membrane. They are key determinants of mitochondrial health and homeostasis by modulating membrane integrity and fluidity, mitochondrial shapes, and metabolic pathways. Disturbances in mitochondrial CL composition can lead to tissue malfunction and diseases. It is therefore important to develop analytical tools to study the mitochondrial lipidome, and more particularly the CL. The method described here allows the quantification of cardiolipins at the sum composition level in isolated mitochondria or in liver tissue by flow injection analysis coupled to differential mobility spectrometry (FIA-DMS), also known as DMS-based shotgun lipidomics.
    Keywords:  Cardiolipins; Differential mobility spectrometry; Flow injection analysis; Mass spectrometry; Mitochondria
    DOI:  https://doi.org/10.1007/978-1-0716-4116-3_22
  50. Front Neurol. 2024 ;15 1413762
    Mapping the research of mitochondria and Parkinson's disease: a bibliometric analysis.
    Yan-Jun Chen, Ming-Rong Xie, Sheng-Qiang Zhou, Fang Liu.
       Background: Parkinson's disease (PD) is a chronic, progressive neurodegenerative disorder primarily affecting the elderly. Relevant studies suggest a significant connection between the mitochondria and PD. Publications exploring this connection have steadily increased in recent years. This study employs a bibliometric approach to comprehensively analyze the current status and future directions of the research on mitochondria and PD.
    Method: We retrieved data from the Web of Science database and used CiteSpace, VOSviewer, and "Bibliometrix" software to visually analyze various aspects of the research field. These aspects included the number of published papers, contributing countries and institutions, authors, publishing journals, cited references, and keywords.
    Results: Our analysis identified a total of 3,291 publications involving 14,670 authors from 2,836 organizations across 78 countries. The publication volume exhibited a continuous upward trend from 1999 to 2023. The United States emerged as the leading force in this research area, contributing the highest number of high-quality publications. Notably, the United States collaborated extensively with Germany and the United Kingdom. The University of Pittsburgh stood out as the most prolific institution. Harvard University had the highest academic influence and closely cooperated with the University of Pittsburgh, Juntendo University, and McGill University. Dr. Hattori Nobutaka was identified as the most prolific author, while Dr. Youle, Richard J emerged as the most influential author based on the highest average citation frequency. The Journal of Neurochemistry was the most published journal. The most co-cited paper was titled "Hereditary early-onset Parkinson's disease caused by mutations in PINK1." The major keywords included oxidative stress, alpha-synuclein, pink1, mitophagy, and mitochondrial dysfunction. Mitofusin 2, ubiquitin, and mitochondrial quality control have been identified as new research hotspots in recent years.
    Conclusion: Mitochondria-PD research is experiencing a steady increase in activity, fueled by increasing close collaboration between countries and different institutions. However, there is a need to further strengthen collaboration and communication between developed and developing nations. Current research has focused on the specific mechanisms of mitochondrial dysfunction and their relationship with PD. Mitofusin 2, ubiquitin, and mitochondrial quality control are positioned to be the hotspots and future research directions.
    Keywords:  CiteSpace; Parkinson’s disease; VOSviewer; Web of Science; bibliometrics; mitochondria
    DOI:  https://doi.org/10.3389/fneur.2024.1413762
  51. Biomed Pharmacother. 2024 Sep 27. pii: S0753-3322(24)01396-9. [Epub ahead of print]180 117510
    Morusin, a novel inhibitor of ACLY, induces mitochondrial apoptosis in hepatocellular carcinoma cells through ROS-mediated mitophagy.
    Desheng Li, Xiaoqing Yuan, Jianjun Ma, Tao Lu, Jinjin Zhang, Huan Liu, Guanqing Zhang, Yue Wang, Xiaohan Liu, Qiqiang Xie, Ling Zhou, Maolei Xu.
       OBJECTIVE: Morusin (Mor), a prenylated flavonoid isolated from the root bark of Morus alba L., exhibits potent anti-tumour effects; however, the molecular target of Mor is still not entirely clear. This study aimed to elucidate the mechanism of Mor against hepatocellular carcinoma (HCC) and identify potential molecular targets.
    METHODS: Mitochondrial function was assessed by measuring the mitochondrial membrane potential, mitochondrial ultrastructure, oxygen consumption, and ATP levels. Mor-induced mitophagy was confirmed using western blotting, immunofluorescence, and fluorescent probes. Transcriptomics, flow cytometry, western blotting, qRT-PCR and biochemical assays were used to reveal the molecular mechanisms and targets of Mor against HCC. We further validated the interaction between Mor and the target proteins using molecular docking and biolayer interferometry (BLI). The inhibitory effect of Mor in vivo was evaluated using a Hep3B murine xenograft model.
    RESULTS: Mor significantly reduced the ATP citrate lyase (ACLY) expression and inhibited ACLY activity in HCC cells. BLI analysis demonstrated a direct interaction between Mor and the ACLY active domain. Mor-induced ACLY inhibition led to ROS accumulation in HCC cells, which caused mitochondrial damage, triggered PINK1/Parkin-mediated mitophagy, and ultimately induced mitochondrial apoptosis. We further verified that ROS is crucial in the apoptotic action of Mor through experiments regarding an ROS scavenger. Mor also significantly inhibited tumour xenograft growth in vivo. In addition, analysis of human liver cancer clinical samples revealed elevated ACLY levels positively correlated with histologic grade.
    CONCLUSION: Collectively, our findings highlight Mor as a potent bioactive inhibitor of ACLY and a promising candidate for HCC therapy.
    Keywords:  ATP-citrate synthase; Hepatocellular carcinoma; Mitochondrial apoptosis; Mitophagy; Morusin
    DOI:  https://doi.org/10.1016/j.biopha.2024.117510
  52. Cell Prolif. 2024 Oct 01. e13746
    Matrix stiffness regulates mitochondria-lysosome contacts to modulate the mitochondrial network, alleviate the senescence of MSCs.
    Kang Wang, Chingchun Ho, Xiangyu Li, Jianfeng Hou, Qipei Luo, Jiahong Wu, Yuxin Yang, Xinchun Zhang.
      The extracellular microenvironment encompasses the extracellular matrix, neighbouring cells, cytokines, and fluid components. Anomalies in the microenvironment can trigger aging and a decreased differentiation capacity in mesenchymal stem cells (MSCs). MSCs can perceive variations in the firmness of the extracellular matrix and respond by regulating mitochondrial function. Diminished mitochondrial function is intricately linked to cellular aging, and studies have shown that mitochondria-lysosome contacts (M-L contacts) can regulate mitochondrial function to sustain cellular equilibrium. Nonetheless, the influence of M-L contacts on MSC aging under varying matrix stiffness remains unclear. In this study, utilizing single-cell RNA sequencing and atomic force microscopy, we further demonstrate that reduced matrix stiffness in older individuals leads to MSC aging and subsequent decline in osteogenic ability. Mechanistically, augmented M-L contacts under low matrix stiffness exacerbate MSC aging by escalating mitochondrial oxidative stress and peripheral division. Moreover, under soft matrix stiffness, cytoskeleton reorganization facilitates rapid movement of lysosomes. The M-L contacts inhibitor ML282 ameliorates MSC aging by reinstating mitochondrial network and function. Overall, our findings confirm that MSC aging is instigated by disruption of the mitochondrial network and function induced by matrix stiffness, while also elucidating the potential mechanism by which M-L Contact regulates mitochondrial homeostasis. Crucially, this presents promise for cellular anti-aging strategies centred on mitochondria, particularly in the realm of stem cell therapy.
    DOI:  https://doi.org/10.1111/cpr.13746
  53. Biomolecules. 2024 Aug 30. pii: 1089. [Epub ahead of print]14(9):
    Bcl-2 Orthologues, Buffy and Debcl, Can Suppress Drp1-Dependent Age-Related Phenotypes in Drosophila.
    Azra Hasan, Brian E Staveley.
      The relationship of Amyotrophic Lateral Sclerosis, Parkinson's disease, and other age-related neurodegenerative diseases with mitochondrial dysfunction has led to our study of the mitochondrial fission gene Drp1 in Drosophila melanogaster and aspects of aging. Previously, the Drp1 protein has been demonstrated to interact with the Drosophila Bcl-2 mitochondrial proteins, and Drp1 mutations can lead to mitochondrial dysfunction and neuronal loss. In this study, the Dopa decarboxylase-Gal4 (Ddc-Gal4) transgene was exploited to direct the expression of Drp1 and Drp1-RNAi transgenes in select neurons. Here, the knockdown of Drp1 seems to compromise locomotor function throughout life but does not alter longevity. The co-expression of Buffy suppresses the poor climbing induced by the knockdown of the Drp1 function. The consequences of Drp1 overexpression, which specifically reduced median lifespan and diminished climbing abilities over time, can be suppressed through the directed co-overexpression of pro-survival Bcl-2 gene Buffy or by the co-knockdown of the pro-cell death Bcl-2 homologue Debcl. Alteration of the expression of Drp1 acts to phenocopy neurodegenerative disease phenotypes in Drosophila, while overexpression of Buffy can counteract or rescue these phenotypes to improve overall health. The diminished healthy aging due to either the overexpression of Drp1 or the RNA interference of Drp1 has produced novel Drosophila models for investigating mechanisms underlying neurodegenerative disease.
    Keywords:  Amyotrophic Lateral Sclerosis; Buffy; Debcl; Drosophila melanogaster; Drp1; Parkinson’s disease; mitochondrial dysfunction; mitochondrial fission
    DOI:  https://doi.org/10.3390/biom14091089
  54. J Ethnopharmacol. 2024 Sep 27. pii: S0378-8741(24)01122-X. [Epub ahead of print] 118823
    Gypenosides alleviate oxidative stress in the hippocampus, promote mitophagy, and mitigate depressive-like behaviors induced by CUMS via SIRT1.
    Yuhang Liu, Yingfeng Li, Jingqi Li, Hui Rao, Jianfei Sun, Jiangfan Xiu, Ning Wu.
       ETHNOPHARMACOLOGICAL RELEVANCE: The use and efficacy of Gynostemma [Gynostemma pentaphyllum (Thunb.) Makino], a versatile traditional Chinese herb, was first documented in the renowned pharmacopoeia, "Compendium of Materia Medica". Gypenosides (Gps), saponin components are the primary constituents responsible for its biological activities and clinical effects, which include antioxidant, immunoregulatory, antitumor, and neuroprotective properties. Pharmacological studies have shown that Gps has the potential to combat depression. However, the exact molecular mechanisms underlying its antidepressant effects remain unclear.
    AIM OF THE STUDY: This study aims to elucidate the mechanisms underlying the antidepressant effects of Gps through antioxidative stress, utilizing an integrated approach that includes network pharmacology, molecular simulations, and experimental validation.
    MATERIALS AND METHODS: Sprague-Dawley rats were subjected to chronic unpredictable mild stress (CUMS) and were orally administered doses of Gps (50 and 100 mg/kg) and fluoxetine (10 mg/kg). The regulatory effects of Gps on depression-like behaviors in CUMS rats and their impact on oxidative stress levels in the hippocampus region were evaluated. Network pharmacology was used to investigate the mechanisms by which Gps affects oxidative stress in depression, and was accompanied by molecular docking and dynamics simulations. CUMS rats were treated orally with Gps (100 mg/kg) and injected with EX527 for rescue experiments to validate the role of SIRT1 in antioxidative stress and evaluate the impact of Gps on mitophagy.
    RESULTS: Gps ameliorated depression-like behaviors induced by CUMS in rats. The improvements observed included an increased sucrose preference, reduced immobility time in the tail suspension and forced swim tests, and an increased movement distance in the open-field test. Additionally, Gps effectively reduced reactive oxygen species, malondialdehyde, and 8-hydroxy-2'-deoxyguanosine levels in the hippocampus, while increasing the contents of ATP, catalase, superoxide dismutase, and glutathione, indicating an increased capacity for antioxidative stress in the hippocampus. Furthermore, Gps increased the number of neuronal cells in the hippocampal CA1 region and the level of mitochondrial autophagy, with SIRT1 as a potential key target. Inhibition of SIRT1 expression by exposure to EX527 reversed the beneficial effects of Gps, further validating the critical role of SIRT1 in the regulation of oxidative stress and improving depression-like behavior.
    CONCLUSION: Gps improved the antioxidative stress capacity of the hippocampus and promoted mitophagy in CUMS rats through SIRT1, thus protecting hippocampal neurons and improving depression-like behavior.
    Keywords:  Depression; Gypenosides; Network pharmacology; Oxidative stress; SIRT1
    DOI:  https://doi.org/10.1016/j.jep.2024.118823
  55. Mitochondrion. 2024 Oct 01. pii: S1567-7249(24)00130-2. [Epub ahead of print] 101972
    Mitochondrial dysfunction in diabetic neuropathy: Impaired mitophagy triggers NLRP3 inflammasome.
    Keshari Sriwastawa, Ashutosh Kumar.
      Diabetic neuropathy is one of the challenging complications of diabetes and is characterized by peripheral nerve damage due to hyperglycemia in diabetes. Mitochondrial dysfunction is reported as a key pathophysiological factor contributing to nerve damage in diabetic neuropathy, clinically manifesting as neurodegenerative changes, as well as functional and sensorimotor deficits. Accumulating evidence suggests a clear correlation between mitochondrial dysfunction and NLRP3 inflammasome activation. Unraveling deeper molecular aspects of mitochondrial dysfunction may provide stable and effective therapeutic alternatives. This review links mitochondrial dysfunction and appraises its role in the pathophysiology of diabetic neuropathy. We also tried to delineate the role of mitophagy in NLRP3 inflammasome activation in experimental diabetic neuropathy.
    Keywords:  Diabetes; Diabetic neuropathy; Inflammasome; Mitochondria; Mitochondrial dysfunction; Mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2024.101972
  56. J Transl Med. 2024 Sep 30. 22(1): 876
    Comparative evaluation of cigarette smoke and a heated tobacco product on microglial toxicity, oxidative stress and inflammatory response.
    Alfio Distefano, Laura Orlando, Konstantinos Partsinevelos, Lucia Longhitano, Rosalia Emma, Massimo Caruso, Nunzio Vicario, Simona Denaro, Ang Sun, Antonio Giordano, Barbara Tomasello, Amer M Alanazi, Giovanni Li Volti, Angela Maria Amorini.
       BACKGROUND: Tobacco smoking is the leading cause of preventable death and disease worldwide, with over 8 million annual deaths attributed to cigarette smoking. This study investigates the impact of cigarette smoke and heated tobacco products (HTPs) on microglial function, focusing on toxicological profiles, inflammatory responses, and oxidative stress using ISO standard and clinically relevant conditions of exposure.
    METHODS: We assessed cell viability, reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial function, unfolded protein response, and inflammation in human microglial cells (HMC3) exposed to cigarette smoke, HTP aerosol or nicotine.
    RESULTS: Our findings show that cigarette smoke significantly reduces microglial viability, increases ROS formation, induces lipid peroxidation, and reduces intracellular glutathione levels. Cigarette smoke also alters the expression of genes involved in mitochondrial dynamics and biogenesis, leading to mitochondrial dysfunction. Additionally, cigarette smoke impairs the unfolded protein response, activates the NF-κB pathway, and induces a pro-inflammatory state characterized by increased TNF and IL-18 expression. Furthermore, cigarette smoke causes DNA damage and decreases the expression of the aging marker Klotho β. In contrast, HTP, exhibited a lesser degree of microglial toxicity, with reduced ROS production, lipid peroxidation, and mitochondrial dysfunction compared to conventional cigarettes.
    CONCLUSION: These results highlight the differential toxicological profile of cigarette smoke and HTP on microglial cells, suggesting a potential harm reduction strategy for neurodegenerative disease for smokers unwilling or unable to quit.
    Keywords:  Aging; Cigarette smoking; Heated tobacco product; Inflammation; Microglia; Nicotine; Oxidative stress; Toxicity
    DOI:  https://doi.org/10.1186/s12967-024-05688-5
  57. Pathogens. 2024 Aug 23. pii: 717. [Epub ahead of print]13(9):
    Modifications of Mitochondrial Network Morphology Affect the MAVS-Dependent Immune Response in L929 Murine Fibroblasts during Ectromelia Virus Infection.
    Karolina Gregorczyk-Zboroch, Lidia Szulc-Dąbrowska, Pola Pruchniak, Małgorzata Gieryńska, Matylda Barbara Mielcarska, Zuzanna Biernacka, Zbigniew Wyżewski, Iwona Lasocka, Weronika Świtlik, Alicja Szepietowska, Patrycja Kukier, Aleksandra Kwiecień-Dębska, Jakub Kłęk.
      Since smallpox vaccination was discontinued in 1980, there has been a resurgence of poxvirus infections, particularly the monkeypox virus. Without a global recommendation to use the smallpox vaccine, the population is not immune, posing a severe threat to public health. Given these circumstances, it is crucial to understand the relationship between poxviruses and their hosts. Therefore, this study focuses on the ectromelia virus, the causative agent of mousepox, which serves as an excellent model for studying poxvirus pathogenesis. Additionally, we investigated the role of mitochondria in innate antiviral immunity during ECTV infection, focusing specifically on mitochondrial antiviral signaling protein. The study used a Moscow strain of ECTV and L929 mouse fibroblasts. Cells were treated with ECTV and chemical modulators of mitochondrial network: Mdivi-1 and CCCP. Our investigation revealed that an elongated mitochondrial network attenuates the suppression of MAVS-dependent immunity by ECTV and reduces ECTV replication in L929 fibroblasts compared to cells with an unaltered mitochondrial network. Conversely, a fragmented mitochondrial network reduces the number of progeny virions while increasing the inhibition of the virus-induced immune response during infection. In conclusion, our study showed that modifications of mitochondrial network morphology alter MAVS-dependent immunity in ECTV-infected mouse L929 fibroblasts.
    Keywords:  ECTV; MAVS; immunity; mitochondrial dynamics; mitochondrial network; poxviruses
    DOI:  https://doi.org/10.3390/pathogens13090717
  58. Proc Natl Acad Sci U S A. 2024 Oct 08. 121(41): e2418618121
    Correction for Cui et al., HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence.
      
    DOI:  https://doi.org/10.1073/pnas.2418618121
  59. Front Psychiatry. 2024 ;15 1429437
    Analyses of single-cell and bulk RNA sequencing combined with machine learning reveal the expression patterns of disrupted mitophagy in schizophrenia.
    Wei Yang, Kun Lian, Jing Ye, Yuqi Cheng, Xiufeng Xu.
       Background: Mitochondrial dysfunction is an important factor in the pathogenesis of schizophrenia. However, the relationship between mitophagy and schizophrenia remains to be elucidated.
    Methods: Single-cell RNA sequencing datasets of peripheral blood and brain organoids from SCZ patients and healthy controls were retrieved. Mitophagy-related genes that were differentially expressed between the two groups were screened. The diagnostic model based on key mitophagy genes was constructed using two machine learning methods, and the relationship between mitophagy and immune cells was analyzed. Single-cell RNA sequencing data of brain organoids was used to calculate the mitophagy score (Mitoscore).
    Results: We found 7 key mitophagy genes to construct a diagnostic model. The mitophagy genes were related to the infiltration of neutrophils, activated dendritic cells, resting NK cells, regulatory T cells, resting memory T cells, and CD8 T cells. In addition, we identified 12 cell clusters based on the Mitoscore, and the most abundant neurons were further divided into three subgroups. Results at the single-cell level showed that Mitohigh_Neuron established a novel interaction with endothelial cells via SPP1 signaling pathway, suggesting their distinct roles in SCZ pathogenesis.
    Conclusion: We identified a mitophagy signature for schizophrenia that provides new insights into disease pathogenesis and new possibilities for its diagnosis and treatment.
    Keywords:  bulk RNA analysis; machine learning; mitophagy; schizophrenia; single-cell RNA analysis
    DOI:  https://doi.org/10.3389/fpsyt.2024.1429437
  60. Clin Proteomics. 2024 Sep 30. 21(1): 57
    Characterizing age-related changes in intact mitochondrial proteoforms in murine hearts using quantitative top-down proteomics.
    Andrea Ramirez-Sagredo, Anju Teresa Sunny, Kellye A Cupp-Sutton, Trishika Chowdhury, Zhitao Zhao, Si Wu, Ying Ann Chiao.
       BACKGROUND: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, and the prevalence of CVDs increases markedly with age. Due to the high energetic demand, the heart is highly sensitive to mitochondrial dysfunction. The complexity of the cardiac mitochondrial proteome hinders the development of effective strategies that target mitochondrial dysfunction in CVDs. Mammalian mitochondria are composed of over 1000 proteins, most of which can undergo post-translational modifications (PTMs). Top-down proteomics is a powerful technique for characterizing and quantifying proteoform sequence variations and PTMs. However, there are still knowledge gaps in the study of age-related mitochondrial proteoform changes using this technique. In this study, we used top-down proteomics to identify intact mitochondrial proteoforms in young and old hearts and determined changes in protein abundance and PTMs in cardiac aging.
    METHODS: Intact mitochondria were isolated from the hearts of young (4-month-old) and old (24-25-month-old) mice. The mitochondria were lysed, and mitochondrial lysates were subjected to denaturation, reduction, and alkylation. For quantitative top-down analysis, there were 12 runs in total arising from 3 biological replicates in two conditions, with technical duplicates for each sample. The collected top-down datasets were deconvoluted and quantified, and then the proteoforms were identified.
    RESULTS: From a total of 12 LC-MS/MS runs, we identified 134 unique mitochondrial proteins in the different sub-mitochondrial compartments (OMM, IMS, IMM, matrix). 823 unique proteoforms in different mass ranges were identified. Compared to cardiac mitochondria of young mice, 7 proteoforms exhibited increased abundance and 13 proteoforms exhibited decreased abundance in cardiac mitochondria of old mice. Our analysis also detected PTMs of mitochondrial proteoforms, including N-terminal acetylation, lysine succinylation, lysine acetylation, oxidation, and phosphorylation. Data are available via ProteomeXchange with the identifier PXD051505.
    CONCLUSION: By combining mitochondrial protein enrichment using mitochondrial fractionation with quantitative top-down analysis using ultrahigh-pressure liquid chromatography (UPLC)-MS and label-free quantitation, we successfully identified and quantified intact proteoforms in the complex mitochondrial proteome. Using this approach, we detected age-related changes in abundance and PTMs of mitochondrial proteoforms in the heart.
    Keywords:  Cardiac aging; Label-free quantitation; Mitochondria; Post-translational modifications; Top-down proteomics
    DOI:  https://doi.org/10.1186/s12014-024-09509-1
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