bims-mikwok Biomed News
on Mitochondrial quality control
Issue of 2024–11–10
forty-four papers selected by
Gavin McStay, Liverpool John Moores University
  1. Targeting mitochondria by lipid-selenium conjugate drug results in malate/fumarate exhaustion and induces mitophagy-mediated necroptosis suppression.
  2. Methods to analyze the mitochondrial unfolded protein response (UPRmt).
  3. ACSL1 improves pulmonary fibrosis by reducing mitochondrial damage and activating PINK1/Parkin mediated mitophagy.
  4. Mitochondrial elongation impairs breast cancer metastasis.
  5. Estrogen receptor β exerts neuroprotective effects by fine-tuning mitochondrial homeostasis through NRF1/PGC-1α.
  6. NLRX1 and STING alleviate renal ischemia-reperfusion injury by regulating LC3 lipidation during mitophagy.
  7. Inhibition of mitochondrial OMA1 ameliorates osteosarcoma tumorigenesis.
  8. Monitoring retro-translocation of proteins from the mitochondrial intermembrane space.
  9. CARD9 protein SUMOylation regulates HOXB5 nuclear translocation and Parkin-mediated mitophagy in myocardial I/R injury.
  10. Mitochondrial mechanisms in Treg cell regulation: Implications for immunotherapy and disease treatment.
  11. PINK1/Parkin-Mediated Mitophagy Ameliorates Mitochondrial Dysfunction in Lacrimal Gland Acinar Cells During Aging.
  12. Spotlight on Mitochondrial Health: A Trailblazing Fluorescent Tool for Cancer Detection and Surgical Guidance.
  13. METTL3 prevents granulosa cells mitophagy by regulating YTHDF2-mediated BNIP3 mRNA degradation due to arsenic exposure.
  14. Comparison of different processed products of Allium tuberosum Rottler for the treatment of mice asthenozoospermia.
  15. Prognostic value and immunomodulatory role of DNM1L in gastric adenocarcinoma.
  16. USP14 inhibition enhances Parkin-independent mitophagy in iNeurons.
  17. Regulation of mitochondrial autophagy by lncRNA MALAT1 in sepsis-induced myocardial injury.
  18. PINK1-mediated mitophagy attenuates pathological cardiac hypertrophy by suppressing the mtDNA release-activated cGAS-STING pathway.
  19. Sevoflurane exposure accelerates the onset of cognitive impairment via promoting p-Drp1S616-mediated mitochondrial fission in a mouse model of Alzheimer's disease.
  20. SIRT3 mitigates high glucose-induced damage in retinal microvascular endothelial cells via OPA1-mediated mitochondrial dynamics.
  21. Modulation of Mitochondrial Dynamics by the Angiotensin System in Dopaminergic Neurons and Microglia.
  22. Analysis of quality control pathways for the translocase of the outer mitochondrial membrane.
  23. Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury.
  24. Dexmedetomidine alleviates intestinal ischemia/reperfusion injury by modulating intestinal neuron autophagy and mitochondrial homeostasis via Nupr1 regulation.
  25. Mitophagy and Ferroptosis in Sepsis-Induced ALI/ARDS: Molecular Mechanisms, Interactions and Therapeutic Prospects of Medicinal Plants.
  26. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  27. Selenomethionine alleviates kidney necroptosis and inflammation by restoring lipopolysaccharide-mediated mitochondrial dynamics imbalance via the TLR4/RIPK3/DRP1 signaling pathway in laying hens.
  28. Attenuating mitochondrial dysfunction-derived reactive oxygen species and reducing inflammation: the potential of Daphnetin in the viral pneumonia crisis.
  29. Absence of oncomodulin increases susceptibility to noise-induced outer hair cell death and alters mitochondrial morphology.
  30. Analysis of the mitochondria-associated degradation pathway (MAD) in yeast cells.
  31. Low phosphorus causes hepatic energy metabolism disorder through Dynamin-related protein 1-mediated mitochondrial fission in fish.
  32. Analysis of mitochondrial biogenesis regulation by oxidative stress.
  33. PKCδ modulates SP1 mediated mitochondrial autophagy to exacerbate diacetylmorphine-induced ferroptosis in neurons.
  34. Antisecretory Factor 16 (AF16): A Promising Avenue for the Treatment of Traumatic Brain Injury-An In Vitro Model Approach.
  35. MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis.
  36. Aloe Emodin Alleviates Radiation-Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption.
  37. Bay 11-7082 mitigates oxidative stress and mitochondrial dysfunction via NLRP3 inhibition in experimental diabetic neuropathy.
  38. O-GlcNAcylation of hexokinase 2 modulates mitochondrial dynamics and enhances the progression of lung cancer.
  39. Huangqi-Danshen decoction improves heart failure by regulating pericardial adipose tissue derived extracellular vesicular miR-27a-3p to activate AMPKα2 mediated mitophagy.
  40. [Role of Mitophagy Affecting Macrophage Polarization in Immunomodulationin Sepsis and Traditional Chinese Medicine Intervention:A Review].
  41. Novel biomarkers of mitochondrial dysfunction in Long COVID patients.
  42. Analysis of mitochondrial protein aggregation and disaggregation.
  43. Mitochondrial quality control measures, systemic inflammation, and lower-limb muscle power in older adults: a PROMPT secondary analysis.
  44. Aflatoxin B1-induced hepatotoxicity through mitochondrial dysfunction, oxidative stress, and inflammation as central pathological mechanisms: A review of experimental evidence.
  1. Int J Biol Sci. 2024 ;20(14): 5793-5811
    Targeting mitochondria by lipid-selenium conjugate drug results in malate/fumarate exhaustion and induces mitophagy-mediated necroptosis suppression.
    Xing Chang, Hao Zhou, Jinlin Hu, Teng Ge, Kunyang He, Ye Chen, Rongjun Zou, Xiaoping Fan.
      Atherosclerosis (AS) is a chronic vascular disease primarily affecting large and medium-sized arteries and involves various complex pathological mechanisms and factors. Previous studies have demonstrated a close association between atherosclerosis and inflammatory damage, metabolic disorders, and gut microbiota. It is also closely linked to several cellular processes, such as endothelial cell pyroptosis, ferroptosis, mitophagy, mitochondrial dynamics, and mitochondrial biogenesis. Mitophagy has been recognized as a previously unexplored mechanism contributing to endothelial injury in atherosclerosis. Our study aims to further elucidate the potential relationship and mechanisms between AS-induced mitophagy dysfunction and the interaction of TMBIM6 and NDUFS4. Data from the study demonstrated that atherosclerosis in AS mice was associated with substantial activation of inflammatory and oxidative stress damage, along with a marked reduction in endothelial mitophagy expression and increased pathological mitochondrial fission, leading to mitochondrial homeostasis disruption. However, under pharmacological intervention, mitophagy levels significantly increased, pathological mitochondrial fission was notably reduced, and oxidative stress and inflammatory damage were suppressed, while necroptotic pathways in endothelial cells were significantly blocked. Interestingly, the deletion of TMBIM6 or NDUFS4 in animal models or cell lines markedly impaired the therapeutic effects of the drug, disrupting its regulation of mitophagy and mitochondrial fission, and leading to the re-emergence of inflammatory responses and oxidative stress damage. Metabolomics analysis further revealed that autophagy plays a pivotal regulatory role during drug intervention and after genetic modification of TMBIM6 and NDUFS4. The activation of autophagy (macroautophagy/mitophagy) alleviated the negative effects of mitochondrial fission and inflammatory damage induced by lipid stress in endothelial cells, a regulatory mechanism likely associated with the TMBIM6-NDUFS4 axis. Subsequent animal gene modification experiments demonstrated that knocking out TMBIM6-NDUFS4 negates the therapeutic effects of the drug on lipid-induced damage and metabolic function. In summary, our research reveals a phenotypic regulatory mechanism of endothelial cell stress damage through mitophagy, influenced by the interaction of TMBIM6 and NDUFS4. Pharmacological intervention can restore mitochondrial homeostasis in endothelial cells by regulating mitophagy via the TMBIM6-NDUFS4 pathway. This novel insight suggests that TMBIM6-NDUFS4 may serve as a key therapeutic target for atherosclerosis.
    Keywords:  Atherosclerosis; Endothelial Injury.; Mitochondrial; Mitophagy; Necroptosis
    DOI:  https://doi.org/10.7150/ijbs.102424
  2. Methods Enzymol. 2024 ;pii: S0076-6879(24)00365-3. [Epub ahead of print]707 543-564
    Methods to analyze the mitochondrial unfolded protein response (UPRmt).
    Avijit Mallick, Cole M Haynes.
      The mitochondrial unfolded protein response (UPRmt) is a mitochondria-to-nuclear signaling pathway that mediates the transcription of genes required to maintain mitochondrial function during development as well as during aging. In this chapter, we describe the approaches and techniques that we and others have used to elucidate the mechanism(s) by which cells detect mitochondrial stress or dysfunction and communicate with the nucleus to induce transcription of a protective stress response. We also describe approaches to evaluate the impact of UPRmt activation on mitochondrial function and mitochondrial biogenesis including imaging-based approaches as well as approaches to evaluate mitochondrial genome (mtDNA) copy number.
    Keywords:  Deleterious mtDNA heteroplasmy; Mito-nuclear communication; Mitochondrial biogenesis; Mitochondrial unfolded protein response; Molecular chaperones; MtDNA replication
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.029
  3. Sci Rep. 2024 11 03. 14(1): 26504
    ACSL1 improves pulmonary fibrosis by reducing mitochondrial damage and activating PINK1/Parkin mediated mitophagy.
    Qi Lin, Yating Lin, Xinyan Liao, Ziyi Chen, Mengmeng Deng, Zhihao Zhong.
      Pulmonary fibrosis is a chronic interstitial lung disease with no curative therapeutic treatment, leading to significant mortality. The aims of this study were to investigate the regulatory mechanisms of mitophagy in the progression of pulmonary fibrosis. Through bioinformatics analysis, we identified the downregulation of long-chain fatty acyl-CoA synthetase 1 (ACSL1) as being associated with the severity of pulmonary fibrosis. A pulmonary fibrosis model was established through bleomycin (BLM) exposure both in vivo and in vitro. Mitoquinone (MitoQ) pretreatment significantly decreased redox damage, stabilized mitochondrial membrane potential (MMP), improved mitochondrial dynamics, and activated PINK1/Parkin-mediated mitophagy, thereby alleviating pulmonary fibrosis. In vitro, overexpression of ACSL1 mitigated mitochondrial damage and restored PINK1/Parkin-mediated mitophagy under BLM exposure. In contrast, ACSL1 inhibition exacerbated pulmonary fibrosis, and these adverse effects could not be reversed by MitoQ treatment. Taken together, our study reveals a novel mechanism underlying the pathogenesis of pulmonary fibrosis and suggests a potential therapeutic target for its treatment.
    Keywords:  ACSL1; MitoQ; Mitophagy; PINk1/Parkin signaling pathway; Pulmonary fibrosis
    DOI:  https://doi.org/10.1038/s41598-024-78136-5
  4. Sci Adv. 2024 Nov 08. 10(45): eadm8212
    Mitochondrial elongation impairs breast cancer metastasis.
    Lucía Minarrieta, Matthew G Annis, Yannick Audet-Delage, Hellen Kuasne, Alain Pacis, Catherine St-Louis, Alexander Nowakowski, Marco Biondini, Mireille Khacho, Morag Park, Peter M Siegel, Julie St-Pierre.
      Mitochondrial dynamics orchestrate many essential cellular functions, including metabolism, which is instrumental in promoting cancer growth and metastatic progression. However, how mitochondrial dynamics influences metastatic progression remains poorly understood. Here, we show that breast cancer cells with low metastatic potential exhibit a more fused mitochondrial network compared to highly metastatic cells. To study the impact of mitochondrial dynamics on metastasis, we promoted mitochondrial elongation in metastatic breast cancer cells by individual genetic deletion of three key regulators of mitochondrial fission (Drp1, Fis1, Mff) or by pharmacological intervention with leflunomide. Omics analyses revealed that mitochondrial elongation causes substantial alterations in metabolic pathways and processes related to cell adhesion. In vivo, enhanced mitochondrial elongation by loss of mitochondrial fission mediators or treatment with leflunomide notably reduced metastasis formation. Furthermore, the transcriptomic signature associated with elongated mitochondria correlated with improved clinical outcome in patients with breast cancer. Overall, our findings highlight mitochondrial dynamics as a potential therapeutic target in breast cancer.
    DOI:  https://doi.org/10.1126/sciadv.adm8212
  5. Neurochem Int. 2023 Oct 27. pii: S0197-0186(23)00164-X. [Epub ahead of print] 105636
    Estrogen receptor β exerts neuroprotective effects by fine-tuning mitochondrial homeostasis through NRF1/PGC-1α.
    Wei Zhao, Yue Hou, Qiwei Zhang, Haiyang Yu, Meichen Meng, Hanting Zhang, Yanmeng Zhou.
       BACKGROUND: Estrogen deficiency causes mitochondrial defects that precede pathological changes related to Alzheimer's disease (AD) in the mouse model of postmenopause. The aim of this study was to investigate in such a mouse model whether and how estrogen receptor β (ERβ) was involved in prevention of mitochondrial damage and protection of neurons in the hippocampus.
    METHODS: A mouse model of postmenopausal AD was created by ovariectomizing female 3xTg-AD mice, some of which were subcutaneously injected for six weeks with the non-steroidal ERβ agonist diarylpropionitrile. ERβ expression in female C57BL/6J mice was knocked down using shRNA interference. The different groups of animals were compared in terms of cognitive function using the Y-maze test, new object recognition test, and Morris water maze test, expression of numerous proteins related to mitochondrial biogenesis, mitophagy, apoptosis, and mitochondrial membrane potential, as well as deposition of amyloid β and neurofibrillary tangles. To complement these in vivo studies, we probed the effects of diarylpropionitrile on ERβ expression, apoptosis, and mitochondrial homeostasis in primary rat hippocampal neurons treated with amyloid β.
    RESULTS: ERβ knockdown in C57BL/6J mice produced cognitive impairment, reduced mitochondrial biogenesis by downregulating PGC-1α, NRF1, mtTFA, and TOM20, and decreased mitophagy by downregulating Pink1, Parkin, and LC3B while upregulating PARIS and p62. ERβ knockdown promoted neuronal apoptosis by upregulating Cleaved-Caspase 9, Cleaved-Caspase 3, and Bax, while downregulating Bcl2 in hippocampus. Diarylpropionitrile mitigated cognitive decline in ovariectomized 3xTg-AD mice, which was associated with downregulation of BACE1, reduction of Aβ deposition, neurofibrillary tangles, and tau hyperphosphorylation, and upregulation of ERβ, increases in mitochondrial biogenesis and mitophagy, and decreases in apoptosis. The effects of diarylpropionitrile in mice were recapitulated in Aβ-injured primary rat hippocampal neurons.
    CONCLUSIONS: ERβ activation can support learning and memory and alleviate AD symptoms in the postmenopausal AD model, which may involve regulation of neuronal mitochondrial biogenesis and mitophagy via NRF1/PGC-1α. This study supports further research on ERβ as a therapeutic target for postmenopausal women with AD.
    Keywords:  Alzheimer's disease; Estrogen receptor beta; Mitochondria; Mitochondrial biogenesis; Mitophagy
    DOI:  https://doi.org/10.1016/j.neuint.2023.105636
  6. Exp Cell Res. 2024 Nov 04. pii: S0014-4827(24)00414-2. [Epub ahead of print] 114323
    NLRX1 and STING alleviate renal ischemia-reperfusion injury by regulating LC3 lipidation during mitophagy.
    Yinping Liao, Pei Li, Qing Hang, Yang Chong, Wei Long, Xingji Wei, Dong Sun, Ya Liu.
      Mitophagy significantly influences renal ischemia/reperfusion (I/R) injury and recovery. NLRX1 is recognized for its regulatory role in governing mitochondrial damage, autophagy, and the expression of pro-inflammatory factors. Despite the acknowledged involvement of NLRX1 in these crucial cellular processes, its specific function in renal I/R injury remains unclear. We detected the expression of NLRX1, the cGAS-STING pathway, and autophagy-related proteins using Western Blot analysis. RT-qPCR was utilized to measure the expression of NLRX1 mRNA and cytokines, and changes in mitochondrial DNA (mtDNA) within the cytoplasm. Immunofluorescence was applied to observe alterations in DNA distribution within the cytoplasm. The EtBr drug, which depletes mtDNA, and the Mdivi-1 mitophagy inhibitor, were used to verify the promotion of mitophagy by NLRX1. The results demonstrated that NLRX1 was downregulated after H/R injury, and there was an increase in cytoplasmic DNA. NLRX1 overexpression not only reduced IL-1β and IL-6 levels, but also decreased mtDNA in the cytoplasm. Additionally, NLRX1 further increases mitochondrial LC3 lipidation after H/R injury, and this effect is inhibited by Mdivi-1 drugs. The activation of the cGAS-STING pathway after H/R injury is inhibited by EtBr drugs and NLRX1. Co-immunoprecipitation results showed that NLRX1 could bind to STING. Moreover, inhibiting STING reversed NLRX1-induced mitochondrial LC3 lipidation. Our study reveals that NLRX1 can bind to STING to promote mitophagy and inhibits inflammation caused by mtDNA/cGAS/STING signaling.
    Keywords:  Acute kidney injury; Mitophagy; NLRX1; STING
    DOI:  https://doi.org/10.1016/j.yexcr.2024.114323
  7. Cell Death Dis. 2024 Nov 01. 15(11): 786
    Inhibition of mitochondrial OMA1 ameliorates osteosarcoma tumorigenesis.
    Lingyan Chen, Dejian Chen, Yiming Pan, Yimei Mo, Biyu Lai, Huiguang Chen, Da-Wei Zhang, Xiao-Dan Xia.
      OMA1 is an ATP-independent zinc metalloprotease essential for maintaining mitochondrial homeostasis and plays a vital role in tumorigenesis. Depending on the type of cancer, a decrease in OMA1 expression has been linked to a varying prognosis for patients. The role of OMA1 in human osteosarcoma (OS), one of the most prevalent malignant bone tumors, remains elusive. Here, we observed elevated OMA1 expression in OS tumor tissues from four patients with advanced OS. Knockout of OMA1 in OS cells significantly reduces OS tumor weight and size, and lung metastatic nodules in BALB/c nude mice. Immunohistochemistry analysis showed a significant decrease in Ki67 and an increase in Cleaved-caspase 3 in OMA1 knockout tumor samples. Mechanistically, we found that OMA1 deficiency increases the levels of PINK1 and Parkin and consequently induces excessive mitophagy, leading to increased apoptosis and reduced cell proliferation and invasion in OS cells. Specifically, OMA1 deficiency reduces the amount of cytosolic p53 and p53-associated cytosolic Parkin but increases mitochondrial p53, which may lead to enhanced apoptosis. Regarding the effect on cell proliferation and invasion, loss of OMA1 reduces mitochondrial ROS levels and increases cytosolic glycogen synthase kinase 3β (GSK3β) levels, thereby increasing interaction between GSK3β and β-catenin and then reducing cytosolic and nuclear β-catenin. This contributes to reduced cell proliferation and migration in OMA1-deficient cells. Moreover, we found that ciclopirox (CPX), an antifungal drug, induces OMA1 self-cleavage and L-OMA1 degradation in cultured OS cells. CPX also reduces tumor development of control OS cells but not OMA1-deficient OS cells in mice. These findings strongly support the important role of OMA1 in OS tumorigenesis and suggest that OMA1 may be a valuable prognostic marker and a promising therapeutic target for OS.
    DOI:  https://doi.org/10.1038/s41419-024-07127-1
  8. Methods Enzymol. 2024 ;pii: S0076-6879(24)00387-2. [Epub ahead of print]707 173-208
    Monitoring retro-translocation of proteins from the mitochondrial intermembrane space.
    Magda Krakowczyk, Piotr Bragoszewski.
      Mitochondria play multiple essential roles in eukaryotic cells. To perform their functions, mitochondria require an adequate supply of externally produced proteins and an intact two-membrane structure. The structure of mitochondrial membranes separates these organelles from their cytosolic environment, with proteins that make up the mitochondrial proteome either being embedded into or enveloped by these membranes. From the experimental point of view, the structural properties of mitochondria contribute to the relative ease of isolating these organelles from other cellular components. The ability to isolate intact mitochondria and analyze them in a well-controlled environment opens up the possibility of tracking any proteins that enter or escape the membrane-formed enclosure. This chapter discusses assays that monitor the movement of proteins out of mitochondria through intact membranes. These protocols provide insight into the mechanisms behind mitochondrial protein quality control. It was discovered that the retro-translocation of IMS proteins regulates the protein content of this specific sub-compartment of the organelle. Additionally, proteins can move out of the mitochondria to resolve failed import events. Assays based on isolated mitochondria precisely tackle such intricate 'dance' of proteins crossing mitochondrial membranes during import and export, maintaining the dynamics of the organellar proteome.
    Keywords:  Intermembrane space; MIA pathway; Mitochondria; Protease; Protein import; Protein quality control; Protein retro-translocation; Protein transport; Proteostasis
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.047
  9. J Cell Mol Med. 2024 Nov;28(21): e70195
    CARD9 protein SUMOylation regulates HOXB5 nuclear translocation and Parkin-mediated mitophagy in myocardial I/R injury.
    Yuanbin Li, Yuting Tang, Xu Yan, Hui Lin, Wanjin Jiang, Luwei Zhang, Hu Zhao, Zhuang Chen.
      Myocardial injury induced by ischemia-reperfusion (I/R) remains a difficult clinical problem. However, the exact mechanisms underlying I/R-induced have yet to be clarified. CARD9 is an important cytoplasmic-binding protein. In this study, an immunocoprecipitation assay showed that SUMOylation of the CARD9 protein promoted the binding of CARD9 to HOXB5, but hindered the O-GlcNAc glycosylation of HOXB5, a predicted transcription factor of Parkin and a key factor in mitophagy. O-GlcNAc glycosylation is an important signal for translocation of proteins from the cytoplasm to the nucleus. CARD9 protein SUMOylation is regulated by PIAS3, which is related to I/R-induced myocardial injury. Therefore, we propose that knockdown of PIAS3 inhibits SUMOylation of the CARD9 protein, facilitates the dissociation of CARD9 and HOXB5, which increases the O-GlcNAc-mediated glycosylation of HOXB5, while the resulting HOXB5 nuclear translocation promotes Parkin-induced mitophagy and alleviates myocardial I/R injury.
    Keywords:  CARD9; HOXB5 nuclear; Mitophagy; O‐GlcNAc glycosylation; SUMOylation; translocation
    DOI:  https://doi.org/10.1111/jcmm.70195
  10. Mitochondrion. 2024 Nov 02. pii: S1567-7249(24)00133-8. [Epub ahead of print] 101975
    Mitochondrial mechanisms in Treg cell regulation: Implications for immunotherapy and disease treatment.
    Xiaozhen Zhao, Junmei Zhang, Caifeng Li, Weiying Kuang, Jianghong Deng, Xiaohua Tan, Chao Li, Shipeng Li.
      Regulatory T cells (Tregs) play a critical role in maintaining immune homeostasis and preventing autoimmune diseases. Recent advances in immunometabolism have revealed the pivotal role of mitochondrial dynamics and metabolism in shaping Treg functionality. Tregs depend on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) to support their suppressive functions and long-term survival. Mitochondrial processes such as fusion and fission significantly influence Treg activity, with mitochondrial fusion enhancing bioenergetic efficiency and reducing reactive oxygen species (ROS) production, thereby promoting Treg stability. In contrast, excessive mitochondrial fission disrupts ATP synthesis and elevates ROS levels, impairing Treg suppressive capacity. Furthermore, mitochondrial ROS act as critical signaling molecules in Treg regulation, where controlled levels stabilize FoxP3 expression, but excessive ROS leads to mitochondrial dysfunction and immune dysregulation. Mitophagy, as part of mitochondrial quality control, also plays an essential role in preserving Treg function. Understanding the intricate interplay between mitochondrial dynamics and Treg metabolism provides valuable insights for developing novel therapeutic strategies to treat autoimmune disorders and enhance immunotherapy in cancer.
    Keywords:  Autoimmune diseases; Fatty acid oxidation (FAO); Mitochondria; Oxidative phosphorylation (OXPHOS); Regulatory T cells (Tregs)
    DOI:  https://doi.org/10.1016/j.mito.2024.101975
  11. Invest Ophthalmol Vis Sci. 2024 Nov 04. 65(13): 12
    PINK1/Parkin-Mediated Mitophagy Ameliorates Mitochondrial Dysfunction in Lacrimal Gland Acinar Cells During Aging.
    Han Zhao, Yue Zhang, Yujie Ren, Wanpeng Wang.
       Purpose: Aging alters the function of the lacrimal gland and disrupts the balance of the microenvironment on the ocular surface, eventually leading to aqueous-tear-deficient dry eye. Mitophagy has been reported to play an important role in aging, but the underlying mechanism remains unclear.
    Methods: The young (6 weeks) and middle-aged (12 months) male C57BL/6J mice were used in this study, and mitophagy agonist rapamycin and inhibitor Mdivi-1 were used in in vivo experiments. Hematoxylin and eosin, Masson, Oil Red O, and reactive oxygen species (ROS) staining were used to detect histological changes and lipids in lacrimal gland. Changes in the expression of proteins were identified by Western blotting of lacrimal gland lysates. Transmission electron microscopy and immunofluorescence staining were used to assess mitophagy. The single-cell RNA sequencing (scRNA-seq) and bioinformatics analyses were used to detect transcription signature changes during aging.
    Results: In this study, we discovered that aging increased oxidative stress, which increased apoptosis, and generated ROS in acinar epithelial cells. Furthermore, activation of PINK1/Parkin-mediated mitophagy by rapamycin reduced lacrimal gland ROS concentrations and prevented aging-induced apoptosis of acinar cells, thereby causing histological alterations, microstructural degradation, and increasing tear secretion associated with ROS accumulation. By contrast, Mdivi-1 aggregates mitochondrial function and thereafter leads to lacrimal gland function impairment by inhibiting mitochondrial fission and giving rise to mitophagy.
    Conclusions: Overall, our findings suggested that aging could impair mitochondrial function of acinar cells, and age-related alterations may be treated with therapeutic approaches that enhance mitophagy while maintaining mitochondrial function.
    DOI:  https://doi.org/10.1167/iovs.65.13.12
  12. Anal Chem. 2024 Nov 05.
    Spotlight on Mitochondrial Health: A Trailblazing Fluorescent Tool for Cancer Detection and Surgical Guidance.
    Wei Zhang, Shuo Wang, Hongyong Zheng, Wenjing Zhang, Lei Yang, Zhanxian Li, Mingming Yu.
      Mitochondria play a pivotal role in maintaining normal physiological functions. Mitochondrial autophagy, namely, mitophagy, is a selective catabolic disposal of impaired mitochondria through an autophagic mechanism during episodes of mitochondrial harm. This selective removal, e.g., mitophagy, is essential for mitochondrial quality control and is closely related to the pathogenesis of many diseases. The abnormal buildup of defective mitochondria in vivo was used as a target to prevent the development of cancer. The mitochondrial autophagy process of disease-related cells is usually accompanied by a decrease in polarity and pH, and the fluorescence sensing effects caused by these two factors are usually contradictory. Here, we propose a reinventing strategy to develop a dual-channel and dual-responsive fluorescent probe HDTVB that is capable of tracking mitochondrial autophagy by monitoring fluctuations in mitochondrial pH and polarity. Based on the aggregation-induced emission (AIE) moiety and hemicarpine moiety push-pull system with activated near-infrared (NIR) emission and pH-activatable cyclization reaction, HDTVB was able to differentiate tumors from normal sites via polarity- and acidity-triggered structural changes of the probe in the course of mitochondrial autophagy. HDTVB is expected to be applied to clinical diagnosis and tumor excision guided by fluorescence, offering a new route in physiological and biochemical research.
    DOI:  https://doi.org/10.1021/acs.analchem.4c03706
  13. Ecotoxicol Environ Saf. 2024 Nov 01. pii: S0147-6513(24)01309-5. [Epub ahead of print]286 117233
    METTL3 prevents granulosa cells mitophagy by regulating YTHDF2-mediated BNIP3 mRNA degradation due to arsenic exposure.
    Tuo Zhang, Jin Niu, Tianhe Ren, Huan Lin, Meina He, Zhiyi Sheng, Yuntong Tong, Bangming Jin, Yingmin Wu, Jigang Pan, Ziwen Xiao, Bing Guo, Zhengrong Wang, Tengxiang Chen, Wei Pan.
      The ovary is an important reproductive and endocrine organ for the continuation of the species and the homeostasis of the body's internal environment. Arsenic exposure is a global public health problem. However, the damage to the ovaries caused by exposure to arsenic-contaminated drinking water from neonatal mice period remains unclear. Here, we showed that arsenic exposure resulted in reduced granulosa cell proliferation, diminished ovarian reserve, decreased oogenesis, and endocrine disruption in mice. Mechanistically, arsenic exposure decreased the protein level of METTL3 in granulosa cells. The m6A modification levels of mitophagy regulated gene BNIP3 in 3'UTR region was decreased in arsenic exposed granulosa cells. Meanwhile, YTHDF2, which decays mRNA, bound to the 3'UTR region of BNIP3 was also decreased in arsenic exposed ovarian granulosa cells. Thus, BNIP3 mRNA becames more stable, and mitophagy was increased. The excessive mitophagy in granulosa cells led to endocrine disruption, follicular atresia and diminished ovarian reserve. In summary, our study reveals that METTL3-dependent m6A modification regulates granulosa cell mitophagy and follicular atresia by targeting BNIP3 which are induced by arsenic exposure.
    Keywords:  Arsenic; Granulosa cells; M(6)A; Mitophagy; Ovary
    DOI:  https://doi.org/10.1016/j.ecoenv.2024.117233
  14. Transl Androl Urol. 2024 Oct 31. 13(10): 2209-2228
    Comparison of different processed products of Allium tuberosum Rottler for the treatment of mice asthenozoospermia.
    Wenhui Wu, Xiaohong Guo, Jie Li, Min Yang, Yongai Xiong.
       Background: Allium tuberosum Rottler improves sexual function and is used in the treatment of impotence and spermatorrhea. However, its chemical composition and mechanism of action remain unclear. This study investigates the chemical composition and mechanism of action of Allium tuberosum Rottler co-processed with salt and wine (GZP) in modulating testicular mitochondrial autophagy for the treatment of asthenozoospermia in mice.
    Methods: Adenine gavage + cyclophosphamide intraperitoneal injection was used to establish the model of asthenozoospermia, and six Allium tuberosum Rottler processed products were compared in the pharmacological efficacy for the treatment of asthenozoospermia in mice. The liquid chromatograph mass spectrometer (LC-MS) assay was performed to analyse the compositional changes in the GZP. The mechanism of GZP in the treatment of asthenozoospermia in mice was further investigated. The mitophagy was detected by transmission electron microscope (TEM) and immunofluorescence, respectively. Reactive oxygen species (ROS) were detected by probe. Protein expression was determined by Western blotting.
    Results: GZP exhibited optimal therapeutic effects on asthenozoospermia in mice. It showed the best therapeutic effect in improving the total number of spermatozoa, sperm survival rate, improving sperm viability and reducing sperm deformity rate, alleviating the abnormal pathological morphology of mice testis, and increasing the serum testosterone (T), follicle-stimulating hormone (FSH) and prolactin (PRL) levels in mice. The LC-MS detection found that Allicin showed the most significant increase in GZP. Besides, GZP reduced ROS level and inhibited mitophagy in mice testicular tissues. Meanwhile, it restrained the expression of PINK1, Parkin, Light chain 3II (LC3-II)/Light chain 3I (LC3-I) and Caspase-3 proteins.
    Conclusions: GZP improves asthenozoospermia via inhibiting excessive mitophagy and protects the integrity of mitochondria by blocking the PINK1/Parkin signaling pathway. During which, the Allicin may play an important role.
    Keywords:  Allicin; Allium tuberosum Rottler; Asthenozoospermia; mitophagy
    DOI:  https://doi.org/10.21037/tau-24-274
  15. Front Oncol. 2024 ;14 1453795
    Prognostic value and immunomodulatory role of DNM1L in gastric adenocarcinoma.
    Zhuo Zhao, Lingxia Li, Yan Liu, Lei Shi, Meijie Yuan, Hongshuo Shi, Qing Ji, Guobin Liu, Jian Sun.
       Background: Mitochondrial fusion and fission are critical for the morphology and function of cells. DNM1L encodes dynamin-related protein 1 (DRP1), a key protein mediating mitochondrial fission, which is upregulated in a variety of cancers and is strongly associated with tumorigenesis. We aim to investigate the relationship between DNM1L and the prognosis of gastric cancer, as well as to explore the function and mechanism of DNM1L in gastric cancer (GC).
    Materials and methods: In this study, we analyzed the expression differences of DNM1L in gastric cancer tissues and paracancerous tissues using The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. This was followed by validation through tissue microarrays. We then utilized the cohort information from these microarrays to explore the relationship between DNM1L expression and gastric cancer prognosis. Furthermore, we conducted enrichment analysis to investigate the function and mechanisms of DNM1L in gastric cancer, and lastly, we performed immune cell infiltration analysis using the CIBERSORT algorithm.
    Results: We discovered that the expression of DNM1L is elevated in GC tissues. TCGA data showed that the overexpression of DNM1L was positively correlated with the T-stage of GC but not with lymph node metastasis, which was also corroborated by our immunohistochemistry experiments. Based on the Kaplan-Meier curves, the high DNM1L expression was remarkably correlated with poor overall survival in patients with GC. In addition, results of COX regression analysis indicated that high DNM1L expression was an independent prognostic factor in patients with GC. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene set enrichment analysis (GSEA) showed that DNM1L was closely associated with multiple signaling pathways and immune responses. CIBERSORT analysis indicated that increased DNM1L expression may affect the infiltration of immune cells in the tumor microenvironment.
    Conclusion: The results of this study indicate that DNM1L is upregulated in gastric cancer (GC) and positively correlates with the T-stage and poor prognosis of GC patients, and it plays an important role in tumor immune infiltration.
    Keywords:  DNM1L; gastric cancer; immune infiltration; mitochondria; prognosis
    DOI:  https://doi.org/10.3389/fonc.2024.1453795
  16. Pharmacol Res. 2024 Oct 30. pii: S1043-6618(24)00429-8. [Epub ahead of print] 107484
    USP14 inhibition enhances Parkin-independent mitophagy in iNeurons.
    Bernardo Greta, A Prado Miguel, Dashtmian Anna Roshani, Mariavittoria Favaro, Sofia Mauri, Alice Borsetto, Elena Marchesan, Joao A Paulo, Steve P Gygi, Daniel J Finley, Elena Ziviani.
      Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson's Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.
    Keywords:  Autophagy; MARCH5/MITOL; Mitophagy; PINK1; Parkin; UPS; USP14
    DOI:  https://doi.org/10.1016/j.phrs.2024.107484
  17. Eur J Med Res. 2024 Nov 01. 29(1): 524
    Regulation of mitochondrial autophagy by lncRNA MALAT1 in sepsis-induced myocardial injury.
    Guangqing Huang, Xu Zhao, Yong Bai, Jie Liu, Wei Li, Yongquan Wu.
       BACKGROUND: Sepsis-induced myocardial injury (SIMI) is a severe complication of sepsis, contributing significantly to mortality. Mitochondrial dysfunction and dysregulated autophagy are implicated in SIMI pathogenesis. Long non-coding RNA MALAT1 has been associated with various diseases, including sepsis, but its role in SIMI remains unclear.
    OBJECTIVE: This study aimed to investigate the role of lncRNA MALAT1 in SIMI, specifically in the regulation of mitochondrial autophagy.
    METHODS: A sepsis-induced cardiomyopathy model was established in mice, and the cardiac tissues were analyzed. The expression of lncRNA MALAT1 was modulated and its effects on mitochondrial autophagy, myocardial injury, inflammation, and apoptosis were assessed. Furthermore, the interaction between MALAT1 and miR-146a was explored, as well as the involvement of the TLR4/NF-kB/MAPK signaling pathway.
    RESULTS: Activation of mitochondrial autophagy by urolithin A (UA) alleviated SIMI, inflammation, and cardiac dysfunction. Downregulation of MALAT1 enhanced mitochondrial autophagy, stabilized the mitochondrial membrane potential, and inhibited mitochondrial reactive oxygen species (ROS) production, leading to improved cell viability and reduced myocardial injury. Furthermore, MALAT1 interacted with miR-146a, and their modulation influenced mitochondrial autophagy, myocardial injury, and inflammation. The TLR4/NF-kB/MAPK signaling pathway was implicated in these processes.
    CONCLUSION: Our findings suggest that lncRNA MALAT1 plays a crucial role in SIMI by modulating miR-146a-mediated mitochondrial autophagy and the TLR4/NF-kB/MAPK signaling pathway. These results provide new insights into the pathogenesis of SIMI and potential therapeutic targets.
    Keywords:  LncRNA MALAT1; MiR-146a; Mitophagy; Myocardial injury; Sepsis
    DOI:  https://doi.org/10.1186/s40001-024-02098-7
  18. Cardiovasc Res. 2024 Nov 05. pii: cvae238. [Epub ahead of print]
    PINK1-mediated mitophagy attenuates pathological cardiac hypertrophy by suppressing the mtDNA release-activated cGAS-STING pathway.
    Haobin Zhou, Xiao Wang, Tianyu Xu, Daojing Gan, Zhuang Ma, Hao Zhang, Jian Zhang, Qingchun Zeng, Dingli Xu.
       AIMS: Sterile inflammation is implicated in the development of heart failure (HF). Mitochondria plays important roles in triggering and maintaining inflammation. Mitophagy is important for regulation of mitochondrial quality and maintenance of cardiac function under pressure overload. The association of mitophagy with inflammation in HF is largely unclear. As PINK1 is a central mediator of mitophagy, our objective was to investigate its involvement in cardiac hypertrophy, and the effect of PINK1-mediated mitophagy on cGAS-STING activation during cardiac hypertrophy.
    METHODS AND RESULTS: PINK1 knockout and cardiac-specific PINK1-overexpressing transgenic mice were created and subsequently subjected to transverse aortic constriction (TAC) surgery. In order to explore whether PINK1 regulates STING-mediated inflammation during HF, PINK1/STING (stimulator of interferon genes) double-knockout mice were created. Pressure overload was induced by TAC. Our findings indicate a significantly decline in PINK1 expression in TAC-induced hypertrophy. Cardiac hypertrophic stimuli caused the release of mitochondrial DNA (mtDNA) into the cytosol, activating the cGAS-STING signaling, which in turn initiated cardiac inflammation and promoted the progression of cardiac hypertrophy. PINK1 deficiency inhibited mitophagy activity, promoted mtDNA release, and then drove the overactivation of cGAS-STING signaling, exacerbating cardiac hypertrophy. Conversely, cardiac-specific PINK1 overexpression protected against hypertrophy thorough inhibition of the cGAS-STING signaling. Double-knockout mice revealed that the effects of PINK1 on hypertrophy were dependent on STING.
    CONCLUSIONS: Our findings suggest that PINK1-mediated mitophagy plays a protective role in pressure overload-induced cardiac hypertrophy via inhibiting the mtDNA-cGAS-STING pathway.
    Keywords:  Mitophagy; PINK1; STING; cardiac hypertrophy; inflammation
    DOI:  https://doi.org/10.1093/cvr/cvae238
  19. Free Radic Biol Med. 2024 Oct 25. pii: S0891-5849(24)01010-4. [Epub ahead of print]
    Sevoflurane exposure accelerates the onset of cognitive impairment via promoting p-Drp1S616-mediated mitochondrial fission in a mouse model of Alzheimer's disease.
    Kaiwu He, Youzhi Li, Wei Xiong, Yanmei Xing, Wenli Gao, Yuting Du, Wei Kong, Lixin Chen, Xifei Yang, Zhongliang Dai.
      Sevoflurane is an inhalational anesthetic widely used in clinical settings. Accumulating evidence has shown that sevoflurane exposure may impair cognitive function, potentially contributing to Alzheimer's disease (AD)-related changes. However, the underlying mechanism remains poorly understood. In the present study, 4-month-old 5xFAD mice were used to investigate the effect of sevoflurane exposure on cognitive decline by Y-maze test and novel object recognition test. We found that sevoflurane exposure promoted the appearance of cognitive impairment of 5xFAD mice, accompanied with the deterioration of Aβ accumulation, synaptic defects, and neuroinflammation. Additionally, sevoflurane was also found to aggravate mitochondrial fission of 5xFAD mice, as indicated by the further upregulated expression of p-Drp1S616. Moreover, sevoflurane significantly increased mitochondrial damage and dysfunction of AD models both in vitro and in vivo experiments. Seahorse XF analysis further indicated that sevoflurane exposure facilitated a metabolic shift from oxidative phosphorylation to glycolysis. Further rescue experiments revealed that a key mechanism underlying sevoflurane-induced cognitive impairment was the excessive mitochondrial fission, as supported by the result that the mitochondrial fission inhibitor Mdivi-1 counteracted the sevoflurane-mediated deteriorative effects in 5xFAD mice. These findings provided evidence for a new mechanism of sevoflurane exposure accelerating AD-related cognitive decline.
    Keywords:  Cognitive impairment; Glycolysis; Mitochondrial fission; Sevoflurane
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.10.301
  20. Exp Cell Res. 2024 Nov 02. pii: S0014-4827(24)00411-7. [Epub ahead of print] 114320
    SIRT3 mitigates high glucose-induced damage in retinal microvascular endothelial cells via OPA1-mediated mitochondrial dynamics.
    Jiemei Shi, Min Liu, Haohao Zhu, Chunhui Jiang.
      Oxidative stress in endothelial cells is pivotal in diabetic retinopathy (DR), with mitochondrial homeostasis being crucial to mitigate this stress. This study explored the roles of mitochondrial sirtuins (SIRTs) in high glucose (HG)-induced oxidative stress, related endothelial impairment, and mitochondrial homeostasis damage in rat retinal microvascular endothelial cells (RMECs). RMECs were cultured under HG or equivalent osmotic conditions. Cell viability was assessed using the Cell Counting Kit-8 assay, whereas cell death and survival were determined via calcein-AM/propidium iodide double staining. Reactive oxygen species (ROS) levels were measured using 2',7'-dichlorofluorescein fluorescence. Expression of mitochondrial SIRTs3-5 and key mitochondrial homeostasis molecules was quantified by the quantitative real-time polymerase chain reaction and confirmed by western blotting. Mitochondrial morphology was evaluated using electron microscopy and the MitoTracker fluorescent probe. A SIRT3-overexpressing RMEC line was constructed to assess the role of SIRT3 in oxidative stress and mitochondrial dynamics. After 48 h of HG exposure, cell viability was significantly reduced, with a concomitant increase in cell death and ROS levels, alongside a marked decrease in SIRT3 expression and molecules associated with mitochondrial dynamics. SIRT3 overexpression reversed these effects, particularly increasing the mitochondrial fusion-related molecule, optic atrophy 1 (OPA1). However, the OPA1 inhibitor, MYLS22, blocked the protective effect of SIRT3, leading to more dead cells, a higher ROS level, and intensified mitochondrial fragmentation. These results suggest that SIRT3 is involved in HG-induced imbalanced mitochondrial dynamics of endothelial cells in DR, potentially through the OPA1 pathway.
    Keywords:  OPA1; SIRT3; diabetic retinopathy; mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.yexcr.2024.114320
  21. Aging Dis. 2024 Oct 31.
    Modulation of Mitochondrial Dynamics by the Angiotensin System in Dopaminergic Neurons and Microglia.
    Aloia Quijano, Ana I Rodriguez-Perez, María Alicia Costa-Besada, Andrea Lopez-Lopez, María J Guerra, Jose Luis Labandeira-Garcia, Rita Valenzuela.
      Renin-angiotensin system (RAS) dysfunctions have been associated to life-spam, and aging-related diseases, including neurodegenerative diseases, such as Parkinson's disease, and the neuroinflammatory associated processes. Mitochondrial dysfunctions play a major role in aging-related diseases, including dopaminergic neurodegeneration and neuroinflammation. However, the mechanisms of RAS/mitochondria interactions remain to be clarified. In the present work, we studied the role of major RAS components in the mitochondrial dynamics in dopaminergic neurons and microglia using in vitro and in vivo models. In dopaminergic neurons, we observed that activation of the RAS pro-oxidative/pro-inflammatory axis (Angiotensin II/Angiotensin type-1 receptor, AT1/NADPH oxidase complex) produces a dysregulation of mitochondrial dynamics towards mitochondrial fission, via Drp1 phosphorylation at Ser616 and translocation to mitochondria. However, activation of the RAS antioxidative/anti-inflammatory axis, using Angiotensin 1-7, counteracts this effect. RAS components also modulated the microglial inflammatory response through mitochondrial dynamic changes. After interferon-γ-induced activation of human microglial cells, we observed increased mitochondrial fission and superoxide production that was inhibited by Angiotensin 1-7 treatment. Angiotensin 1-7 also inhibited mitochondrial metabolic changes induced by pro-inflammatory microglial activation. The role of RAS in mitochondrial dynamic changes was confirmed in vivo using the LPS-induced inflammation model in wild-type, AT1-KO, and AT2-KO mice. The effect of Angiotensin 1-7 is mediated by IL-10, specifically by decreasing the post-transcriptional phosphorylated Drp1 form, and translocation of STAT3 to mitochondria. Angiotensin 1-7, acting on mitochondrial Angiotensin 1-7 receptors (Mas/Mas related receptors), increased the phosphorylated form of STAT3 at Ser727, which is mediated by mitochondrial PKA activation. In conclusion, the present findings show the role of RAS components in modulation of mitochondrial dynamics and mitochondrial function, revealing the associated signaling pathways. The results lead to better understanding of the effects of RAS dysfunction in aging-related diseases, and particularly dopaminergic degeneration and neuroinflammation in Parkinson's disease.
    DOI:  https://doi.org/10.14336/AD.2024.0981
  22. Methods Enzymol. 2024 ;pii: S0076-6879(24)00395-1. [Epub ahead of print]707 565-584
    Analysis of quality control pathways for the translocase of the outer mitochondrial membrane.
    Lara Calvo Santos, Fabian den Brave.
      The functionality of mitochondria depends on the import of proteins synthesized on cytosolic ribosomes. Impaired import into mitochondria results in mitochondrial dysfunction and proteotoxic accumulation of precursor proteins in the cytosol. All proteins sorted to inner mitochondrial compartments are imported via the translocase of the outer membrane (TOM) complex. Premature protein folding, a reduction of the mitochondrial membrane potential or defects in translocases can result in precursor arrest during translocation, thereby clogging the TOM channel and blocking protein import. In recent years, different pathways have been identified, which employ the cytosolic ubiquitin-proteasome system in the extraction and turnover of precursor proteins from the TOM complex. Central events in this process are the modification of arrested precursor proteins with ubiquitin, their extraction by AAA-ATPases and subsequent degradation by the 26 S proteasome. Analysis of these processes is largely facilitated by the expression of model proteins that function as efficient "cloggers" of the import machinery. Here we describe the use of such clogger proteins and how their handling by the protein quality control machinery can be monitored. We provide protocols to study the extent of clogging, the ubiquitin-modification of arrested precursor proteins and their turnover by the 26 S proteasome.
    Keywords:  Mitochondria; Proteasome; Protein import; Protein quality control; Ubiquitin
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.050
  23. Cell Death Differ. 2024 Nov 05.
    Tufm lactylation regulates neuronal apoptosis by modulating mitophagy in traumatic brain injury.
    Weiji Weng, Zhenghui He, Zixuan Ma, Jialin Huang, Yuhan Han, Qiyuan Feng, Wenlan Qi, Yidong Peng, Jiangchang Wang, Jiacheng Gu, Wenye Wang, Yong Lin, Gan Jiang, Jiyao Jiang, Junfeng Feng.
      Lactates accumulation following traumatic brain injury (TBI) is detrimental. However, whether lactylation is triggered and involved in the deterioration of TBI remains unknown. Here, we first report that Tufm lactylation pathway induces neuronal apoptosis in TBI. Lactylation is found significantly increased in brain tissues from patients with TBI and mice with controlled cortical impact (CCI), and in neuronal injury cell models. Tufm, a key factor in mitophagy, is screened and identified to be mostly lactylated. Tufm is detected to be lactylated at K286 and the lactylation inhibits the interaction of Tufm and Tomm40 on mitochondria. The mitochondrial distribution of Tufm is then inhibited. Consequently, Tufm-mediated mitophagy is suppressed while mitochondria-induced neuronal apoptosis is increased. In contrast, the knockin of a lactylation-deficient TufmK286R mutant in mice rescues the mitochondrial distribution of Tufm and Tufm-mediated mitophagy, and improves functional outcome after CCI. Likewise, mild hypothermia, as a critical therapeutic method in neuroprotection, helps in downregulating Tufm lactylation, increasing Tufm-mediated mitophagy, mitigating neuronal apoptosis, and eventually ameliorating the outcome of TBI. A novel molecular mechanism in neuronal apoptosis, TBI-initiated Tufm lactylation suppressing mitophagy, is thus revealed.
    DOI:  https://doi.org/10.1038/s41418-024-01408-0
  24. Mol Med. 2024 Nov 06. 30(1): 203
    Dexmedetomidine alleviates intestinal ischemia/reperfusion injury by modulating intestinal neuron autophagy and mitochondrial homeostasis via Nupr1 regulation.
    Qiong Wu, Qiuhong Chen, Sisi Liang, Jinping Nie, Yingjie Wang, Chenlu Fan, Zhen Liu, Xuekang Zhang.
      Intestinal ischemia/reperfusion injury (I/R) is a common yet challenging-to-treat condition, presenting a significant clinical challenge. This study aims to investigate the protective mechanisms of Dexmedetomidine (Dex) against I/R injury, with a particular focus on its role in regulating autophagy activity in intestinal neurons and maintaining mitochondrial homeostasis. Experimental findings demonstrate that Dex can mitigate intestinal damage induced by I/R through the modulation of autophagy activity and mitochondrial function in intestinal neurons by suppressing the expression of Nupr1. This discovery sheds light on a new molecular mechanism underlying the potential efficacy of Dex in treating intestinal I/R injury, offering valuable insights for clinical therapy.
    Keywords:  Autophagy; Dexmedetomidine; Intestinal ischemia/reperfusion injury; Mitochondrial homeostasis; Neuron; Nupr1
    DOI:  https://doi.org/10.1186/s10020-024-00952-2
  25. J Inflamm Res. 2024 ;17 7819-7835
    Mitophagy and Ferroptosis in Sepsis-Induced ALI/ARDS: Molecular Mechanisms, Interactions and Therapeutic Prospects of Medicinal Plants.
    Huixin Cheng, Xuehan Wang, Juyi Yao, Chunbo Yang, Jian Liu.
      Sepsis is a common critical illness characterized by high mortality rates and a significant disease burden. In the context of sepsis-induced organ dysfunction, the lungs are among the initial organs affected, which may progress to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Recent studies have highlighted the crucial roles of mitophagy and ferroptosis in the development and progression of sepsis-induced ALI/ARDS. Identifying key convergence points in these processes may provide valuable insights for the treatment of this condition. In recent years, certain herbs and their bioactive compounds have demonstrated unique benefits in managing sepsis-induced ALI/ARDS by modulating mitophagy or ferroptosis. This review summary the mechanisms of mitophagy and ferroptosis, explores their interactions, and emphasizes their regulatory roles in the progression of sepsis-induced ALI/ARDS. Additionally, it offers a novel perspective on treatment strategies by summarizing various herbs and their bioactive compounds relevant to this condition.
    Keywords:  acute lung injury; acute respiratory distress syndrome; ferroptosis; mitophagy; sepsis
    DOI:  https://doi.org/10.2147/JIR.S488655
  26. Nature. 2024 Nov 06.
    Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
    Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.
      Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.
    DOI:  https://doi.org/10.1038/s41586-024-08146-w
  27. Poult Sci. 2024 Oct 24. pii: S0032-5791(24)01017-4. [Epub ahead of print]103(12): 104439
    Selenomethionine alleviates kidney necroptosis and inflammation by restoring lipopolysaccharide-mediated mitochondrial dynamics imbalance via the TLR4/RIPK3/DRP1 signaling pathway in laying hens.
    Xinzhang Chen, Yixuan Wang, Muyue Zhang, Yongzhen Du, Yujiao He, Shu Li.
      Selenomethionine (SeMet) is a beneficial organic source of selenium that is extensively used as a food additive owing to its antioxidant and anti-inflammatory properties. Due to the sensitivity of the kidneys to noxious stimuli, they are more susceptible to various injuries. To investigate the protective mechanisms of SeMet supplementation against kidney injury, we established an in vivo experimental model using laying hens treated with SeMet (0.5 mg/kg diet) and/or lipopolysaccharide (LPS) (0.2 mg/kg. BW) and an in vitro model of chicken embryo primary kidney (CEK) cells treated with SeMet (0.075 mM) and with/ without LPS (60 μg/mL). SeMet treatment alleviated the LPS-induced kidney insufficiency and mitochondrial damage. Furthermore, it reduced the expression of TLR4, RIPK3, MLKL, DRP1, NLRP3, and IL-1β in the kidneys of laying hens. RIPK3 is known to induced necroptosis and inflammation by activating of the downstream factors DRP1 and MLKL. To investigate the mechanism whereby SeMet alleviates LPS-induced necroptosis in the kidney, we pretreated CEK cells with TLR4, RIPK3, and DRP1 inhibitors. The results demonstrated that RIPK3 inhibition resulted in a significantly increased in the mitochondrial membrane potential and downregulation of DRP1. Upon the inhibition of DRP1 expression, MLKL, NLRP3, and IL-1β expression also decreased. In summary, SeMet regulates the TLR4/RIPK3/DRP1 signaling pathway to restore the LPS-induced imbalances in mitochondrial dynamics, thereby alleviating necroptosis and inflammation in the kidneys of laying hen. Selenium also increases the expression of selenoproteins. This study provides valuable information for the development of new therapeutic strategies using SeMet to alleviate kidney injury.
    Keywords:  Inflammation; Laying Hen; Mitochondrial dynamics; Necroptosis; Selenomethionine
    DOI:  https://doi.org/10.1016/j.psj.2024.104439
  28. Front Pharmacol. 2024 ;15 1477680
    Attenuating mitochondrial dysfunction-derived reactive oxygen species and reducing inflammation: the potential of Daphnetin in the viral pneumonia crisis.
    Yuan Yuan, Runyuan Li, Yinji Zhang, Yuanxin Zhao, Qingqing Liu, Jian Wang, Xiaoyu Yan, Jing Su.
      Amidst the global burden of viral pneumonia, mitigating the excessive inflammatory response induced by viral pneumonia has emerged as a significant challenge. Pneumovirus infections can lead to the persistent activation of M1 macrophages, culminating in cytokine storms that exacerbate pulmonary inflammation and contribute to the development of pulmonary fibrosis. Mitochondria, beyond their role as cellular powerhouses, are pivotal in integrating inflammatory signals and regulating macrophage polarization. Mitochondrial damage in alveolar macrophages is postulated to trigger excessive release of reactive oxygen species (ROS), thereby amplifying macrophage-mediated inflammatory pathways. Recent investigations have highlighted the anti-inflammatory potential of Daphnetin, particularly in the context of cardiovascular and renal disorders. This review elucidates the mechanisms by which viral infection-induced mitochondrial damage promotes ROS generation, leading to the phenotypic shift of alveolar macrophages towards a pro-inflammatory state. Furthermore, we propose a mechanism whereby Daphnetin attenuates inflammatory signaling by inhibiting excessive release of mitochondrial ROS, thus offering mitochondrial protection. Daphnetin may represent a promising pharmacological intervention for viral pneumonia and could play a crucial role in addressing future pandemics.
    Keywords:  Daphnetin; antioxidant; inflammation; mitochondrial; oxidationreduction regulation
    DOI:  https://doi.org/10.3389/fphar.2024.1477680
  29. Front Neurol. 2024 ;15 1435749
    Absence of oncomodulin increases susceptibility to noise-induced outer hair cell death and alters mitochondrial morphology.
    Kaitlin E Murtha, Weintari D Sese, Kiah Sleiman, Janith Halpage, Pravallika Padyala, Yang Yang, Aubrey J Hornak, Dwayne D Simmons.
      Cochlear outer hair cells (OHCs) play a fundamental role in the hearing sensitivity and frequency selectivity of mammalian hearing and are especially vulnerable to noise-induced damage. The OHCs depend on Ca2+ homeostasis, which is a balance between Ca2+ influx and extrusion, as well as Ca2+ buffering by proteins and organelles. Alterations in OHC Ca2+ homeostasis is not only an immediate response to noise, but also associated with impaired auditory function. However, there is little known about the contribution of Ca2+ buffering proteins and organelles to the vulnerability of OHCs to noise. In this study, we used a knockout (KO) mouse model where oncomodulin (Ocm), the major Ca2+ binding protein preferentially expressed in OHCs, is deleted. We show that Ocm KO mice were more susceptible to noise induced hearing loss compared to wildtype (WT) mice. Following noise exposure (106 dB SPL, 2 h), Ocm KO mice had higher threshold shifts and increased OHC loss and TUNEL staining, compared to age-matched WT mice. Mitochondrial morphology was significantly altered in Ocm KO OHCs compared to WT OHCs. Before noise exposure, Ocm KO OHCs showed decreased mitochondrial abundance, volume, and branching compared to WT OHCs, as measured by immunocytochemical staining of outer mitochondrial membrane protein, TOM20. Following noise exposure, mitochondrial proteins were barely visible in Ocm KO OHCs. Using a mammalian cell culture model of prolonged cytosolic Ca2+ overload, we show that OCM has protective effects against changes in mitochondrial morphology and apoptosis. These experiments suggest that disruption of Ca2+ buffering leads to an increase in noise vulnerability and mitochondrial-associated changes in OHCs.
    Keywords:  Ca2+; Ca2+ buffer; cell death; cochlea; mitochondria; noise-induced hearing loss; oncomodulin; outer hair cells
    DOI:  https://doi.org/10.3389/fneur.2024.1435749
  30. Methods Enzymol. 2024 ;pii: S0076-6879(24)00425-7. [Epub ahead of print]707 585-610
    Analysis of the mitochondria-associated degradation pathway (MAD) in yeast cells.
    Pin-Chao Liao, Liza A Pon.
      Mitochondria are critical for cellular function in health, disease and aging. Mitochondria-associated degradation (MAD), a pathway for quality control of the organelle, recognizes and ubiquitinates unfolded mitochondrial proteins, removes them from the organelle using a conserved segregase complex, which contains an AAA-ATPase Cdc48 and its cofactors, and degrades them using the ubiquitin-proteasome system (UPS). Here, we describe an approach to (1) study the turnover and ubiquitination of candidate MAD substrates, (2) assay retrotranslocation and export of MAD substrates from the mitochondrial matrix in vitro, and (3) study interactions between MAD substrates and Cdc48 using the budding yeast, Saccharomyces cerevisiae, as a model organism.
    Keywords:  Affinity purification; Budding yeast; Co-immunoprecipitation; Mitochondrial isolation; Mitochondrial quality control
    DOI:  https://doi.org/10.1016/bs.mie.2024.09.001
  31. J Nutr. 2024 Nov 02. pii: S0022-3166(24)01121-0. [Epub ahead of print]
    Low phosphorus causes hepatic energy metabolism disorder through Dynamin-related protein 1-mediated mitochondrial fission in fish.
    Jibin Lin, Xueshan Li, Kangle Lu, Kai Song, Ling Wang, Weiwei Dai, Mohsen Mohamed, Chunxiao Zhang.
       BACKGROUND: Low phosphorus (LP) diets perturb hepatic energy metabolism homeostasis in fish. However, the specific mechanisms in LP-induced hepatic energy metabolism disorders remain to be fully elucidated.
    OBJECTIVES: This study sought to elucidate the underlying mechanisms of mitochondria involved in LP-induced energy metabolism disorders.
    METHODS: Spotted seabass were fed diets with 0.72% (S-AP, control) or 0.36% (S-LP) available phosphorus for 10 weeks. Drp1 was knocked down or protein kinase A (PKA) was activated using 8Br-cAMP (5 μM, a PKA activator) in spotted seabass hepatocytes under LP medium. Zebrafish were fed Z-LP diets (0.30% available phosphorus) containing Mdivi-1 (5 mg/kg, a Drp1 inhibitor) or 8Br-cAMP (0.5 mg/kg) for 6 weeks. Biochemical and molecular parameters, along with transmission electron microscopy and immunofluorescence, were used to assess hepatic glycolipid metabolism, mitochondrial function and morphology.
    RESULTS: Spotted seabass fed S-LP diets showed reduced ATP (0.52-fold) and cyclic adenosine monophosphate (cAMP) (0.52-fold) levels, along with reduced Drp1 (s582) (0.38-fold) and PKA (0.61-fold) phosphorylation levels in the liver compared with those fed S-AP diets (P < 0.05). Drp1 knockdown elevated ATP levels (1.99-fold), decreased mitochondrial DRP1 protein levels (0.45-fold), and increased mitochondrial aspect ratio (1.82-fold) in LP-treated hepatocytes (P < 0.05). Furthermore, 8Br-cAMP-treated hepatocytes exhibited higher PKA phosphorylation (2.85-fold), ATP levels (1.60-fold), and mitochondrial aspect ratio (2.00-fold), along with decreased mitochondrial DRP1 protein levels (0.29-fold) under LP medium (P < 0.05). However, mutating s582 to alanine mimic Drp1 dephosphorylation decreased ATP levels (0.63-fold) and mitochondrial aspect ratio (0.53-fold) in 8Br-cAMP-treated hepatocytes (P < 0.05). In addition, zebrafish were fed Z-LP diets containing Mdivi-1 or 8Br-cAMP had higher ATP levels (3.44-fold or 1.98-fold) than that fed Z-LP diets (P < 0.05).
    CONCLUSIONS: These findings provide a potential mechanistic elucidation for LP-induced energy metabolism disorders through the cAMP/PKA/Drp1-mediated mitochondrial fission signaling pathway.
    Keywords:  Drp1; Glycolipid metabolism; Mitochondrial dynamic; Phosphorus deficiency; cAMP/PKA signaling pathway
    DOI:  https://doi.org/10.1016/j.tjnut.2024.10.044
  32. Methods Enzymol. 2024 ;pii: S0076-6879(24)00405-1. [Epub ahead of print]707 519-539
    Analysis of mitochondrial biogenesis regulation by oxidative stress.
    Dheeraj Pathak, Thanuja Krishnamoorthy, Naresh Babu V Sepuri.
      Of all the causes of metabolic and neurological disorders, oxidative stress distinguishes itself by its sweeping effect on the dynamic cellular redox homeostasis and, in its wake, exposing the vulnerabilities of the protein machinery of the cell. High levels of Reactive Oxygen Species (ROS) that mitochondria produce during ATP synthesis can damage mtDNA, lipids, and essential mitochondrial proteins. ROS majorly oxidizes cysteine and methionine amino acids in peptides, which can lead to protein unfolding or misfolding of proteins, which ultimately can have a toll on their function. As mitochondrial biogenesis relies on the continuous import of nuclear-encoded proteins into mitochondria mediated by mitochondrial protein import complexes, oxidative stress triggered by mitochondria can rapidly and detrimentally affect mitochondrial biogenesis and homeostasis. Functional Mge1 is a homodimer and acts as a cochaperone and a nucleotide exchange factor of mitochondrial heat shock protein 70 (mHsp70), crucial for mitochondrial protein import. Oxidative stress like ROS, oxidizes Met 155 in Mge1, compromising its ability to dimerize and interact with mHsp70. The cell employs Methionine sulphoxide reductase 2 (Mxr2), a member of the methionine sulphoxide reductase family, to reduce oxidized Met 155 and thereby restore the essential function of Mge1. Oxidation of methionine as a regulated post-translational modification has been gaining traction. Future high throughput studies that can scan the entire mitochondrial proteome to interrogate methionine oxidation and reversal may increase the repertoire of mitochondrial proteins undergoing regulated oxidation and reduction. In this chapter, we describe the methods followed in our laboratory to study the oxidation of Mge1 and its reduction by Mxr2 in vitro.
    Keywords:  Cross linking; Methionine oxidation; Methionine sulfoixde reductase 2; Mge1; Mitochondria; Reactive Oxygen Species
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.060
  33. Int Immunopharmacol. 2024 Oct 25. pii: S1567-5769(24)01990-8. [Epub ahead of print]143(Pt 2): 113468
    PKCδ modulates SP1 mediated mitochondrial autophagy to exacerbate diacetylmorphine-induced ferroptosis in neurons.
    Mengjie Zhuang, Sensen Zhu, Liping Su, Li Liu, Min Ji, Chenlu Dai, Jingyu Liu, Wei Zhang, Hongwei Pu.
      Diacetylmorphine (DA) is widely implicated in neuronal injury; however, the underlying mechanisms remain unclear. We investigated the role of iron metamorphosis in DA-induced neurotoxicity using Sprague-Dawley rats and PC12 and SH-SY5Y cells. Tandem mass tag proteomics analysis showed that the upregulation of protein kinase C delta (PKCδ) and iron metabolism-related protein transferrin receptor (TFRC) significantly the enriched iron metabolism pathway. Subsequent experiments showed that DA exposure significantly upregulated PKCδ in PC12 cells, which increased the nuclear translocation of specificity protein 1 (SP1), and the intracellular free iron and lipid peroxide levels. In addition, silencing of PKCδ in rats improved behaviour and restored the expression level of glutathione peroxidase 4 (GPX4). In addition, DA exposure activated mitochondrial autophagy in PC12 cells, leading to a decrease in the mitochondrial membrane potential, accumulation of reactive oxygen species (ROS), elevation of LC3 (which plays a key role in autophagy), and a decrease in p62 expression. Following the inhibition of autophagy, the mitochondrial membrane potential and ROS were restored, as was the expression of voltage-dependent anion channel 1 (VDAC1) and GPX4. In conclusion, the present study suggests that PKCδ regulates SP1, further exacerbating DA-induced neuronal ferroptosis. Therefore, inhibition of PKCδ and mitochondrial autophagy or ferroptosis may be a key therapeutic target to ameliorate neurotoxicity following DA exposure.
    Keywords:  Diacetylmorphine; Mitophagy; Neuronal ferroptosis; PKCδ; SP1
    DOI:  https://doi.org/10.1016/j.intimp.2024.113468
  34. J Mol Neurosci. 2024 Nov 07. 74(4): 106
    Antisecretory Factor 16 (AF16): A Promising Avenue for the Treatment of Traumatic Brain Injury-An In Vitro Model Approach.
    Nicola Vahrmeijer, Jurgen Kriel, Bradley M Harrington, Anton Du Preez van Staden, Adriaan Johannes Vlok, Lize Engelbrecht, Andre Du Toit, Ben Loos.
      Traumatic brain injury (TBI) is caused by an external mechanical force to the head, resulting in abnormal brain functioning and clinical manifestations. Antisecretory factor (AF16) is a potential therapeutic agent for TBI treatment due to its ability to inhibit fluid secretion and decrease inflammation, intracranial pressure, and interstitial fluid build-up, key hallmarks presented in TBI. Here, we investigated the effect of AF16 in an in vitro model of neuronal injury, as well as its impact on key components of the autophagy pathway and mitochondrial dynamics. N2Awt cells were treated with AF16, injured using a scratch assay, and analysed using confocal microscopy, correlative light and electron microscopy (CLEM), flow cytometry, and western blotting. Our results reveal that AF16 enhances autophagy activity, regulates mitochondrial dynamics, and provides protection as early as 6 h post-injury. Fluorescently labelled AF16 was observed to localise to lysosomes and the autophagy compartment, suggesting a role for autophagy and mitochondrial quality control in conferring AF16-associated neuronal protection. This study concludes that AF16 has potential as a therapeutic agent for TBI treatment through is regulation of autophagy and mitochondrial dynamics.
    Keywords:  Antisecretory factor (AF16); Autophagy; Correlative light and electron microscopy (CLEM); Mitochondrial dynamics; Traumatic brain injury (TBI)
    DOI:  https://doi.org/10.1007/s12031-024-02268-6
  35. Apoptosis. 2024 Nov 02.
    MRG15 promotes cell apoptosis through inhibition of mitophagy in hyperlipidemic acute pancreatitis.
    Boyuan Gu, Wenhao Yu, Zhiwei Huang, Junjie Bai, Shenglu Liu, Bingyu Ren, Pengru Wang, Lei Sun, Jian Wen, Yang Zheng, Peng Tan, Wenguang Fu.
      Hyperlipidemia is a common cause of acute pancreatitis (AP), often leading to more severe clinical symptoms. The mortality factor 4-like protein 1 (MORF4L1, also called MRG15) plays a crucial role in regulating lipid metabolism. Therefore, this study aimed to explore the mechanism of MRG15 in hyperlipidemic acute pancreatitis (HAP). Mendelian randomization, transcriptome analysis, and single-cell analysis were employed to explore the association between MRG15 and AP by utilizing publicly available databases. In vivo, hypertriglyceridemia mouse models were created by intraperitoneal injection of P407 or using APOE-deficient mice. Subsequently, the HAP model was induced by cerulean. In vitro, a cell model of HAP was established by initially exposing cells to palmitic acid to simulate a high-fat environment, followed by cerulein treatment. Subsequently, MRG15-related indicators were measured. Through Mendelian randomization, it was discovered that there is a positive correlation between genetic expression of MRG15 and the risk of AP. Transcriptome and single-cell analysis revealed that elevated MRG15 expression in AP contributes to lipid metabolism disorders and the activation of apoptosis pathways in pancreatic acinar cells. MRG15 is found to be significantly upregulated in cases of HAP. Knocking down MRG15 led to an increase in mitophagy and a decrease in apoptosis in pancreatic cells, and this effect was reversed when the mitochondrial Tu translation elongation factor (TUFM) was simultaneously knocked down. MRG15 inhibits mitophagy by degrading TUFM, ultimately promoting cell apoptosis and worsening the progression of HAP.
    Keywords:  Apoptosis; Hyperlipidemic acute pancreatitis; MRG15; Mitophagy; TUFM
    DOI:  https://doi.org/10.1007/s10495-024-02034-4
  36. Adv Sci (Weinh). 2024 Nov 04. e2406026
    Aloe Emodin Alleviates Radiation-Induced Heart Disease via Blocking P4HB Lactylation and Mitigating Kynurenine Metabolic Disruption.
    Fan Ouyang, Yaling Li, Haoming Wang, Xiangyang Liu, Xiaoli Tan, Genyuan Xie, Junfa Zeng, Gaofeng Zeng, Qiong Luo, Hong Zhou, Siming Chen, Kai Hou, Jinren Fang, Xia Zhang, Linlin Zhou, Yukun Li, Anbo Gao.
      Aloe emodin is an anthraquinone of traditional Chinese medicine monomer, which plays a protective action in cardiovascular diseases. However, the regulatory mechanisms of aloe emodin in the protection of radiation-induced heart damage (RIHD) are unclear. As a novel post-translational modification, lactylation is considered as a critical mediator in inflammatory cascade and cardiac injury. Here, using a cross of differential omics and 4D label-free lactylation omics, protein disulfide-isomerase (P4HB) is identified as a novel target for lactylation, and aloe emodin inhibits the binding of lactate to the K311 site of P4HB. Aloe emodin stabilizes kynurenine metabolism through inhibition of aspartate aminotransferase (GOT2) accumulation on damaged mitochondria. Mechanistically, aloe emodin inhibits phosphorylated glycogen synthase kinase 3B (p-GSK3B) transcription in the nucleus to repress the interaction of prostaglandin G/H synthase 2 (PTGS2) with SH3 domain of SH3 domain-containing GRB2-like protein B1 (SH3GLB1), thereby disrupting the functions of mitochondrial complexes and reducing SH3GLB1-mediated mitoROS accumulation, eventually suppressing calcium-binding and coiled-coil domain-containing protein 2 (NDP52)-induced mitophagy. This study unveils the regulatory role of aloe emodin in RIHD alleviation through PTGS2/SH3GLB1/NDP52 axis, indicates aloe emodin stabilizes GOT2-mediated kynurenine metabolism through P4HB lactylation. Collectively, this study provides novel insights into the regulatory mechanisms underlying the protective role of aloe emodin in cardiac injury, and opens new avenues for therapeutic strategies of aloe emodin in preventing RIHD by regulating lactylation.
    Keywords:  aloe emodin; kynurenine metabolism; lactylation; mitophagy; radiation‐induced heart damage
    DOI:  https://doi.org/10.1002/advs.202406026
  37. Life Sci. 2024 Oct 31. pii: S0024-3205(24)00793-8. [Epub ahead of print]359 123203
    Bay 11-7082 mitigates oxidative stress and mitochondrial dysfunction via NLRP3 inhibition in experimental diabetic neuropathy.
    Lokesh Sharan, Anubroto Pal, S Sarath Babu, Ashutosh Kumar, Sugato Banerjee.
       OBJECTIVE: Diabetic neuropathy is associated with mitochondrial dysfunction and neuroinflammation. Chronic hyperglycemia triggers inflammatory responses and oxidative stress, causing peripheral neuropathy, whereas mitochondrial dysfunction caused by increased ROS generation and reduced bioenergetics maintains the inflammatory cycle. The purpose of this study is to evaluate the pharmacological efficacy of Bay 11-7082 (B11) against diabetic neuropathy in rats.
    METHODS: B11 was administered at doses of 1 and 3 mg/kg to STZ-induced diabetic animals (55 mg/kg, i.p). Behavioral and functional assessments were conducted to assess neuropathy. Molecular protein expressions were evaluated for B11's efficacy against STZ-induced diabetic neuropathic rats and in SHSY5Y cells exposed to 175 mM of d-glucose.
    RESULTS: Diabetic rats exhibited deficits in nerve functions, altered nociceptive parameters, and increased expression of NLRP3, ASC, Caspase-1, and NF-κB. Additionally, diabetic animals showed reduced levels of PGC1α/Nrf2/HO-1, with an overexpression of PARP1. Compromised mitochondrial function was evident through increased mitochondrial dynamic marker DRP1 and elevated levels of inflammatory cytokines TNF-α, IL-1β, IL-18, and IL-6. However, B11 administration significantly ameliorated these changes, suggesting that B11's NLRP3 inhibition may be attributed to the activation of the mitochondrial biogenesis pathway via PGC1α/Nrf2/HO-1, along with improved mitochondrial health. In high glucose exposed SHSY5Y cells, B11 treatment attenuated neuroinflammation by inhibiting NLRP3 activation and reducing mitochondrial damage.
    CONCLUSION: B11, showed a protective effect against diabetic neuropathy by inhibiting oxidative stress, NLRP3 activation, and improving mitochondrial health in experimental diabetic neuropathy. This study provides new mechanistic insights into the neuroprotective role of Bay 11-7082 against diabetic neuropathy.
    Keywords:  Antioxidant properties; Bay 11-7082; Diabetic neuropathy; Mitochondrial quality; NLRP3 Inflammasomes; Neuroinflammation
    DOI:  https://doi.org/10.1016/j.lfs.2024.123203
  38. Mol Cell Biochem. 2024 Nov 04.
    O-GlcNAcylation of hexokinase 2 modulates mitochondrial dynamics and enhances the progression of lung cancer.
    S I Panpan, G E Wei, W U Kaiming, Renquan Zhang.
      Non-small cell lung cancer (NSCLC) stands as the prevailing manifestation of lung cancer, with current therapeutic modalities linked to a dismal prognosis, necessitating further advancements. Hexokinase 2 (HK2), a critical enzyme positioned on the mitochondrial membrane, exerts control over diverse biological pathways, thereby regulating cancer. Nevertheless, the precise role and mechanism of HK2 in NSCLC remain inadequately elucidated, warranting comprehensive investigation. HK2 expression in NSCLC tissues and cell lines was detected through immunohistochemistry and western blot analysis. Concurrently, shRNA assays were applied to scrutinize the impact of HK2 on cell proliferation, apoptosis, migration, and invasion processes in NSCLC cell lines, utilizing CCK8, flow cytometry, wound-healing assay, and transwell techniques. The involvement of HK2 in mitochondrial dynamics was probed through western blot analysis, mitochondrial membrane potential assay, and assessment of ROS generation. Next, the functional role of HK2 was assessed by examining its influence on xenograft tumor growth in nude mice in vivo. Further research has demonstrated that HK2 played a role in NSCLC through its O-GlcNAcylation process. The results of the study revealed that HK2 O-GlcNAcylation promoted the proliferation, migration, and invasive characteristics of NSCLC cells, while alleviating mitochondrial damage, whereas O-GlcNAcylation inactivation yielded the opposite effect. Furthermore, in vivo experiments in nude mice illustrated that HK2 O-GlcNAcylation could stimulate tumor growth in NSCLC. These results suggested that HK2 may impact mitochondrial dynamics in NSCLC through its O-GlcNAcylation, thereby contributing to the progression of NSCLC.
    Keywords:   O-GlcNAcylation; Hexokinase 2; Mitochondrial dynamics; NSCLC
    DOI:  https://doi.org/10.1007/s11010-024-05146-2
  39. Phytomedicine. 2024 Oct 28. pii: S0944-7113(24)00844-4. [Epub ahead of print]135 156187
    Huangqi-Danshen decoction improves heart failure by regulating pericardial adipose tissue derived extracellular vesicular miR-27a-3p to activate AMPKα2 mediated mitophagy.
    Zhaoyang Chen, Meng Zhang, Qiyao Xu, Pengyu Lu, Min Liu, Rui Yin, Xuan Liu, Yang Dai, Xin Gao, Juexiao Gong, Sujie Zhang, Xindong Wang.
       BACKGROUND: Huangqi-Danshen decoction (HDD) is a classic traditional Chinese medicine for treating heart failure. Pericardial adipose tissue (PAT) has recently gained increasing attention in cardiovascular diseases.
    PURPOSE: This study aimed to investigate the effect of pericardial adipose tissue-derived extracellular vesicles on heart failure, the protective effect of HDD on myocardial remodel in heart failure rats, and identify the potential molecular mechanisms involved.
    METHODS: UPLC-MS/MS identified active components of HDD. Extracellular vesicles (EVs) from pericardial adipose tissue of sham-operated and HF rats were identified through transmission electron microscopy, nanoparticle tracking analysis and western blot. EVs were co-cultured with H9c2 cardiomyocytes in order to examine their uptake and effects. MicroRNA sequencing, dual-luciferase reporter assay and PCR were conducted for exploring specific mechanisms of EVs on hypertrophic cardiomyocytes. In vivo, heart failure was modeled in rats via transverse aortic constriction (TAC). In vitro, the hypertrophic cardiomyocyte model were established using Ang II-induced H9c2 cardiomyocytes.
    RESULTS: UPLC-MS/MS identified 11 active components in serum of HDD administrated rats. Echocardiography showed HDD improved cardiac function in TAC model rats. HE and Masson staining indicated HDD ameliorated myocardial hypertrophy and fibrosis. MicroRNA sequencing found that HDD treatment resulted in 37 differentially expressed miRNAs (DMEs) (p < 0.05 and |log2FC| ≥ 1). KEGG analysis revealed that DEMs were enriched in the AMPK signaling pathway. PCR identified miR-27a-3p with the greatest difference in AMPK-related DMEs. Dual-luciferase reporter assay and Targetscan website were utilized to identify the target relationship between miR-27a-3p and PRKAA2 (AMPKα2). The miR-27a-3p negatively regulated AMPKα2 to inhibit mitophagy mediated by PINK1/Parkin pathway. HDD inhibited miR-27a-3p secretion from failing heart pericardial adipose tissue-derived extracellular vesicles, thereby improving inflammation, cardiac function, and myocardial remodeling through above pathways.
    CONCLUSION: HDD inhibited the PAT-derived extracellular vesicular miR-27a-3p in failing hearts to activate AMPK/PINK1/Parkin signaling-mediated mitophagy, which improved cardiomyocyte energy metabolism, myocardial remodeling and heart failure.
    Keywords:  Extracellular vesicles; Heart failure; Huangqi-danshen; Mitophagy; Pericardial adipose tissue
    DOI:  https://doi.org/10.1016/j.phymed.2024.156187
  40. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2024 Oct;46(5): 720-731
    [Role of Mitophagy Affecting Macrophage Polarization in Immunomodulationin Sepsis and Traditional Chinese Medicine Intervention:A Review].
    Lu-Yao Qi, Ji-Xiang Xing, Bing-Qing Ouyang, Yun-Feng Li, Ming Lei.
      Sepsis,a syndrome characterized by organ dysfunction caused by infection,exhibits high incidence and mortality.The pathogenesis of sepsis is complex and involves a cascade of immune reactions,with no specific drugs currently available.Sepsis is mainly treated with Western medical supportive therapies such as antibiotics,hemodynamic management,and mechanical ventilation.However,the occurrence of immune cascades significantly increases patients' vulnerability to secondary infections,leading to septic shock and unfavorable prognoses.International consensus indicates that initiating dynamic monitoring of patients' immune function within 48 h post-sepsis diagnosis can effectively decelerate sepsis progression.Extensive studies have indicated that macrophages,serving as the first line of defense in the innate immune system against pathogens,play a vital role in treating immune system disorders by regulating macrophage polarization and the ratio of cytokines activated.Mitophagy,a hot topic in recent years,has increasingly been shown to play a crucial role in regulating inflammatory signal transduction.Promoting mitophagy during the stage of cytokine storm can mitigate uncontrolled infection and excessive inflammation in sepsis,and inhibiting mitophagy during immunosuppression can enhance host immunity,facilitate bacterial clearance,and improve the survival rate of patients.The idea of treating disease before its onset in traditional Chinese medicine (TCM) coincides with the current consensus among sepsis experts on prevention and interception.The TCM therapies such as extracts of Chinese medicine decoction pieces,TCM compound prescriptions,and acupuncture and moxibustion have the effects of clearing heat and detoxifying,activating blood and resolving stasis,reinforcing healthy qi and consolidating root,and purging.These approaches dynamically regulate the levels of mitophagy-related proteins,such as phosphatase and tension homology-induced putative kinase 1,Parkin-E3 ubiquitin protein ligase,light chain 3,and p62,while maintaining a suitable ratio between M1 and M2 macrophages.Consequently,they effectively prevent,halt,or even reverse the progression of sepsis,offering a novel perspective on sepsis management by emphasizing prevention before disease onset and controlling development of existing disease.
    Keywords:  immunomodulation; mitophagy; polarization of macrophages; sepsis; traditional Chinese medicine
    DOI:  https://doi.org/10.3881/j.issn.1000-503X.15849
  41. Geroscience. 2024 Nov 04.
    Novel biomarkers of mitochondrial dysfunction in Long COVID patients.
    Titanilla Szögi, Barbara N Borsos, Dejana Masic, Bence Radics, Zsolt Bella, Andrea Bánfi, Nóra Ördög, Csenge Zsiros, Ágnes Kiricsi, Gabriella Pankotai-Bodó, Ágnes Kovács, Dóra Paróczai, Andrea Lugosi Botkáné, Béla Kajtár, Farkas Sükösd, Andrea Lehoczki, Tamás Polgár, Annamária Letoha, Tibor Pankotai, László Tiszlavicz.
      Coronavirus disease 2019 (COVID-19) can lead to severe acute respiratory syndrome, and while most individuals recover within weeks, approximately 30-40% experience persistent symptoms collectively known as Long COVID, post-COVID-19 syndrome, or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC). These enduring symptoms, including fatigue, respiratory difficulties, body pain, short-term memory loss, concentration issues, and sleep disturbances, can persist for months. According to recent studies, SARS-CoV-2 infection causes prolonged disruptions in mitochondrial function, significantly altering cellular energy metabolism. Our research employed transmission electron microscopy to reveal distinct mitochondrial structural abnormalities in Long COVID patients, notably including significant swelling, disrupted cristae, and an overall irregular morphology, which collectively indicates severe mitochondrial distress. We noted increased levels of superoxide dismutase 1 which signals oxidative stress and elevated autophagy-related 4B cysteine peptidase levels, indicating disruptions in mitophagy. Importantly, our analysis also identified reduced levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in these patients, serving as a novel biomarker for the condition. These findings underscore the crucial role of persistent mitochondrial dysfunction in the pathogenesis of Long COVID. Further exploration of the cellular and molecular mechanisms underlying post-viral mitochondrial dysfunction is critical, particularly to understand the roles of autoimmune reactions and the reactivation of latent viruses in perpetuating these conditions. This comprehensive understanding could pave the way for targeted therapeutic interventions designed to alleviate the chronic impacts of Long COVID. By utilizing circulating ccf-mtDNA and other novel mitochondrial biomarkers, we can enhance our diagnostic capabilities and improve the management of this complex syndrome.
    Keywords:  Mitochondria; Mitophagy; Oxidative damage; Post-COVID; mtDNA
    DOI:  https://doi.org/10.1007/s11357-024-01398-4
  42. Methods Enzymol. 2024 ;pii: S0076-6879(24)00388-4. [Epub ahead of print]707 475-498
    Analysis of mitochondrial protein aggregation and disaggregation.
    Wolfgang Voos, Anne Wilkening, Robin Ostermann, Michael Bruderek, Witold Jaworek, Laura Ruland.
      Deficits of mitochondrial functions have been identified in many human pathologies, in particular in age-related human neurodegenerative diseases. Hence, the molecular causes for mitochondrial dysfunction and potential protection mechanisms have become a major topic in modern cell biology. Apart from defects in their structural integrity, problems in mitochondrial protein biogenesis, including polypeptide transport, folding and assembly to active enzymes, all may result in some degree of functional defects of the organelle. An accumulation of misfolded polypeptides inside mitochondria, confounded by the dual source of mitochondrial polypeptides, will result in the formation of protein aggregates. Such aggregate accumulation bears a cell-toxic potential, resulting in mitochondrial and correlated cellular damages, summarized in the term "aggregate proteotoxicity". Here, we discuss methods to analyze protein aggregation in the mitochondrial matrix compartment. We also address techniques to characterize the biochemical mechanisms that reduce aggregate proteotoxicity, the disaggregation or resolubilization of aggregated polypeptides and the sequestration and neutralization of mitochondrial aggregates at specific sites inside a cell.
    Keywords:  ATP-dependent proteases; Human cells; Mitochondria; Molecular chaperones; Protein aggregation; Proteotoxicity; Yeast
    DOI:  https://doi.org/10.1016/bs.mie.2024.07.048
  43. J Nutr Health Aging. 2024 Nov 05. pii: S1279-7707(24)00496-2. [Epub ahead of print]28(12): 100408
    Mitochondrial quality control measures, systemic inflammation, and lower-limb muscle power in older adults: a PROMPT secondary analysis.
    Helio José Coelho-Junior, Emanuele Marzetti, Casey L Sexton, Kevin Wu, Robert Mankowski, Stephen D Anton, Christiaan Leeuwenburgh, Anna Picca.
       OBJECTIVES: The study was conducted to explore associations between markers of mitochondrial quality control (MQC) from vastus lateralis muscle biopsies, serum inflammatory markers, and measures of muscle power assessed by two different tools in a sample of older adults.
    DESIGN: Secondary analysis of data collected in the PeppeR develOpMental ProjecT (PROMPT) at the University of Florida (Gainesville, FL, USA).
    METHODS: Forty-three older adults (n = 20 women) were included in the study. Muscle volume of the calf and thigh was quantified by three-dimensional magnetic resonance imaging. Lower-limb muscle power was estimated using 5-time sit-to-stand (5STS) muscle power equations and isokinetic test. Protein markers of MQC were measured in muscle samples by Western immoblotting (n = 12-23), while type I and II fiber cross-sectional area (CSA) and their proportion were quantified using immunohistochemistry (n = 12). Cytochrome C oxidase enzyme activity was measured spectrophotometrically. Finally, inflammatory markers were quantified in the serum using a multiplex immunoassay (n = 39).
    RESULTS: Mean age of participants was 78.1 ± 5.5 years, and the average body mass index was 26.2 ± 4.5 kg/m2. Markers of mitochondrial biogenesis (i.e., PGC-1α), mitochondrial import proteins (i.e., cHsp70 and mtHsp70), and type I fiber CSA were significantly associated with muscle power estimated via both 5STS muscle power equations and isokinetic test (p < 0.05). Specific associations were also found according to the muscle power assessment method. 5STS muscle power measures were negatively correlated with ClvCasp3, P-AMPK, T-AMPK, P-p38, GM-CSF, INF-γ, IL1b, IL6, IL8, and TNF-α, whereas positive associations were found with BAX (p < 0.05). In contrast, isokinetic measures were significantly and positively correlated with RIP140, Hsp60, and type II muscle fiber CSA (p < 0.05).
    CONCLUSIONS: Markers of mitochondrial biogenesis (PGC-1α), mitochondrial import proteins (cHsp70 and mtHsp70), and type I muscle fiber CSA were significantly linked to lower-limb muscle power in older adults. These results suggest that muscle power is influenced by mitochondrial signaling. We also found that the relationship between mitochondrial mediators, inflammatory markers, and muscle power varied according to the assessment tool used.
    Keywords:  Apoptosis; Inflammaging; Mitochondria; Muscle aging; Physical performance; Sarcopenia
    DOI:  https://doi.org/10.1016/j.jnha.2024.100408
  44. Toxicology. 2024 Nov 02. pii: S0300-483X(24)00264-6. [Epub ahead of print]509 153983
    Aflatoxin B1-induced hepatotoxicity through mitochondrial dysfunction, oxidative stress, and inflammation as central pathological mechanisms: A review of experimental evidence.
    Tsholofelo P Moloi, Khanyisani Ziqubu, Sithandiwe E Mazibuko-Mbeje, Nonduduzo H Mabaso, Zibele Ndlovu.
      Aflatoxin B1 (AFB1) is a class of mycotoxin known to contaminate agricultural products, animal feed and animal food products, subsequently causing detrimental effects on human and animal health. AFB1 is the most common and potent aflatoxin found in food and contributes significantly to liver injury as well as the development of hepatocellular carcinoma. Although the liver is a primary target organ for AFB1 toxicity and biotransformation, underlying mechanisms implicated in liver injuries induced by these mycotoxins remain to be fully elucidated for therapeutic purposes. This review aims to dissect the complexities of the pathophysiological and molecular mechanisms implicated in hepatotoxicity induced by AFB1, including mitochondrial dysfunction, oxidative stress and hepatic inflammation. Mechanistically, AFB1 disrupt mitochondrial bioenergetics and membrane potential, promotes mitochondrial cholesterol trafficking and induces mitophagy. Moreover, mitochondrial dysfunction may lead to hepatic oxidative stress as a consequence of uncontrolled production of reactive oxygen species and defects in the antioxidant defense system. Retrieved experimental evidence also showed that AFB1 may lead to hepatic inflammation through gut microbiota dysbiosis, the release of DAMPs and cytokines, and immune cell recruitment. Overall, these mechanisms could be utilized as potential targets to extrapolate treatment for liver injury caused by AFB1.
    Keywords:  Aflatoxin B(1); Hepatotoxicity; Inflammation; Mitochondrial dysfunction; Oxidative stress
    DOI:  https://doi.org/10.1016/j.tox.2024.153983
This page is being maintained by Thomas Krichel. It was last updated on 2024‒12‒26 at 8:19.