bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2023‒09‒24
twelve papers selected by
Omkar Joshi, Turku Bioscience
  1. Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.
  2. Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
  3. Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.
  4. Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer.
  5. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.
  6. Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.
  7. Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
  8. Exercise ameliorating myocardial injury in type 2 diabetic rats by inhibiting excessive mitochondrial fission involving increased irisin expression and AMP-activated protein kinase phosphorylation.
  9. Protocol for real-time imaging of membrane fission by mitofissin.
  10. IRF2BP2 drives lymphatic metastasis in OSCC cells by elevating mitochondrial fission-dependent fatty acid oxidation.
  11. MYC-an emerging player in mitochondrial diseases.
  12. Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
  1. Neurotoxicology. 2023 Sep 16. pii: S0161-813X(23)00124-9. [Epub ahead of print]99 50-58
    Mitophagy-dependent mitochondrial ROS mediates 2,5-hexanedione-induced NLRP3 inflammasome activation in BV2 microglia.
    Wenqiong Wang, Rui Chang, Yan Wang, Liyan Hou, Qingshan Wang.
      We recently revealed a pivotal role of NLRP3 inflammasome in the neurotoxicity induced by n-hexane, owing to its activation and release of pro-inflammatory cytokines. However, the mechanisms of how the activation of NLRP3 inflammasome was triggered by 2,5-hexanedione (HD), the toxic product of n-hexane metabolism, remain to be explored. Here, we investigated whether mitochondrial reactive oxygen species (mtROS) was involved in HD-elicited NLRP3 inflammasome activation in microglia. We demonstrated that exposure to HD at 4 and 8 mM elevated production of mtROS in BV2 microglia. Scavenging mtROS by Mito-TEMPO, an mtROS scavenger, dramatically reduced HD-induced NLRP3 expression, caspase-1 activation and interleukin-1β production, pointing a crucial role of mtROS in NLRP3 inflammasome activation. Mechanistic study revealed that HD intoxication promoted activation of mitophagy. HD induced expression of Beclin-1, LC3II, and two mitophagy-related proteins, i.e., Pink1 and Parkin and simultaneously, reduced p62 expression in both whole cell and isolated mitochondria of microglia. Furthermore, inhibition of mitophagy by 3-methyladenine (3-MA) greatly reduced production of mtROS, expression of mitochondrial fission-related proteins, dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1) and activation of NLRP3 inflammasome in HD-intoxicated microglia. Blocking mitochondrial fission by Mdivi-1 also prevented HD-induced mtROS production and NLRP3 inflammasome activation in microglia. In conclusion, our data indicated that HD triggered activation of NLRP3 inflammasome through mitophagy-dependent mtROS production, offering an important insight for the immunopathogenesis of environmental toxins-induced neuroinflammation and neurotoxicity.
    Keywords:  Mitochondrial ROS; Mitochondrial fission; Mitophagy; N-Hexane; NLRP3 inflammasome
    DOI:  https://doi.org/10.1016/j.neuro.2023.09.008
  2. PLoS Biol. 2023 Sep 18. 21(9): e3002310
    Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
    Xenia Chelius, Veronika Bartosch, Nathalie Rausch, Magdalena Haubner, Jana Schramm, Ralf J Braun, Till Klecker, Benedikt Westermann.
      Decline of mitochondrial function is a hallmark of cellular aging. To counteract this process, some cells inherit mitochondria asymmetrically to rejuvenate daughter cells. The molecular mechanisms that control this process are poorly understood. Here, we made use of matrix-targeted D-amino acid oxidase (Su9-DAO) to selectively trigger oxidative damage in yeast mitochondria. We observed that dysfunctional mitochondria become fusion-incompetent and immotile. Lack of bud-directed movements is caused by defective recruitment of the myosin motor, Myo2. Intriguingly, intact mitochondria that are present in the same cell continue to move into the bud, establishing that quality control occurs directly at the level of the organelle in the mother. The selection of healthy organelles for inheritance no longer works in the absence of the mitochondrial Myo2 adapter protein Mmr1. Together, our data suggest a mechanism in which the combination of blocked fusion and loss of motor protein ensures that damaged mitochondria are retained in the mother cell to ensure rejuvenation of the bud.
    DOI:  https://doi.org/10.1371/journal.pbio.3002310
  3. Nat Commun. 2023 09 18. 14(1): 5781
    Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.
    Ting Huang, Ruyi Lin, Yuanqin Su, Hao Sun, Xixi Zheng, Jinsong Zhang, Xiaoyan Lu, Baiqin Zhao, Xinchi Jiang, Lingling Huang, Ni Li, Jing Shi, Xiaohui Fan, Donghang Xu, Tianyuan Zhang, Jianqing Gao.
      The use of exogenous mitochondria to replenish damaged mitochondria has been proposed as a strategy for the treatment of pulmonary fibrosis. However, the success of this strategy is partially restricted by the difficulty of supplying sufficient mitochondria to diseased cells. Herein, we report the generation of high-powered mesenchymal stem cells with promoted mitochondrial biogenesis and facilitated mitochondrial transfer to injured lung cells by the sequential treatment of pioglitazone and iron oxide nanoparticles. This highly efficient mitochondrial transfer is shown to not only restore mitochondrial homeostasis but also reactivate inhibited mitophagy, consequently recovering impaired cellular functions. We perform studies in mouse to show that these high-powered mesenchymal stem cells successfully mitigate fibrotic progression in a progressive fibrosis model, which was further verified in a humanized multicellular lung spheroid model. The present findings provide a potential strategy to overcome the current limitations in mitochondrial replenishment therapy, thereby promoting therapeutic applications for fibrotic intervention.
    DOI:  https://doi.org/10.1038/s41467-023-41529-7
  4. J Transl Med. 2023 Sep 19. 21(1): 635
    Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer.
    Carmine Rocca, Teresa Soda, Ernestina Marianna De Francesco, Marco Fiorillo, Francesco Moccia, Giuseppe Viglietto, Tommaso Angelone, Nicola Amodio.
      A large body of evidence indicates the existence of a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism and calcium signaling to mitochondrial dynamics, cell death and mitophagy. Emerging data indicate that impaired mitochondrial quality control drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, myocardial infarction, ischaemia/reperfusion damage and metabolic cardiomyopathies. On the other hand, diverse human cancers also dysregulate mitochondrial quality control to promote their initiation and progression, suggesting that modulating mitochondrial homeostasis may represent a promising therapeutic strategy both in cardiology and oncology. In this review, first we briefly introduce the physiological mechanisms underlying the mitochondrial quality control system, and then summarize the current understanding about the impact of dysregulated mitochondrial functions in cardiovascular diseases and cancer. We also discuss key mitochondrial mechanisms underlying the increased risk of cardiovascular complications secondary to the main current anticancer strategies, highlighting the potential of strategies aimed at alleviating mitochondrial impairment-related cardiac dysfunction and tumorigenesis. It is hoped that this summary can provide novel insights into precision medicine approaches to reduce cardiovascular and cancer morbidities and mortalities.
    Keywords:  Anticancer therapy; Cancer; Cardiotoxicity; Cardiovascular diseases; Mitochondrial dynamics; Mitochondrial dysfunction
    DOI:  https://doi.org/10.1186/s12967-023-04498-5
  5. iScience. 2023 Oct 20. 26(10): 107780
    Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.
    Margaret E Maes, Gloria Colombo, Florianne E Schoot Uiterkamp, Felix Sternberg, Alessandro Venturino, Elena E Pohl, Sandra Siegert.
      Mitochondrial networks remodel their connectivity, content, and subcellular localization to support optimized energy production in conditions of increased environmental or cellular stress. Microglia rely on mitochondria to respond to these stressors, however our knowledge about mitochondrial networks and their adaptations in microglia in vivo is limited. Here, we generate a mouse model that selectively labels mitochondria in microglia. We identify that mitochondrial networks are more fragmented with increased content and perinuclear localization in vitro vs. in vivo. Mitochondrial networks adapt similarly in microglia closest to the injury site after optic nerve crush. Preventing microglial UCP2 increase after injury by selective knockout induces cellular stress. This results in mitochondrial hyperfusion in male microglia, a phenotype absent in females due to circulating estrogens. Our results establish the foundation for mitochondrial network analysis of microglia in vivo, emphasizing the importance of mitochondrial-based sex effects of microglia in other pathologies.
    Keywords:  Biological sciences; Natural sciences; Neuroscience; Physiology; Sensory neuroscience; Systems neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2023.107780
  6. Sci Immunol. 2023 Sep 29. 8(87): eabq2424
    Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.
    Jie-Feng Yang, Xudong Xing, Li Luo, Xin-Wei Zhou, Jian-Xiong Feng, Kang-Bo Huang, Huashan Liu, Shanzhao Jin, Yi-Na Liu, Shi-Hui Zhang, Yi-Hui Pan, Bing Yu, Jin-Yu Yang, Yu-Lu Cao, Yun Cao, Cliff Y Yang, Yuan Wang, Yuxia Zhang, Jiang Li, Xiaojun Xia, Tiebang Kang, Rui-Hua Xu, Ping Lan, Jun-Hang Luo, Hui Han, Fan Bai, Song Gao.
      Metabolic fitness of T cells is essential for their vitality, which is largely dependent on the behavior of the mitochondria. The nature of mitochondrial behavior in tumor-infiltrating T cells remains poorly understood. In this study, we show that mitofusin-2 (MFN2) expression is positively correlated with the prognosis of multiple cancers. Genetic ablation of Mfn2 in CD8+ T cells dampens mitochondrial metabolism and function and promotes tumor progression. In tumor-infiltrating CD8+ T cells, MFN2 enhances mitochondria-endoplasmic reticulum (ER) contact by interacting with ER-embedded Ca2+-ATPase SERCA2, facilitating the mitochondrial Ca2+ influx required for efficient mitochondrial metabolism. MFN2 stimulates the ER Ca2+ retrieval activity of SERCA2, thereby preventing excessive mitochondrial Ca2+ accumulation and apoptosis. Elevating mitochondria-ER contact by increasing MFN2 in CD8+ T cells improves the efficacy of cancer immunotherapy. Thus, we reveal a tethering-and-buffering mechanism of organelle cross-talk that regulates the metabolic fitness of tumor-infiltrating CD8+ T cells and highlights the therapeutic potential of enhancing MFN2 expression to optimize T cell function.
    DOI:  https://doi.org/10.1126/sciimmunol.abq2424
  7. Cell Chem Biol. 2023 Aug 31. pii: S2451-9456(23)00280-5. [Epub ahead of print]
    Metabolic modulation of mitochondrial mass during CD4+ T cell activation.
    Kiran Kurmi, Dan Liang, Robert van de Ven, Peter Georgiev, Brandon Mark Gassaway, SeongJun Han, Giulia Notarangelo, Isaac S Harris, Cong-Hui Yao, Joon Seok Park, Song-Hua Hu, Jingyu Peng, Jefte M Drijvers, Sarah Boswell, Artem Sokolov, Stephanie K Dougan, Peter K Sorger, Steven P Gygi, Arlene H Sharpe, Marcia C Haigis.
      Mitochondrial biogenesis initiates within hours of T cell receptor (TCR) engagement and is critical for T cell activation, function, and survival; yet, how metabolic programs support mitochondrial biogenesis during TCR signaling is not fully understood. Here, we performed a multiplexed metabolic chemical screen in CD4+ T lymphocytes to identify modulators of metabolism that impact mitochondrial mass during early T cell activation. Treatment of T cells with pyrvinium pamoate early during their activation blocks an increase in mitochondrial mass and results in reduced proliferation, skewed CD4+ T cell differentiation, and reduced cytokine production. Furthermore, administration of pyrvinium pamoate at the time of induction of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis in mice, prevented the onset of clinical disease. Thus, modulation of mitochondrial biogenesis may provide a therapeutic strategy for modulating T cell immune responses.
    Keywords:  CD4(+) T cells; T cell differentiation; high-throughput metabolic screen; mitochondrial biogenesis; pyruvate oxidation; pyrvinium pamoate
    DOI:  https://doi.org/10.1016/j.chembiol.2023.08.008
  8. J Diabetes. 2023 Sep 18.
    Exercise ameliorating myocardial injury in type 2 diabetic rats by inhibiting excessive mitochondrial fission involving increased irisin expression and AMP-activated protein kinase phosphorylation.
    Bin Wang, Chen Zhao, Yuanxin Wang, Xin Tian, Junjie Lin, Baishu Zhu, Yalan Zhou, Xin Zhang, Nan Li, Yu Sun, Haocheng Xu, Renqing Zhao.
      PURPOSE: Though exercise generates beneficial effects on diabetes-associated cardiac damage, the underlying mechanism is largely unclear. Therefore, we prescribed a program of 8-week treadmill training for type 2 diabetes mellitus (T2DM) rats and determined the role of irisin signaling, via interacting with AMP-activated protein kinase (AMPK), in mediating the effects of exercise on myocardial injuries and mitochondrial fission.METHODS: Forty 8-week-old male Wistar rats were randomly divided into groups of control (Con), diabetes mellitus (DM), diabetes plus exercise (Ex), and diabetes plus exercise and Cyclo RGDyk (ExRg). Ex and ExRg rats received 8 weeks of treadmill running, and the rats in the ExRg group additionally were treated with a twice weekly injection of Cyclo RGDyk, an irisin receptor-αV/β5 antagonist. At the end of the experiment, murine blood samples and heart tissues were collected and analyzed with methods of ELISA, Western blot, real-time quantitative polymerase chain reaction, as well as immunofluorescence staining.
    RESULTS: Exercise effectively mitigated T2DM-related hyperglycemia, hyperinsulinemia, lipid dysmetabolism, and inflammation, which could be diminished by Cyclo RGDyk treatment. Additionally, exercise alleviated T2DM-induced myocardial injury and excessive mitochondrial fission, whereas the beneficial effects were blocked by the administration of Cyclo RGDyk. T2DM significantly decreased serum irisin concentrations and fibronectin type III domain-containing protein 5 (FNDC5)/irisin gene and protein expression levels in the rat heart, whereas exercise could rescue T2DM-reduced FNDC5/irisin expression. Blocking irisin receptor signaling diminished the exercise-alleviated mitochondrial fission protein expression and elevated AMPK phosphorylation.
    CONCLUSION: Exercise is effective in mitigating diabetes-related insulin resistance, metabolic dysfunction, and inflammation. Irisin signaling engages in exercise-associated beneficial effects on myocardial injury and excessive mitochondrial fission in diabetes rats involving elevated AMPK phosphorylation.
    Keywords:  exercise; irisin; mitochondrial fission; myocardial injury; type 2 diabetes
    DOI:  https://doi.org/10.1111/1753-0407.13475
  9. STAR Protoc. 2023 Sep 21. pii: S2666-1667(23)00557-9. [Epub ahead of print]4(4): 102590
    Protocol for real-time imaging of membrane fission by mitofissin.
    Tatsuro Maruyama, Nobuo N Noda.
      Yeast mitofissin Atg44 is a mitochondrial intermembrane space protein that causes membrane fission required for mitophagy. Here, we present a protocol for observing Atg44-mediated membrane fission. We describe steps for recombinant Atg44 purification, lipid nanotube preparation as model membranes, and Atg44-mediated membrane fission real-time observation. We then detail procedures for tube radius estimation using confocal microscopy. This protocol can also be adapted to the study of membrane fission by other proteins. For complete details on the use and execution of this protocol, please refer to Fukuda et al. (2023).1.
    Keywords:  Biophysics; Microscopy; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2023.102590
  10. Mol Carcinog. 2023 Sep 22.
    IRF2BP2 drives lymphatic metastasis in OSCC cells by elevating mitochondrial fission-dependent fatty acid oxidation.
    Xin Pang, Tian-Jiao Li, Rong-Jia Shi, Zi-Xin Wan, Yue-Yang Tang, Ya-Ling Tang, Xin-Hua Liang.
      Lymph node metastasis (LNM) is a major determinant for the poor outcome of oral squamous cell carcinoma (OSCC). Interferon regulatory factor 2 binding protein 2 (IRF2BP2) has been reported to modulate the development and progression of several types of cancers, while its role in OSCC with LNM has not been reported yet. The expression of IRF2BP2 and its association with LNM were evaluated by immunohistochemistry and qualitative reverse transcription polymerase chain reaction in clinically collected OSCC tissues. Then, loss-of-function and rescue assays were conducted to identify the role of IRF2BP2-mediated fatty acid oxidation (FAO) in the invasion, lymphoinvasion, and epithelial-mesenchymal transition (EMT) in OSCC cells. Importantly, confocal microscope, transmission electron microscope, immunofluorescence, and Western blot were applied to identify the involvement of mitochondrial fission in IRF2BP2-regulated FAO. Lastly, the in vivo models were established to evaluate the role of IRF2BP2 in OSCC. IRF2BP2 overexpression has been associated with LNM in OSCC, whose knockdown inhibited invasion, lymphoinvasion, and EMT of OSCC cells, as well as retarded FAO rate with CPT1A downregulation. And CPT1A overexpression rescued invasion, lymphoinvasion, and induced EMT in IRF2BP2-silenced OSCC cells. Mechanically, IRF2BP2 accelerated mitochondrial fission by contributing to Drp1 S616 phosphorylation and mitochondrial localization, resulting in the upregulation of CPT1A. In addition, IRF2BP2 knockdown significantly inhibited tumor growth and LNM in vivo. The highly expressed IRF2BP2 may induce the phosphorylation and mitochondrial translocation of Drp1 to activate mitochondrial fission, which upregulated CPT1A expression and FAO rate, resulting in LNM in OSCC. This highlighted a potential therapeutic vulnerability for the treatment of LNM+ OSCC via targeting IRF2BP2-FAO.
    Keywords:  IRF2BP2; fatty acid oxidation; lymph node metastasis; mitochondrial fission; oral squamous cell carcinoma
    DOI:  https://doi.org/10.1002/mc.23635
  11. Front Cell Dev Biol. 2023 ;11 1257651
    MYC-an emerging player in mitochondrial diseases.
    Janne Purhonen, Juha Klefström, Jukka Kallijärvi.
      The mitochondrion is a major hub of cellular metabolism and involved directly or indirectly in almost all biological processes of the cell. In mitochondrial diseases, compromised respiratory electron transfer and oxidative phosphorylation (OXPHOS) lead to compensatory rewiring of metabolism with resemblance to the Warburg-like metabolic state of cancer cells. The transcription factor MYC (or c-MYC) is a major regulator of metabolic rewiring in cancer, stimulating glycolysis, nucleotide biosynthesis, and glutamine utilization, which are known or predicted to be affected also in mitochondrial diseases. Albeit not widely acknowledged thus far, several cell and mouse models of mitochondrial disease show upregulation of MYC and/or its typical transcriptional signatures. Moreover, gene expression and metabolite-level changes associated with mitochondrial integrated stress response (mt-ISR) show remarkable overlap with those of MYC overexpression. In addition to being a metabolic regulator, MYC promotes cellular proliferation and modifies the cell cycle kinetics and, especially at high expression levels, promotes replication stress and genomic instability, and sensitizes cells to apoptosis. Because cell proliferation requires energy and doubling of the cellular biomass, replicating cells should be particularly sensitive to defective OXPHOS. On the other hand, OXPHOS-defective replicating cells are predicted to be especially vulnerable to high levels of MYC as it facilitates evasion of metabolic checkpoints and accelerates cell cycle progression. Indeed, a few recent studies demonstrate cell cycle defects and nuclear DNA damage in OXPHOS deficiency. Here, we give an overview of key mitochondria-dependent metabolic pathways known to be regulated by MYC, review the current literature on MYC expression in mitochondrial diseases, and speculate how its upregulation may be triggered by OXPHOS deficiency and what implications this has for the pathogenesis of these diseases.
    Keywords:  Warburg effect; cellular senescence; electron transport chain; mitochondrial integrated stress response; oxidative phosphorylation; respiratory complex III
    DOI:  https://doi.org/10.3389/fcell.2023.1257651
  12. Sci Adv. 2023 Sep 22. 9(38): eadh8228
    Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
    Louise Uoselis, Runa Lindblom, Wai Kit Lam, Catharina J Küng, Marvin Skulsuppaisarn, Grace Khuu, Thanh N Nguyen, Danielle L Rudler, Aleksandra Filipovska, Ralf B Schittenhelm, Michael Lazarou.
      Breakdown of mitochondrial proteostasis activates quality control pathways including the mitochondrial unfolded protein response (UPRmt) and PINK1/Parkin mitophagy. However, beyond the up-regulation of chaperones and proteases, we have a limited understanding of how the UPRmt remodels and restores damaged mitochondrial proteomes. Here, we have developed a functional proteomics framework, termed MitoPQ (Mitochondrial Proteostasis Quantification), to dissect the UPRmt's role in maintaining proteostasis during stress. We find essential roles for the UPRmt in both protecting and repairing proteostasis, with oxidative phosphorylation metabolism being a central target of the UPRmt. Transcriptome analyses together with MitoPQ reveal that UPRmt transcription factors drive independent signaling arms that act in concert to maintain proteostasis. Unidirectional interplay between the UPRmt and PINK1/Parkin mitophagy was found to promote oxidative phosphorylation recovery when the UPRmt failed. Collectively, this study defines the network of proteostasis mediated by the UPRmt and highlights the value of functional proteomics in decoding stressed proteomes.
    DOI:  https://doi.org/10.1126/sciadv.adh8228
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