bims-mitdyn Biomed News
on Mitochondrial dynamics: mechanisms
Issue of 2023‒09‒24
ten papers selected by
Edmond Chan, Queen’s University, School of Medicine
  1. Manipulating mitochondrial electron flow enhances tumor immunogenicity.
  2. Temporal landscape of mitochondrial proteostasis governed by the UPRmt.
  3. Mitochondria-ER contact mediated by MFN2-SERCA2 interaction supports CD8+ T cell metabolic fitness and function in tumors.
  4. Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.
  5. Molecular basis for maternal inheritance of human mitochondrial DNA.
  6. Efficient intervention for pulmonary fibrosis via mitochondrial transfer promoted by mitochondrial biogenesis.
  7. Protocol for real-time imaging of membrane fission by mitofissin.
  8. Mitochondrial network adaptations of microglia reveal sex-specific stress response after injury and UCP2 knockout.
  9. Selective retention of dysfunctional mitochondria during asymmetric cell division in yeast.
  10. Metabolic control of antitumor immunity.
  1. Science. 2023 Sep 22. 381(6664): 1316-1323
    Manipulating mitochondrial electron flow enhances tumor immunogenicity.
    Kailash Chandra Mangalhara, Siva Karthik Varanasi, Melissa A Johnson, Mannix J Burns, Gladys R Rojas, Pau B Esparza Moltó, Alva G Sainz, Nimesha Tadepalle, Keene L Abbott, Gaurav Mendiratta, Dan Chen, Yagmur Farsakoglu, Tenzin Kunchok, Filipe Araujo Hoffmann, Bianca Parisi, Mercedes Rincon, Matthew G Vander Heiden, Marcus Bosenberg, Diana C Hargreaves, Susan M Kaech, Gerald S Shadel.
      Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
    DOI:  https://doi.org/10.1126/science.abq1053
  2. 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
  3. 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
  4. Proc Natl Acad Sci U S A. 2023 Sep 26. 120(39): e2304884120
    Coenzyme Q10 trapping in mitochondrial complex I underlies Leber's hereditary optic neuropathy.
    Jack T Fuller, Steven Barnes, Lorenzo A Sadun, Pujan Ajmera, Anastassia N Alexandrova, Alfredo A Sadun.
      How does a single amino acid mutation occurring in the blinding disease, Leber's hereditary optic neuropathy (LHON), impair electron shuttling in mitochondria? We investigated changes induced by the m.3460 G>A mutation in mitochondrial protein ND1 using the tools of Molecular Dynamics and Free Energy Perturbation simulations, with the goal of determining the mechanism by which this mutation affects mitochondrial function. A recent analysis suggested that the mutation's replacement of alanine A52 with a threonine perturbs the stability of a region where binding of the electron shuttling protein, Coenzyme Q10, occurs. We found two functionally opposing changes involving the role of Coenzyme Q10. The first showed that quantum electron transfer from the terminal Fe/S complex, N2, to the Coenzyme Q10 headgroup, docked in its binding pocket, is enhanced. However, this positive adjustment is overshadowed by our finding that the mobility of Coenzyme Q10 in its oxidized and reduced states, entering and exiting its binding pocket, is disrupted by the mutation in a manner that leads to conditions promoting the generation of reactive oxygen species. An increase in reactive oxygen species caused by the LHON mutation has been proposed to be responsible for this optic neuropathy.
    Keywords:  Coenzyme Q10; blinding genetic disease; mitochondria; molecular dynamics simulation; quantum electron tunneling
    DOI:  https://doi.org/10.1073/pnas.2304884120
  5. Nat Genet. 2023 Sep 18.
    Molecular basis for maternal inheritance of human mitochondrial DNA.
    William Lee, Angelica Zamudio-Ochoa, Gina Buchel, Petar Podlesniy, Nuria Marti Gutierrez, Margalida Puigròs, Anna Calderon, Hsin-Yao Tang, Li Li, Aleksei Mikhalchenko, Amy Koski, Ramon Trullas, Shoukhrat Mitalipov, Dmitry Temiakov.
      Uniparental inheritance of mitochondrial DNA (mtDNA) is an evolutionary trait found in nearly all eukaryotes. In many species, including humans, the sperm mitochondria are introduced to the oocyte during fertilization1,2. The mechanisms hypothesized to prevent paternal mtDNA transmission include ubiquitination of the sperm mitochondria and mitophagy3,4. However, the causative mechanisms of paternal mtDNA elimination have not been defined5,6. We found that mitochondria in human spermatozoa are devoid of intact mtDNA and lack mitochondrial transcription factor A (TFAM)-the major nucleoid protein required to protect, maintain and transcribe mtDNA. During spermatogenesis, sperm cells express an isoform of TFAM, which retains the mitochondrial presequence, ordinarily removed upon mitochondrial import. Phosphorylation of this presequence prevents mitochondrial import and directs TFAM to the spermatozoon nucleus. TFAM relocalization from the mitochondria of spermatogonia to the spermatozoa nucleus directly correlates with the elimination of mtDNA, thereby explaining maternal inheritance in this species.
    DOI:  https://doi.org/10.1038/s41588-023-01505-9
  6. 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
  7. 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
  8. 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
  9. 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
  10. Science. 2023 Sep 22. 381(6664): 1287-1288
    Metabolic control of antitumor immunity.
    Andromachi Pouikli, Christian Frezza.
      Mitochondrial metabolite reduces melanoma growth by boosting antigen presentation.
    DOI:  https://doi.org/10.1126/science.adk1785
This page is being maintained by Thomas Krichel. It was last updated on 2023‒09‒25 at 19:59.