bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2024‒02‒25
fourteen papers selected by
Omkar Joshi, Turku Bioscience
  1. Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.
  2. Gonococcal OMV-delivered PorB induces epithelial cell mitophagy.
  3. Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
  4. GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells.
  5. HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia.
  6. Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
  7. Identification of myoferlin as a mitochondria-associated membranes component required for calcium signaling in PDAC cell lines.
  8. Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
  9. Mechanism and role of mitophagy in the development of severe infection.
  10. Impaired Mitochondrial Network Morphology and Reactive Oxygen Species Production in Fibroblasts from Parkinson's Disease Patients.
  11. ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.
  12. Recent advances in FRET probes for mitochondrial imaging and sensing.
  13. Electrical stimulation enhances mitochondrial trafficking as a neuroprotective mechanism against chemotherapy-induced peripheral neuropathy.
  14. Proteins that carry dual targeting signals can act as tethers between peroxisomes and partner organelles.
  1. Proc Natl Acad Sci U S A. 2024 Feb 27. 121(9): e2311160121
    Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.
    Rui Wang, Huan Lei, Hongxiang Wang, Lei Qi, Yu'e Liu, Yunhui Liu, Yufeng Shi, Juxiang Chen, Qing-Tao Shen.
      Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.
    Keywords:  cryo-electron tomography; glioblastoma; mitochondria; organelle crosstalk
    DOI:  https://doi.org/10.1073/pnas.2311160121
  2. Nat Commun. 2024 Feb 23. 15(1): 1669
    Gonococcal OMV-delivered PorB induces epithelial cell mitophagy.
    Shuai Gao, Lingyu Gao, Dailin Yuan, Xu'ai Lin, Stijn van der Veen.
      The bacterial pathogen Neisseria gonorrhoeae is able to invade epithelial cells and survive intracellularly. During this process, it secretes outer membrane vesicles (OMVs), however, the mechanistic details for interactions between gonococcal OMVs and epithelial cells and their impact on intracellular survival are currently not established. Here, we show that gonococcal OMVs induce epithelial cell mitophagy to reduce mitochondrial secretion of reactive oxygen species (ROS) and enhance intracellular survival. We demonstrate that OMVs deliver PorB to mitochondria to dissipate the mitochondrial membrane potential, resulting in mitophagy induction through a conventional PINK1 and OPTN/NDP52 mechanism. Furthermore, PorB directly recruits the E3 ubiquitin ligase RNF213, which decorates PorB lysine residue 171 with K63-linked polyubiquitin to induce mitophagy in a p62-dependent manner. These results demonstrate a mechanism in which polyubiquitination of a bacterial virulence factor that targets mitochondria directs mitophagy processes to this organelle to prevent its secretion of deleterious ROS.
    DOI:  https://doi.org/10.1038/s41467-024-45961-1
  3. Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00133-5. [Epub ahead of print]43(3): 113805
    Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
    Jon V Busto, Iniyan Ganesan, Hannah Mathar, Conny Steiert, Eva F Schneider, Sebastian P Straub, Lars Ellenrieder, Jiyao Song, Sebastian B Stiller, Philipp Lübbert, Ritwika Chatterjee, Jana Elsaesser, Laura Melchionda, Christina Schug, Fabian den Brave, Uwe Schulte, Till Klecker, Claudine Kraft, Bernd Fakler, Thomas Becker, Nils Wiedemann.
      The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.
    Keywords:  CP: Cell biology; ERMES complex; Mdm10; SAM complex; TOM complex; mitochondria; outer membrane; protein import; protein translocation; β-barrel protein
    DOI:  https://doi.org/10.1016/j.celrep.2024.113805
  4. Cells. 2024 Feb 08. pii: 316. [Epub ahead of print]13(4):
    GOLPH3 Participates in Mitochondrial Fission and Is Necessary to Sustain Bioenergetic Function in MDA-MB-231 Breast Cancer Cells.
    Catalina M Polanco, Viviana A Cavieres, Abigail J Galarza, Claudia Jara, Angie K Torres, Jorge Cancino, Manuel Varas-Godoy, Patricia V Burgos, Cheril Tapia-Rojas, Gonzalo A Mardones.
      In this study, we investigated the inter-organelle communication between the Golgi apparatus (GA) and mitochondria. Previous observations suggest that GA-derived vesicles containing phosphatidylinositol 4-phosphate (PI(4)P) play a role in mitochondrial fission, colocalizing with DRP1, a key protein in this process. However, the functions of these vesicles and potentially associated proteins remain unknown. GOLPH3, a PI(4)P-interacting GA protein, is elevated in various types of solid tumors, including breast cancer, yet its precise role is unclear. Interestingly, GOLPH3 levels influence mitochondrial mass by affecting cardiolipin synthesis, an exclusive mitochondrial lipid. However, the mechanism by which GOLPH3 influences mitochondria is not fully understood. Our live-cell imaging analysis showed GFP-GOLPH3 associating with PI(4)P vesicles colocalizing with YFP-DRP1 at mitochondrial fission sites. We tested the functional significance of these observations with GOLPH3 knockout in MDA-MB-231 cells of breast cancer, resulting in a fragmented mitochondrial network and reduced bioenergetic function, including decreased mitochondrial ATP production, mitochondrial membrane potential, and oxygen consumption. Our findings suggest a potential negative regulatory role for GOLPH3 in mitochondrial fission, impacting mitochondrial function and providing insights into GA-mitochondria communication.
    Keywords:  DRP1; GOLPH3; Golgi apparatus; Golgi–mitochondria communication; PI(4)P; mitochondrial bioenergetics; mitochondrial fission and fusion; mitochondrial fragmentation
    DOI:  https://doi.org/10.3390/cells13040316
  5. Cell Death Dis. 2024 Feb 20. 15(2): 155
    HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia.
    Mengjia Jing, Xiaofeng Xiong, Xin Mao, Qianben Song, Lumiao Zhang, Yiming Ouyang, Yingzhi Pang, Yu Fu, Wei Yan.
      Mitochondrial transfer plays an important role in various diseases, and many mitochondrial biological functions can be regulated by HMGB1. To explore the role of mitochondrial transfer in hepatocellular carcinoma (HCC) and its relationship with HMGB1, field emission scanning electron microscopy, immunofluorescence, and flow cytometry were used to detect the mitochondrial transfer between HCC cells. We found that mitochondrial transfer between HCC cells was confirmed using tunnel nanotubes (TNTs). The transfer of mitochondria from the highly invasive HCC cells to the less invasive HCC cells could enhance the migration and invasion ability of the latter. The hypoxic conditions increased the mitochondrial transfer between HCC cells. Then the mechanism was identified using co-immunoprecipitation, luciferase reporter assay, and chromatin immunoprecipitation. We found that RHOT1, a mitochondrial transport protein, promoted mitochondrial transfer and the migration and metastasis of HCC cells during this process. Under hypoxia, HMGB1 further regulated RHOT1 expression by increasing the expression of NFYA and NFYC subunits of the NF-Y complex. RAC1, a protein associated with TNTs formation, promoted mitochondrial transfer and HCC development. Besides, HMGB1 regulated RAC1 aggregation to the cell membrane under hypoxia. Finally, the changes and significance of related molecules in clinical samples of HCC were analyzed using bioinformatics and tissue microarray analyses. We found that HCC patients with high HMGB1, RHOT1, or RAC1 expression exhibited a relatively shorter overall survival period. In conclusion, under hypoxic conditions, HMGB1 promoted mitochondrial transfer and migration and invasion of HCC cells by increasing the expression of mitochondrial transport protein RHOT1 and TNTs formation-related protein RAC1.
    DOI:  https://doi.org/10.1038/s41419-024-06536-6
  6. Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772
    Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
    Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.
      The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.
    Keywords:  CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain
    DOI:  https://doi.org/10.1016/j.celrep.2024.113772
  7. Cell Commun Signal. 2024 Feb 17. 22(1): 133
    Identification of myoferlin as a mitochondria-associated membranes component required for calcium signaling in PDAC cell lines.
    Sandy Anania, Martin Farnir, Raphaël Peiffer, Yasmine Boumahd, Marc Thiry, Ferman Agirman, Naima Maloujahmoum, Akeila Bellahcène, Olivier Peulen.
      BACKGROUND: Pancreatic ductal adenocarcinoma is an aggressive cancer type with one of the lowest survival rates due to late diagnosis and the absence of effective treatments. A better understanding of PDAC biology will help researchers to discover the Achilles' heel of cancer cells. In that regard, our research team investigated the function of an emerging oncoprotein known as myoferlin. Myoferlin is overexpressed in PDAC and its silencing/targeting has been shown to affect cancer cell proliferation, migration, mitochondrial dynamics and metabolism. Nevertheless, our comprehension of myoferlin functions in cells remains limited. In this study, we aimed to understand the molecular mechanism linking myoferlin silencing to mitochondrial dynamics.METHODS: Experiments were performed on two pancreas cancer cell lines, Panc-1 and MiaPaCa-2. Myoferlin localization on mitochondria was evaluated by immunofluorescence, proximity ligation assay, and cell fractionation. The presence of myoferlin in mitochondria-associated membranes was assessed by cell fractionation and its function in mitochondrial calcium transfer was evaluated using calcium flow experiments, proximity ligation assays, co-immunoprecipitation, and timelapse fluorescence microscopy in living cells.
    RESULTS: Myoferlin localization on mitochondria was investigated. Our results suggest that myoferlin is unlikely to be located on mitochondria. Instead, we identified myoferlin as a new component of mitochondria-associated membranes. Its silencing significantly reduces the mitochondrial calcium level upon stimulation, probably through myoferlin interaction with the inositol 1,4,5-triphosphate receptors 3.
    CONCLUSIONS: For the first time, myoferlin was specifically demonstrated to be located in mitochondria-associated membranes where it participates to calcium flow. We hypothesized that this function explains our previous results on mitochondrial dynamics. This study improves our comprehension of myoferlin localization and function in cancer biology.
    Keywords:  Calcium signaling; ER-mitochondria contact sites; IP3R3; Mitochondria; Mitochondria-associated membranes; Myoferlin; Pancreatic cancer
    DOI:  https://doi.org/10.1186/s12964-024-01514-z
  8. Cell Death Differ. 2024 Feb 23.
    Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
    Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.
      During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.
    DOI:  https://doi.org/10.1038/s41418-024-01260-2
  9. Cell Death Discov. 2024 Feb 19. 10(1): 88
    Mechanism and role of mitophagy in the development of severe infection.
    Lixiu Ma, Tianyu Han, Yi-An Zhan.
      Mitochondria produce adenosine triphosphate and potentially contribute to proinflammatory responses and cell death. Mitophagy, as a conservative phenomenon, scavenges waste mitochondria and their components in the cell. Recent studies suggest that severe infections develop alongside mitochondrial dysfunction and mitophagy abnormalities. Restoring mitophagy protects against excessive inflammation and multiple organ failure in sepsis. Here, we review the normal mitophagy process, its interaction with invading microorganisms and the immune system, and summarize the mechanism of mitophagy dysfunction during severe infection. We highlight critical role of normal mitophagy in preventing severe infection.
    DOI:  https://doi.org/10.1038/s41420-024-01844-4
  10. Biomedicines. 2024 Jan 25. pii: 282. [Epub ahead of print]12(2):
    Impaired Mitochondrial Network Morphology and Reactive Oxygen Species Production in Fibroblasts from Parkinson's Disease Patients.
    Kristina A Kritskaya, Evgeniya I Fedotova, Alexey V Berezhnov.
      The mitochondrial network (MN) is a dynamic structure undergoing constant remodeling in the cell. It is assumed that perturbations to the MN may be associated with various pathologies, including Parkinson's disease (PD). Using automatic image analysis and super-resolution microscopy, we have assessed the MN parameters in fibroblasts from patients with established hereditary PD mutations (associated with PINK1, LRRK2, and α-synuclein, as well as PINK1 and Parkin proteins simultaneously) under normal conditions and after hydrogen peroxide-induced stress. Fibroblasts with the Pink1/Parkin mutation are most different in morphology to fibroblasts obtained from conditionally healthy donors: the MN is larger, and it contains longer mitochondria and accumulated individual mitochondria. In addition to MN, we evaluated other cellular parameters, such as cytosolic and mitochondrial ROS production and mitochondrial membrane potential. It has been shown that mitochondria of fibroblasts with mutations in genes encoding PINK1, α-synuclein, and Pink/Parkin tend towards hyperpolarization and cytosolic ROS overproduction, while mitochondrial ROS production was higher only in fibroblasts with PINK1 and α-synuclein mutations.
    Keywords:  Parkinson’s disease; fibroblasts; mitochondrial network; super-resolution microscopy
    DOI:  https://doi.org/10.3390/biomedicines12020282
  11. Nat Commun. 2024 Feb 17. 15(1): 1460
    ALLO-1- and IKKE-1-dependent positive feedback mechanism promotes the initiation of paternal mitochondrial autophagy.
    Taeko Sasaki, Yasuharu Kushida, Takuya Norizuki, Hidetaka Kosako, Ken Sato, Miyuki Sato.
      Allophagy is responsible for the selective removal of paternally inherited organelles, including mitochondria, in Caenorhabditis elegans embryos, thereby facilitating the maternal inheritance of mitochondrial DNA. We previously identified two key factors in allophagy: an autophagy adaptor allophagy-1 (ALLO-1) and TBK1/IKKε family kinase IKKE-1. However, the precise mechanisms by which ALLO-1 and IKKE-1 regulate local autophagosome formation remain unclear. In this study, we identify two ALLO-1 isoforms with different substrate preferences during allophagy. Live imaging reveals a stepwise mechanism of ALLO-1 localization with rapid cargo recognition, followed by ALLO-1 accumulation around the cargo. In the ikke-1 mutant, the accumulation of ALLO-1, and not the recognition of cargo, is impaired, resulting in the failure of isolation membrane formation. Our results also suggest a feedback mechanism for ALLO-1 accumulation via EPG-7/ATG-11, a worm homolog of FIP200, which is a candidate for IKKE-1-dependent phosphorylation. This feedback mechanism may underlie the ALLO-1-dependent initiation and progression of autophagosome formation around paternal organelles.
    DOI:  https://doi.org/10.1038/s41467-024-45863-2
  12. Chem Commun (Camb). 2024 Feb 21.
    Recent advances in FRET probes for mitochondrial imaging and sensing.
    Fei Peng, Xiangnan Ai, Jing Sun, Linshuai Yang, Baoxiang Gao.
      Mitochondria, as essential organelles in cells, play a crucial role in cellular growth and apoptosis. Monitoring mitochondria is of great importance, as mitochondrial dysfunction is often considered a hallmark event of cell apoptosis. Traditional fluorescence probes used for mitochondrial imaging and sensing are mostly intensity-based and are susceptible to factors such as concentration, the probe environment, and fluorescence intensity. Probes based on fluorescence resonance energy transfer (FRET) can effectively overcome external interference and achieve high-contrast imaging of mitochondria as well as quantitative monitoring of mitochondrial microenvironments. This review focuses on recent advances in the application of FRET-based probes for mitochondrial structure imaging and microenvironment sensing.
    DOI:  https://doi.org/10.1039/d4cc00018h
  13. iScience. 2024 Mar 15. 27(3): 109052
    Electrical stimulation enhances mitochondrial trafficking as a neuroprotective mechanism against chemotherapy-induced peripheral neuropathy.
    Bayne Albin, Prashant Adhikari, Arjun Prasad Tiwari, Khayzaran Qubbaj, In Hong Yang.
      Electrical stimulation (ESTIM) has shown to be an effective symptomatic treatment to treat pain associated with peripheral nerve damage. However, the neuroprotective mechanism of ESTIM on peripheral neuropathies is still unknown. In this study, we identified that ESTIM has the ability to enhance mitochondrial trafficking as a neuroprotective mechanism against chemotherapy-induced peripheral neuropathies (CIPNs). CIPN is a debilitating and painful sequalae of anti-cancer chemotherapy treatment which results in degeneration of peripheral nerves. Mitochondrial dynamics were analyzed within axons in response to two different antineoplastic mechanisms by chemotherapy drug treatments paclitaxel and oxaliplatin in vitro. Mitochondrial trafficking response to chemotherapy drug treatment was observed to decrease in conjunction with degeneration of distal axons. Using low-frequency ESTIM, we observed enhanced mitochondrial trafficking to be a neuroprotective mechanism against CIPN. This study confirms ESTIM enhances regeneration of peripheral nerves by increased mitochondrial trafficking.
    Keywords:  Biochemistry; Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2024.109052
  14. PLoS Biol. 2024 Feb 20. 22(2): e3002508
    Proteins that carry dual targeting signals can act as tethers between peroxisomes and partner organelles.
    Elena Bittner, Thorsten Stehlik, Jason Lam, Lazar Dimitrov, Thomas Heimerl, Isabelle Schöck, Jannik Harberding, Anita Dornes, Nikola Heymons, Gert Bange, Maya Schuldiner, Einat Zalckvar, Michael Bölker, Randy Schekman, Johannes Freitag.
      Peroxisomes are organelles with crucial functions in oxidative metabolism. To correctly target to peroxisomes, proteins require specialized targeting signals. A mystery in the field is the sorting of proteins that carry a targeting signal for peroxisomes and as well as for other organelles, such as mitochondria or the endoplasmic reticulum (ER). Exploring several of these proteins in fungal model systems, we observed that they can act as tethers bridging organelles together to create contact sites. We show that in Saccharomyces cerevisiae this mode of tethering involves the peroxisome import machinery, the ER-mitochondria encounter structure (ERMES) at mitochondria and the guided entry of tail-anchored proteins (GET) pathway at the ER. Our findings introduce a previously unexplored concept of how dual affinity proteins can regulate organelle attachment and communication.
    DOI:  https://doi.org/10.1371/journal.pbio.3002508
This page is being maintained by Thomas Krichel. It was last updated on 2024‒02‒27 at 14:29.