bims-midtic Biomed News
on Mitochondrial dynamics and trafficking in cells
Issue of 2024‒04‒07
fourteen papers selected by
Omkar Joshi, Turku Bioscience
  1. Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.
  2. The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
  3. Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.
  4. The dynamin-related protein Dyn2 is essential for both apicoplast and mitochondrial fission in Plasmodium falciparum.
  5. Intertwined relationship of dynamin-related protein 1, mitochondrial metabolism and circadian rhythm.
  6. Myosin A and F-Actin play a critical role in mitochondrial dynamics and inheritance in Toxoplasma gondii.
  7. Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
  8. Membrane fission via transmembrane contact.
  9. Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes.
  10. An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections.
  11. PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
  12. AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis.
  13. Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.
  14. Homocysteine-induced sustained GluN2A NMDA receptor stimulation leads to mitochondrial ROS generation and neurotoxicity.
  1. bioRxiv. 2024 Mar 22. pii: 2024.03.21.586162. [Epub ahead of print]
    Human CCDC51 and yeast Mdm33 are functionally conserved mitochondrial inner membrane proteins that demarcate a subset of organelle fission events.
    Alia R Edington, Olivia M Connor, Madeleine Marlar-Pavey, Jonathan R Friedman.
      Mitochondria are highly dynamic double membrane-bound organelles that exist in a semi- continuous network. Mitochondrial morphology arises from the complex interplay of numerous processes, including opposing fission and fusion dynamics and the formation of highly organized cristae invaginations of the inner membrane. While extensive work has examined the mechanisms of mitochondrial fission, it remains unclear how fission is coordinated across two membrane bilayers and how mitochondrial inner membrane organization is coupled with mitochondrial fission dynamics. Previously, the yeast protein Mdm33 was implicated in facilitating fission by coordinating with inner membrane homeostasis pathways. However, Mdm33 is not conserved outside fungal species and its precise mechanistic role remains unclear. Here, we use a bioinformatic approach to identify a putative structural ortholog of Mdm33 in humans, CCDC51 (also called MITOK). We find that the mitochondrial phenotypes associated with altered CCDC51 levels implicate the protein in mitochondrial fission dynamics. Further, using timelapse microscopy, we spatially and temporally resolve Mdm33 and CCDC51 to a subset of mitochondrial fission events. Finally, we show that CCDC51 can partially rescue yeast Δ mdm33 cells, indicating the proteins are functionally analogous. Our data reveal that Mdm33/CCDC51 are conserved mediators of mitochondrial morphology and suggest the proteins play a crucial role in maintaining normal mitochondrial dynamics and organelle homeostasis.
    DOI:  https://doi.org/10.1101/2024.03.21.586162
  2. EMBO Rep. 2024 Apr 02.
    The ER-SURF pathway uses ER-mitochondria contact sites for protein targeting to mitochondria.
    Christian Koch, Svenja Lenhard, Markus Räschle, Cristina Prescianotto-Baschong, Anne Spang, Johannes M Herrmann.
      Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis.
    Keywords:  Contact sites; ERMES; Endoplasmic reticulum; Mitochondria; Protein import
    DOI:  https://doi.org/10.1038/s44319-024-00113-w
  3. Acta Pharmacol Sin. 2024 Apr 02.
    Decreasing mitochondrial fission ameliorates HIF-1α-dependent pathological retinal angiogenesis.
    Shu-Qi Huang, Kai-Xiang Cao, Cai-Ling Wang, Pei-Ling Chen, Yi-Xin Chen, Yu-Ting Zhang, Shi-Hui Yu, Zai-Xia Bai, Shuai Guo, Mu-Xi Liao, Qiao-Wen Li, Guo-Qi Zhang, Jun He, Yi-Ming Xu.
      Angiogenesis plays a critical role in many pathological processes, including irreversible blindness in eye diseases such as retinopathy of prematurity. Endothelial mitochondria are dynamic organelles that undergo constant fusion and fission and are critical signalling hubs that modulate angiogenesis by coordinating reactive oxygen species (ROS) production and calcium signalling and metabolism. In this study, we investigated the role of mitochondrial dynamics in pathological retinal angiogenesis. We showed that treatment with vascular endothelial growth factor (VEGF; 20 ng/ml) induced mitochondrial fission in HUVECs by promoting the phosphorylation of dynamin-related protein 1 (DRP1). DRP1 knockdown or pretreatment with the DRP1 inhibitor Mdivi-1 (5 μM) blocked VEGF-induced cell migration, proliferation, and tube formation in HUVECs. We demonstrated that VEGF treatment increased mitochondrial ROS production in HUVECs, which was necessary for HIF-1α-dependent glycolysis, as well as proliferation, migration, and tube formation, and the inhibition of mitochondrial fission prevented VEGF-induced mitochondrial ROS production. In an oxygen-induced retinopathy (OIR) mouse model, we found that active DRP1 was highly expressed in endothelial cells in neovascular tufts. The administration of Mdivi-1 (10 mg·kg-1·d-1, i.p.) for three days from postnatal day (P) 13 until P15 significantly alleviated pathological angiogenesis in the retina. Our results suggest that targeting mitochondrial fission may be a therapeutic strategy for proliferative retinopathies and other diseases that are dependent on pathological angiogenesis.
    Keywords:  Dynamin-related protein 1; Mdivi-1; ROS.; glycolysis; mitochondrial fission; pathological angiogenesis
    DOI:  https://doi.org/10.1038/s41401-024-01262-3
  4. bioRxiv. 2024 Mar 17. pii: 2024.03.15.585229. [Epub ahead of print]
    The dynamin-related protein Dyn2 is essential for both apicoplast and mitochondrial fission in Plasmodium falciparum.
    Alexander A Morano, Wei Xu, Neeta Shadija, Jeffrey D Dvorin, Hangjun Ke.
      Dynamins, or dynamin-related proteins (DRPs), are large mechano-sensitive GTPases mediating membrane dynamics or organellar fission/fusion events. Plasmodium falciparum encodes three dynamin-like proteins whose functions are poorly understood. Here, we demonstrate that PfDyn2 mediates both apicoplast and mitochondrial fission. Using super-resolution and ultrastructure expansion microscopy, we show that PfDyn2 is expressed in the schizont stage and localizes to both the apicoplast and mitochondria. Super-resolution long-term live cell microscopy shows that PfDyn2-deficient parasites cannot complete cytokinesis because the apicoplast and mitochondria do not undergo fission. Further, the basal complex or cytokinetic ring in Plasmodium cannot fully contract upon PfDyn2 depletion, a phenotype secondary to physical blockage of undivided organelles in the middle of the ring. Our data suggest that organellar fission defects result in aberrant schizogony, generating unsuccessful merozoites. The unique biology of PfDyn2, mediating both apicoplast and mitochondrial fission, has not been observed in other organisms possessing two endosymbiotic organelles.Highlights: PfDyn2 is essential for schizont-stage development.PfDyn2 mediates both apicoplast and mitochondrial fission.Deficiency of PfDyn2 leads to organellar fission failures and blockage of basal complex contraction.Addition of apicoplast-derived metabolite IPP does not rescue the growth defects.
    DOI:  https://doi.org/10.1101/2024.03.15.585229
  5. Mol Biol Rep. 2024 Apr 05. 51(1): 488
    Intertwined relationship of dynamin-related protein 1, mitochondrial metabolism and circadian rhythm.
    Indrani Paramasivan Latha Laxmi, Anica Tholath Job, Venkatraman Manickam, Ramasamy Tamizhselvi.
      In recent years, mitochondria have gained significant interest in the field of biomedical research due to their impact on human health and ageing. As mitochondrial dynamics are strongly controlled by clock genes, misalignment of the circadian rhythm leads to adverse metabolic health effects. In this review, by exploring various aspects of research and potential links, we hope to update the current understanding of the intricate relationship between DRP1-mediated mitochondrial dynamics and changes in circadian rhythmicity leading to health issues. Thus, this review addresses the potential bidirectional relationships between DRP1-linked mitochondrial function and circadian rhythm misalignment, their impact on different metabolic pathways, and the potential therapeutics for metabolic and systemic disorders.
    Keywords:  Brain and muscle ARNT-like 1; Circadian locomotor output cycles Kaput; Dynamin-related protein 1; Inflammation; Mitochondrial fission
    DOI:  https://doi.org/10.1007/s11033-024-09430-8
  6. bioRxiv. 2024 Mar 18. pii: 2024.03.18.585462. [Epub ahead of print]
    Myosin A and F-Actin play a critical role in mitochondrial dynamics and inheritance in Toxoplasma gondii.
    Rodolpho Ornitz Oliveira Souza, Chunlin Yang, Gustavo Arrizabalaga.
      The single mitochondrion of the obligate intracellular parasite Toxoplasma gondii is highly dynamic. Toxoplasma's mitochondrion changes morphology as the parasite moves from the intracellular to the extracellular environment and during division. Toxoplasma's mitochondrial dynamic is dependent on an outer mitochondrion membrane-associated protein LMF1 and its interaction with IMC10, a protein localized at the inner membrane complex (IMC). In the absence of either LMF1 or IMC10, parasites have defective mitochondrial morphology and inheritance defects. As little is known about mitochondrial inheritance in Toxoplasma , we have used the LMF1/IMC10 tethering complex as an entry point to dissect the machinery behind this process. Using a yeast two-hybrid screen, we previously identified Myosin A (MyoA) as a putative interactor of LMF1. Although MyoA is known to be located at the parasite's pellicle, we now show through ultrastructure expansion microscopy (U-ExM) that this protein accumulates around the mitochondrion in the late stages of parasite division. Parasites lacking MyoA show defective mitochondrial morphology and a delay in mitochondrion delivery to the daughter parasite buds during division, indicating that this protein is involved in organellar inheritance. Disruption of the parasite's actin network also affects mitochondrion morphology. We also show that parasite-extracted mitochondrion vesicles interact with actin filaments. Interestingly, mitochondrion vesicles extracted out of parasites lacking LMF1 pulled down less actin, showing that LMF1 might be important for mitochondrion and actin interaction. Accordingly, we are showing for the first time that actin and Myosin A are important for Toxoplasma mitochondrial morphology and inheritance.
    DOI:  https://doi.org/10.1101/2024.03.18.585462
  7. Sci Adv. 2024 Apr 05. 10(14): eadl0389
    Drp1 controls complex II assembly and skeletal muscle metabolism by Sdhaf2 action on mitochondria.
    Zhenqi Zhou, Alice Ma, Timothy M Moore, Dane M Wolf, Nicole Yang, Peter Tran, Mayuko Segawa, Alexander R Strumwasser, Wenjuan Ren, Kai Fu, Jonathan Wanagat, Alexander M van der Bliek, Rachelle Crosbie-Watson, Marc Liesa, Linsey Stiles, Rebecca Acin-Perez, Sushil Mahata, Orian Shirihai, Mark O Goodarzi, Michal Handzlik, Christian M Metallo, David W Walker, Andrea L Hevener.
      The dynamin-related guanosine triphosphatase, Drp1 (encoded by Dnm1l), plays a central role in mitochondrial fission and is requisite for numerous cellular processes; however, its role in muscle metabolism remains unclear. Here, we show that, among human tissues, the highest number of gene correlations with DNM1L is in skeletal muscle. Knockdown of Drp1 (Drp1-KD) promoted mitochondrial hyperfusion in the muscle of male mice. Reduced fatty acid oxidation and impaired insulin action along with increased muscle succinate was observed in Drp1-KD muscle. Muscle Drp1-KD reduced complex II assembly and activity as a consequence of diminished mitochondrial translocation of succinate dehydrogenase assembly factor 2 (Sdhaf2). Restoration of Sdhaf2 normalized complex II activity, lipid oxidation, and insulin action in Drp1-KD myocytes. Drp1 is critical in maintaining mitochondrial complex II assembly, lipid oxidation, and insulin sensitivity, suggesting a mechanistic link between mitochondrial morphology and skeletal muscle metabolism, which is clinically relevant in combatting metabolic-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.adl0389
  8. Nat Commun. 2024 Mar 30. 15(1): 2793
    Membrane fission via transmembrane contact.
    Russell K W Spencer, Isaac Santos-Pérez, Izaro Rodríguez-Renovales, Juan Manuel Martinez Galvez, Anna V Shnyrova, Marcus Müller.
      Division of intracellular organelles often correlates with additional membrane wrapping, e.g., by the endoplasmic reticulum or the outer mitochondrial membrane. Such wrapping plays a vital role in proteome and lipidome organization. However, how an extra membrane impacts the mechanics of the division has not been investigated. Here we combine fluorescence and cryo-electron microscopy experiments with self-consistent field theory to explore the stress-induced instabilities imposed by membrane wrapping in a simple double-membrane tubular system. We find that, at physiologically relevant conditions, the outer membrane facilitates an alternative pathway for the inner-tube fission through the formation of a transient contact (hemi-fusion) between both membranes. A detailed molecular theory of the fission pathways in the double membrane system reveals the topological complexity of the process, resulting both in leaky and leakless intermediates, with energies and topologies predicting physiological events.
    DOI:  https://doi.org/10.1038/s41467-024-47122-w
  9. JACC Basic Transl Sci. 2024 Mar;9(3): 303-318
    Small Molecule Activators of Mitochondrial Fusion Prevent Congenital Heart Defects Induced by Maternal Diabetes.
    Guanglei Wang, Wenhui Lu, Wei-Bin Shen, Mariusz Karbowski, Sunjay Kaushal, Peixin Yang.
      Most congenital heart defect (CHD) cases are attributed to nongenetic factors; however, the mechanisms underlying nongenetic factor-induced CHDs are elusive. Maternal diabetes is one of the nongenetic factors, and this study aimed to determine whether impaired mitochondrial fusion contributes to maternal diabetes-induced CHDs and if mitochondrial fusion activators, teriflunomide and echinacoside, could reduce CHD incidence in diabetic pregnancy. We demonstrated maternal diabetes-activated FoxO3a increases miR-140 and miR-195, which in turn represses Mfn1 and Mfn2, leading to mitochondrial fusion defects and CHDs. Two mitochondrial fusion activators are effective in preventing CHDs in diabetic pregnancy.
    Keywords:  congenital heart defect; maternal diabetes; microRNA; mitochondrial fusion; mitofusin 1; mitofusin 2
    DOI:  https://doi.org/10.1016/j.jacbts.2023.11.008
  10. J Cancer Res Clin Oncol. 2024 Apr 03. 150(4): 172
    An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections.
    Mai Sakashita, Noriko Motoi, Gaku Yamamoto, Emi Gambe, Masanori Suzuki, Yukihiro Yoshida, Shun-Ichi Watanabe, Yutaka Takazawa, Kazunori Aoki, Atsushi Ochiai, Shingo Sakashita.
      PURPOSE: Visualizing mitochondria in cancer cells from human pathological specimens may improve our understanding of cancer biology. However, using immunohistochemistry to evaluate mitochondria remains difficult because almost all cells contain mitochondria and the number of mitochondria per cell may have important effects on mitochondrial function. Herein, we established an objective system (Mito-score) for evaluating mitochondria using machine-based processing of hue, saturation, and value color spaces.METHODS: The Mito-score was defined as the number of COX4 (mitochondrial inner membrane) immunohistochemistry-positive pixels divided by the number of nuclei per cell. The system was validated using four lung cancer cell lines, normal tissues, and lung cancer tissues (199 cases).
    RESULTS: The Mito-score correlated with MitoTracker, a fluorescent dye used to selectively label and visualize mitochondria within cells under a microscope (R2 = 0.68) and with the number of mitochondria counted using electron microscopy (R2 = 0.79). Histologically, the Mito-score of small cell carcinoma (57.25) was significantly lower than that of adenocarcinoma (147.5, p < 0.0001), squamous cell carcinoma (120.6, p = 0.0004), and large cell neuroendocrine carcinoma (111.8, p = 0.002).
    CONCLUSION: The Mito-score method enables the analysis of the mitochondrial status of human formalin-fixed paraffin-embedded specimens and may provide insights into the metabolic status of cancer.
    Keywords:  COX4; Cancer; MitoTracker; Mitochondria
    DOI:  https://doi.org/10.1007/s00432-024-05653-1
  11. Stem Cell Reports. 2024 Mar 26. pii: S2213-6711(24)00079-1. [Epub ahead of print]
    PINK1 deficiency alters muscle stem cell fate decision and muscle regenerative capacity.
    George Cairns, Madhavee Thumiah-Mootoo, Mah Rukh Abbasi, Melissa Gourlay, Jeremy Racine, Nikita Larionov, Alexandre Prola, Mireille Khacho, Yan Burelle.
      Maintenance of mitochondrial function plays a crucial role in the regulation of muscle stem cell (MuSC), but the underlying mechanisms remain ill defined. In this study, we monitored mitophagy in MuSCS under various myogenic states and examined the role of PINK1 in maintaining regenerative capacity. Results indicate that quiescent MuSCs actively express mitophagy genes and exhibit a measurable mitophagy flux and prominent mitochondrial localization to autophagolysosomes, which become rapidly decreased during activation. Genetic disruption of Pink1 in mice reduces PARKIN recruitment to mitochondria and mitophagy in quiescent MuSCs, which is accompanied by premature activation/commitment at the expense of self-renewal and progressive loss of muscle regeneration, but unhindered proliferation and differentiation capacity. Results also show that impaired fate decisions in PINK1-deficient MuSCs can be restored by scavenging excess mitochondrial ROS. These data shed light on the regulation of mitophagy in MuSCs and position PINK1 as an important regulator of their mitochondrial properties and fate decisions.
    Keywords:  fate decision; mitochondria; mitochondrial quality control; mitophagy; muscle regeneration; muscle stem cells
    DOI:  https://doi.org/10.1016/j.stemcr.2024.03.004
  12. iScience. 2024 Apr 19. 27(4): 109321
    AP39 through AMPK-ULK1-FUNDC1 pathway regulates mitophagy, inhibits pyroptosis, and improves doxorubicin-induced myocardial fibrosis.
    Junxiong Zhao, Ting Yang, Jiali Yi, Hongmin Hu, Qi Lai, Liangui Nie, Maojun Liu, Chun Chu, Jun Yang.
      Doxorubicin induces myocardial injury and fibrosis. Still, no effective interventions are available. AP39 is an H2S donor that explicitly targets mitochondria. This study investigated whether AP39 could improve doxorubicin-induced myocardial fibrosis. Doxorubicin induced significant myocardial fibrosis while suppressing mitophagy-related proteins and elevating pyroptosis-related proteins. Conversely, AP39 reverses these effects, enhancing mitophagy and inhibiting pyroptosis. In vitro experiments revealed that AP39 inhibited H9c2 cardiomyocyte pyroptosis, improved doxorubicin-induced impairment of mitophagy, reduced ROS levels, ameliorated the mitochondrial membrane potential, and upregulated AMPK-ULK1-FUNDC1 expression. In contrast, AMPK inhibitor (dorsomorphin) and ULK1 inhibitor (SBI-0206965) reversed AP39 antagonism of doxorubicin-induced FUNDC1-mediated impairment of mitophagy and secondary cardiomyocyte pyroptosis. These results suggest that mitochondria-targeted H2S can antagonize doxorubicin-induced pyroptosis and impaired mitophagy in cardiomyocytes via AMPK-ULK1-FUNDC1 and ameliorated myocardial fibrosis and remodeling.
    Keywords:  Health sciences; Toxic substance; Toxicology
    DOI:  https://doi.org/10.1016/j.isci.2024.109321
  13. Neurotherapeutics. 2024 Apr 04. pii: S1878-7479(24)00041-2. [Epub ahead of print] e00355
    Mitochondrial transplantation exhibits neuroprotective effects and improves behavioral deficits in an animal model of Parkinson's disease.
    Hyeyoon Eo, Shin-Hye Yu, Yujin Choi, Yujin Kim, Young Cheol Kang, Hanbyeol Lee, Jin Hee Kim, Kyuboem Han, Hong Kyu Lee, Mi-Yoon Chang, Myung Sook Oh, Chun-Hyung Kim.
      Mitochondria are essential organelles for cell survival that manage the cellular energy supply by producing ATP. Mitochondrial dysfunction is associated with various human diseases, including metabolic syndromes, aging, and neurodegenerative diseases. Among the diseases related to mitochondrial dysfunction, Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic neuronal loss and neuroinflammation. Recently, it was reported that mitochondrial transfer between cells occurred naturally and that exogenous mitochondrial transplantation was beneficial for treating mitochondrial dysfunction. The current study aimed to investigate the therapeutic effect of mitochondrial transfer on PD in vitro and in vivo. The results showed that PN-101 mitochondria isolated from human mesenchymal stem cells exhibited a neuroprotective effect against 1-methyl-4-phenylpyridinium, 6-hydroxydopamine and rotenone in dopaminergic cells and ameliorated dopaminergic neuronal loss in the brains of C57BL/6J mice injected 30 ​mg/kg of methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally. In addition, PN-101 exhibited anti-inflammatory effects by reducing the expression of pro-inflammatory cytokines in microglial cells and suppressing microglial activation in the striatum. Furthermore, intravenous mitochondrial treatment was associated with behavioral improvements during the pole test and rotarod test in the MPTP-induced PD mice. These dual effects of neuroprotection and anti-neuroinflammation support the potential for mitochondrial transplantation as a novel therapeutic strategy for PD.
    Keywords:  Mitochondria; Mitotherapy; Neuroprotective; Parkinson's disease; Transplantation
    DOI:  https://doi.org/10.1016/j.neurot.2024.e00355
  14. J Biol Chem. 2024 Apr 01. pii: S0021-9258(24)01750-2. [Epub ahead of print] 107253
    Homocysteine-induced sustained GluN2A NMDA receptor stimulation leads to mitochondrial ROS generation and neurotoxicity.
    Satya Narayan Deep, Sarah Seelig, Surojit Paul, Ranjana Poddar.
      Homocysteine, a sulfur-containing amino acid derived from methionine metabolism, is a known agonist of N-methyl-D-aspartate receptor (NMDAR) and is involved in neurotoxicity. Our previous findings showed that neuronal exposure to elevated homocysteine levels leads to sustained low-level increase in intracellular Ca2+, which is dependent on GluN2A subunit-containing NMDAR (GluN2A-NMDAR) stimulation. These studies further showed a role of ERK MAPK in homocysteine-GluN2A-NMDAR mediated neuronal death. However, the intracellular mechanisms associated with such sustained GluN2A-NMDAR stimulation and subsequent Ca2+ influx have remained unexplored. Using live cell imaging with Fluo3-AM and biochemical approaches, we show that homocysteine-GluN2A NMDAR induced initial Ca2+ influx triggers sequential phosphorylation and subsequent activation of Pyk2 and Src family kinases (SFK), which in turn phosphorylates GluN2A-Tyr1325 residue of GluN2A-NMDARs to maintain channel activity. The continuity of this cycle of events leads to sustained Ca2+ influx through GluN2A-NMDAR. Our findings also show that lack of activation of the regulatory tyrosine phosphatase STEP, which can limit Pyk2 and SFK activity further contributes to the maintenance of this cycle. Additional studies using live cell imaging of neurons expressing a redox sensitive green fluorescent protein (RoGFP) targeted to the mitochondrial matrix show that treatment with homocysteine leads to a progressive increase in mitochondrial reactive oxygen species (ROS) generation, which is dependent on GluN2A-NMDAR mediated sustained ERK MAPK activation. This later finding demonstrates a novel role of GluN2A-NMDAR in homocysteine-induced mitochondrial ROS generation and highlights the role of ERK MAPK as the intermediary signaling pathway between GluN2A-NMDAR stimulation and mitochondrial ROS generation.
    Keywords:  Ca(2+) influx; ERK MAPK; GluN2A-NMDA receptor; Pyk2; Src family kinase; homocysteine; mitochondrial reactive oxygen species; neurotoxicity
    DOI:  https://doi.org/10.1016/j.jbc.2024.107253
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