bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2023–05–14
sixteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Four-Color STED Super-Resolution RNA Fluorescent In Situ Hybridization and Immunocytochemistry to Visualize Mitochondrial mRNAs in Context with Mitochondrial Ribosomes.
  2. A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis.
  3. Secondary structure of the human mitochondrial genome affects formation of deletions.
  4. Mangiferin protects DNase 2 abundance via Nrf2 activation to prevent cytosolic mtDNA accumulation during liver injury.
  5. Mitochondrial translational defect extends lifespan in C. elegans by activating UPRmt.
  6. Parkin promotes airway inflammatory response to interferon gamma.
  7. Upregulation of the ERRγ-VDAC1 axis underlies the molecular pathogenesis of pancreatitis.
  8. High-throughput interrogation of immune responses using the Human Immune Profiling Pipeline.
  9. Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.
  10. Fission-Fueled Nucleoid Dispersion, a Novel Mitochondrial Metabolic Activation Mechanism.
  11. TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria.
  12. APOE expression and secretion are modulated by mitochondrial dysfunction.
  13. Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.
  14. PTPMT1 protect cardiomyocytes from necroptosis induced by γ-ray irradiation through alleviate mitochondria injury.
  15. Selection of iPSCs without mtDNA deletion for autologous cell therapy in a patient with Pearson syndrome.
  16. Proteome changes in a human retinal pigment epithelial cell line during oxidative stress and following antioxidant treatment.
  1. Methods Mol Biol. 2023 ;2661 303-316
    Four-Color STED Super-Resolution RNA Fluorescent In Situ Hybridization and Immunocytochemistry to Visualize Mitochondrial mRNAs in Context with Mitochondrial Ribosomes.
    Christin A Albus, Rolando Berlinguer-Palmini, Zofia M Chrzanowska-Lightowlers, Robert N Lightowlers.
      High-resolution imaging has enabled scientists to explore the mitochondrial network at remarkable resolution. This has been exploited to help increase our knowledge of how mitochondrial gene expression is compartmentalized in cultured cells. Here, we provide detailed methodology to simultaneously visualize up to four components including mtDNA-encoded transcripts, submitochondrial marker proteins, mitoribosomal subunits, or core members of the translational apparatus using STED super-resolution nanoscopy.
    Keywords:  Mitochondrial mRNA; RNA in situ hybridization; STED super-resolution; Super-resolution nanoscopy
    DOI:  https://doi.org/10.1007/978-1-0716-3171-3_17
  2. J Cell Biol. 2023 Jul 03. pii: e202210019. [Epub ahead of print]222(7):
    A two-step mitochondrial import pathway couples the disulfide relay with matrix complex I biogenesis.
    Esra Peker, Konstantin Weiss, Jiyao Song, Christine Zarges, Sarah Gerlich, Volker Boehm, Aleksandra Trifunovic, Thomas Langer, Niels H Gehring, Thomas Becker, Jan Riemer.
      Mitochondria critically rely on protein import and its tight regulation. Here, we found that the complex I assembly factor NDUFAF8 follows a two-step import pathway linking IMS and matrix import systems. A weak targeting sequence drives TIM23-dependent NDUFAF8 matrix import, and en route, allows exposure to the IMS disulfide relay, which oxidizes NDUFAF8. Import is closely surveyed by proteases: YME1L prevents accumulation of excess NDUFAF8 in the IMS, while CLPP degrades reduced NDUFAF8 in the matrix. Therefore, NDUFAF8 can only fulfil its function in complex I biogenesis if both oxidation in the IMS and subsequent matrix import work efficiently. We propose that the two-step import pathway for NDUFAF8 allows integration of the activity of matrix complex I biogenesis pathways with the activity of the mitochondrial disulfide relay system in the IMS. Such coordination might not be limited to NDUFAF8 as we identified further proteins that can follow such a two-step import pathway.
    DOI:  https://doi.org/10.1083/jcb.202210019
  3. BMC Biol. 2023 May 08. 21(1): 103
    Secondary structure of the human mitochondrial genome affects formation of deletions.
    Victor Shamanskiy, Alina A Mikhailova, Evgenii O Tretiakov, Kristina Ushakova, Alina G Mikhailova, Sergei Oreshkov, Dmitry A Knorre, Natalia Ree, Jonathan B Overdevest, Samuel W Lukowski, Irina Gostimskaya, Valerian Yurov, Chia-Wei Liou, Tsu-Kung Lin, Wolfram S Kunz, Alexandre Reymond, Ilya Mazunin, Georgii A Bazykin, Jacques Fellay, Masashi Tanaka, Konstantin Khrapko, Konstantin Gunbin, Konstantin Popadin.
       BACKGROUND: Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Such deletions are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded mitochondrial DNA (mtDNA) might play a role in the formation of deletions.
    RESULTS: By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a "hot spot" where one deletion breakpoint occurred within the region of 6-9 kb and another within 13-16 kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions, can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11 kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp (base pair) and a second arm at 13,447-13,459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. A comparison of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging.
    CONCLUSIONS: Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.
    Keywords:  Aging; Contact zone; Deletions; Direct repeats; Global secondary structure; Inverted repeats; Mitochondrial DNA; Single-stranded DNA; mtDNA replication
    DOI:  https://doi.org/10.1186/s12915-023-01606-1
  4. Mol Nutr Food Res. 2023 May 09. e2200885
    Mangiferin protects DNase 2 abundance via Nrf2 activation to prevent cytosolic mtDNA accumulation during liver injury.
    Lisi Li, Yifan Zhen, Xi Chen, Lixue Cao, Junna Song, Xifu Liu, Meng Wang.
       SCOPE: Mitochondrial DNA (mtDNA) released into the cytosol serves as a member of damage-associated molecular patterns to initiate inflammatory responses. Mangiferin is a xanthonoid derivative, usually isolated from plants including mangoes and iris unguicularis. This study aimed to investigate whether mangiferin prevents mtDNA accumulation in the cytosol with a focus on DNase 2 protection from oxidative damage.
    METHODS AND RESULTS: Mangiferin administration effectively protected against hepatotoxicity in mice subjected to CCl4 challenge or bile duct ligation (BDL) surgery. Moreover, mangiferin activated Nrf2-antioxidant signalling, reduces cytosolic mtDNA accumulation and suppresses TLR-9/MyD88-dependent inflammation in the liver. We prepared hepatic mtDNA to stimulate hepatocytes, and found that mangiferin protected DNase 2 protein abundance. mtDNA induced ROS production to promote DNase 2 protein degradation though oxidative modification, but mangiferin protected DNase 2 protein stability in a Nrf2-dependent manner. In hepatic Nrf2 deficiency mice, we further confirmed that Nrf2 induction was required for mangiferin to clear cytosolic mtDNA and block mtDNA-mediated TLR9/MyD88/NF-κB inflammatory signaling cascades.
    CONCLUSION: These findings provide new insights into the role of mangiferin as a liver protecting agent, and suggest protection of DNase 2 as a novel therapeutic strategy for pharmacological intervention to prevent liver damage. This article is protected by copyright. All rights reserved.
    Keywords:  DNase 2; Liver damage; Mangiferin; Mitochondrial DNA; Nrf2
    DOI:  https://doi.org/10.1002/mnfr.202200885
  5. Redox Biol. 2023 May 07. pii: S2213-2317(23)00123-4. [Epub ahead of print]63 102722
    Mitochondrial translational defect extends lifespan in C. elegans by activating UPRmt.
    Miaomiao Guo, Xinhua Qiao, Yuanyuan Wang, Zi-Han Li, Chang Shi, Yun Chen, Lu Kang, Chang Chen, Xiao-Long Zhou.
      Aminoacyl-tRNA synthetases (aaRSs) are indispensable players in translation. Usually, two or three genes encode cytoplasmic and mitochondrial threonyl-tRNA synthetases (ThrRSs) in eukaryotes. Here, we reported that Caenorhabditis elegans harbors only one tars-1, generating cytoplasmic and mitochondrial ThrRSs via translational reinitiation. Mitochondrial tars-1 knockdown decreased mitochondrial tRNAThr charging and translation and caused pleotropic phenotypes of delayed development, decreased motor ability and prolonged lifespan, which could be rescued by replenishing mitochondrial tars-1. Mitochondrial tars-1 deficiency leads to compromised mitochondrial functions including the decrease in oxygen consumption rate, complex Ⅰ activity and the activation of the mitochondrial unfolded protein response (UPRmt), which contributes to longevity. Furthermore, deficiency of other eight mitochondrial aaRSs in C. elegans and five in mammal also caused activation of the UPRmt. In summary, we deciphered the mechanism of one tars-1, generating two aaRSs, and elucidated the biochemical features and physiological function of C. elegans tars-1. We further uncovered a conserved connection between mitochondrial translation deficiency and UPRmt.
    Keywords:  Aminoacyl-tRNA synthetases; Lifespan; Mitochondrial translation; UPR(mt); tars-1(ora1) Ⅱ/wt
    DOI:  https://doi.org/10.1016/j.redox.2023.102722
  6. Res Sq. 2023 Apr 24. pii: rs.3.rs-2838551. [Epub ahead of print]
    Parkin promotes airway inflammatory response to interferon gamma.
    Kris Genelyn Dimasuay, Bruce Berg, Niccolette Schaunaman, Taylor Nichols, Hong Wei Chu.
      Background Increased type 2 interferon (i.e., IFN-γ) signaling has been shown to be involved in airway inflammation in a subset of asthma patients who often show high levels of airway neutrophilic inflammation and poor response to corticosteroid treatment. How IFN-γ mediates airway inflammation in a mitochondrial dysfunction setting (e.g., Parkin up-regulation) remains poorly understood. The goal of this study was to determine the role of Parkin, an E3 ubiquitin ligase, in IFN-γ-mediated airway inflammation and the regulation of Parkin by IFN-γ. Results Using a mouse model of IFN-γ treatment in wild-type and Parkin knockout mice, and cultured human primary airway epithelial cells with or without Parkin gene deficiency, we found that Parkin was necessary for the production of neutrophil chemokines (i.e., KC and IL-8) and airway neutrophilic inflammation. Mechanistically, Parkin was induced by IFN-γ treatment both in vivo and in vitro , which was associated with less expression of a Parkin transcriptional repressor Thap11. Overexpression of Thap11 inhibited Parkin expression in IFN-γ-stimulated airway epithelial cells. Conclusions Our data suggests a novel mechanism by which IFN-γ induces airway neutrophilic inflammation through the Thap11/Parkin axis. Inhibition of Parkin expression or activity may provide a new therapeutic target for the treatment of excessive neutrophilic inflammation in an IFN-γ high environment.
    DOI:  https://doi.org/10.21203/rs.3.rs-2838551/v1
  7. Proc Natl Acad Sci U S A. 2023 05 16. 120(20): e2219644120
    Upregulation of the ERRγ-VDAC1 axis underlies the molecular pathogenesis of pancreatitis.
    Dipanjan Chanda, Themis Thoudam, Ibotombi Singh Sinam, Chae Won Lim, Myeongjin Kim, Jiale Wang, Kyeong-Min Lee, Jing Ma, Romil Saxena, Jinhyuk Choi, Chang Joo Oh, Hoyul Lee, Yong Hyun Jeon, Sung Jin Cho, Hoe-Yune Jung, Keun-Gyu Park, Hueng-Sik Choi, Jae Myoung Suh, Johan Auwerx, Baoan Ji, Suthat Liangpunsakul, Jae-Han Jeon, In-Kyu Lee.
      Emerging evidence suggest that transcription factors play multiple roles in the development of pancreatitis, a necroinflammatory condition lacking specific therapy. Estrogen-related receptor γ (ERRγ), a pleiotropic transcription factor, has been reported to play a vital role in pancreatic acinar cell (PAC) homeostasis. However, the role of ERRγ in PAC dysfunction remains hitherto unknown. Here, we demonstrated in both mice models and human cohorts that pancreatitis is associated with an increase in ERRγ gene expression via activation of STAT3. Acinar-specific ERRγ haploinsufficiency or pharmacological inhibition of ERRγ significantly impaired the progression of pancreatitis both in vitro and in vivo. Using systematic transcriptomic analysis, we identified that voltage-dependent anion channel 1 (VDAC1) acts as a molecular mediator of ERRγ. Mechanistically, we showed that induction of ERRγ in cultured acinar cells and mouse pancreata enhanced VDAC1 expression by directly binding to specific site of the Vdac1 gene promoter and resulted in VDAC1 oligomerization. Notably, VDAC1, whose expression and oligomerization were dependent on ERRγ, modulates mitochondrial Ca2+ and ROS levels. Inhibition of the ERRγ-VDAC1 axis could alleviate mitochondrial Ca2+ accumulation, ROS formation and inhibit progression of pancreatitis. Using two different mouse models of pancreatitis, we showed that pharmacological blockade of ERRγ-VDAC1 pathway has therapeutic benefits in mitigating progression of pancreatitis. Likewise, using PRSS1R122H-Tg mice to mimic human hereditary pancreatitis, we demonstrated that ERRγ inhibitor also alleviated pancreatitis. Our findings highlight the importance of ERRγ in pancreatitis progression and suggests its therapeutic intervention for prevention and treatment of pancreatitis.
    Keywords:  ERRγ; VDAC1; mitochondrial Ca2+; nuclear receptor; pancreatitis
    DOI:  https://doi.org/10.1073/pnas.2219644120
  8. STAR Protoc. 2023 May 08. pii: S2666-1667(23)00256-3. [Epub ahead of print]4(2): 102289
    High-throughput interrogation of immune responses using the Human Immune Profiling Pipeline.
    Guanning Wang, Olga Lyudovyk, Justin Y Kim, Ya-Hui Lin, Yuval Elhanati, Divij Mathew, E John Wherry, Ramin S Herati, Allison R Greenplate, Benjamin Greenbaum, Santosha A Vardhana, Alexander C Huang.
      The current abundance of immunotherapy clinical trials presents an opportunity to learn about the underlying mechanisms and pharmacodynamic effects of novel drugs on the human immune system. Here, we present a protocol to study how these immune responses impact clinical outcomes using large-scale high-throughput immune profiling of clinical cohorts. We describe the Human Immune Profiling Pipeline, which comprises an end-to-end solution from flow cytometry results to computational approaches and unsupervised patient clustering based on lymphocyte landscape. For complete details on the use and execution of this protocol, please refer to Lyudovyk et al. (2022).1.
    Keywords:  Flow Cytometry/Mass Cytometry; Health Sciences; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2023.102289
  9. Immunity. 2023 May 02. pii: S1074-7613(23)00177-2. [Epub ahead of print]
    Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.
    Máté G Kiss, John E Mindur, Abi G Yates, Donghoon Lee, John F Fullard, Atsushi Anzai, Wolfram C Poller, Kathleen A Christie, Yoshiko Iwamoto, Vladimir Roudko, Jeffrey Downey, Christopher T Chan, Pacific Huynh, Henrike Janssen, Achilles Ntranos, Jan D Hoffmann, Walter Jacob, Sukanya Goswami, Sumnima Singh, David Leppert, Jens Kuhle, Seunghee Kim-Schulze, Matthias Nahrendorf, Benjamin P Kleinstiver, Fay Probert, Panos Roussos, Filip K Swirski, Cameron S McAlpine.
      Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44hiCD4+ T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ). Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ+ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity. Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS.
    Keywords:  astrocyte; chemokine; interleukin-3; microglia; monocyte; multiple sclerosis; neuroinflammation; recruitment
    DOI:  https://doi.org/10.1016/j.immuni.2023.04.013
  10. Mol Cells. 2023 May 31. 46(5): 278-280
    Fission-Fueled Nucleoid Dispersion, a Novel Mitochondrial Metabolic Activation Mechanism.
    Jeongah Kim.
      
    DOI:  https://doi.org/10.14348/molcells.2023.0043
  11. Cell Rep. 2023 Apr 30. pii: S2211-1247(23)00465-5. [Epub ahead of print] 112454
    TIM23 facilitates PINK1 activation by safeguarding against OMA1-mediated degradation in damaged mitochondria.
    Shiori Akabane, Kiyona Watanabe, Hidetaka Kosako, Shun-Ichi Yamashita, Kohei Nishino, Masahiro Kato, Shiori Sekine, Tomotake Kanki, Noriyuki Matsuda, Toshiya Endo, Toshihiko Oka.
      PINK1 is activated by autophosphorylation and forms a high-molecular-weight complex, thereby initiating the selective removal of damaged mitochondria by autophagy. Other than translocase of the outer mitochondrial membrane complexes, members of PINK1-containing protein complexes remain obscure. By mass spectrometric analysis of PINK1 co-immunoprecipitates, we identify the inner membrane protein TIM23 as a component of the PINK1 complex. TIM23 downregulation decreases PINK1 levels and significantly delays autophosphorylation, indicating that TIM23 promotes PINK1 accumulation in response to depolarization. Moreover, inactivation of the mitochondrial protease OMA1 not only enhances PINK1 accumulation but also represses the reduction in PINK1 levels induced by TIM23 downregulation, suggesting that TIM23 facilitates PINK1 activation by safeguarding against degradation by OMA1. Indeed, deficiencies of pathogenic PINK1 mutants that fail to interact with TIM23 are partially restored by OMA1 inactivation. These findings indicate that TIM23 plays a distinct role in activating mitochondrial autophagy by protecting PINK1.
    Keywords:  CP: Cell biology; OMA1; PINK1; TIM23; mitochondrial quality control
    DOI:  https://doi.org/10.1016/j.celrep.2023.112454
  12. Elife. 2023 May 12. pii: e85779. [Epub ahead of print]12
    APOE expression and secretion are modulated by mitochondrial dysfunction.
    Meghan E Wynne, Oluwaseun Ogunbona, Alicia R Lane, Avanti Gokhale, Stephanie A Zlatic, Chongchong Xu, Zhexing Wen, Duc M Duong, Sruti Rayaprolu, Anna Ivanova, Eric A Ortlund, Eric B Dammer, Nicholas T Seyfried, Blaine R Roberts, Amanda Crocker, Vinit Shanbhag, Michael Petris, Nanami Senoo, Selvaraju Kandasamy, Steven Michael Claypool, Antoni Barrientos, Aliza Wingo, Thomas S Wingo, Srikant Rangaraju, Allan I Levey, Erica Werner, Victor Faundez.
      Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer's disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain, elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.
    Keywords:  cell biology; human; neuroscience
    DOI:  https://doi.org/10.7554/eLife.85779
  13. Neurotox Res. 2023 May 10.
    Mitochondrial Dysfunction as a Signaling Target for Therapeutic Intervention in Major Neurodegenerative Disease.
    Shubhada V Mangrulkar, Nitu L Wankhede, Mayur B Kale, Aman B Upaganlawar, Brijesh G Taksande, Milind J Umekar, Md Khalid Anwer, Hamad Ghaleb Dailah, Syam Mohan, Tapan Behl.
      Neurodegenerative diseases (NDD) are incurable and the most prevalent cognitive and motor disorders of elderly. Mitochondria are essential for a wide range of cellular processes playing a pivotal role in a number of cellular functions like metabolism, intracellular signaling, apoptosis, and immunity. A plethora of evidence indicates the central role of mitochondrial functions in pathogenesis of many aging related NDD. Considering how mitochondria function in neurodegenerative diseases, oxidative stress, and mutations in mtDNA both contribute to aging. Many substantial reports suggested the involvement of numerous contributing factors including, mitochondrial dysfunction, oxidative stress, mitophagy, accumulation of somatic mtDNA mutations, compromised mitochondrial dynamics, and transport within axons in neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis. Therapies therefore target fundamental mitochondrial processes such as energy metabolism, free-radical generation, mitochondrial biogenesis, mitochondrial redox state, mitochondrial dynamics, mitochondrial protein synthesis, mitochondrial quality control, and metabolism hold great promise to develop pharmacological based therapies in NDD. By emphasizing the most efficient pharmacological strategies to target dysfunction of mitochondria in the treatment of neurodegenerative diseases, this review serves the scientific community engaged in translational medical science by focusing on the establishment of novel, mitochondria-targeted treatment strategies.
    Keywords:  Fission; Fusion; Mitochondrial dysfunction; Mitochondrial medicine; Mitochondrial quality control; Oxidative stress
    DOI:  https://doi.org/10.1007/s12640-023-00647-2
  14. Am J Physiol Cell Physiol. 2023 May 08.
    PTPMT1 protect cardiomyocytes from necroptosis induced by γ-ray irradiation through alleviate mitochondria injury.
    Jing Yi, Liang Yue, Yuning Zhang, Ning Tao, Han Duan, Lin Lv, Ying-Xia Tan, Hua Wang.
      Radiation-induced heart disease (RIHD) progresses over time and may manifest decades after the initial radiation exposure, which is associated with significant morbidity and mortality. The clinical benefit of radiotherapy is always counterbalanced by an increased risk of cardiovascular events in survivors. There is an urgent need to explore the effect and the underlying mechanism of radiation-induced heart injury. Mitochondrial damage widely occurs in irradiation-induced injury, and mitochondrial dysfunction contributes to necroptosis development. Experiments were performed using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and rat H9C2 cells to investigate the effect of mitochondrial injury on necroptosis in irradiated cardiomyocytes and to further elucidate the mechanism underlying radiation-induced heart disease and discover possible preventive targets. After γ-ray irradiation, the expression levels of necroptosis markers were increased, along with higher oxidative stress and mitochondrial injury. These effects could be abated by overexpression of PTEN-like mitochondrial phosphatase (PTPMT1). Inhibiting oxidative stress or increasing the expression of PTPMT1 could protect against radiation-induced mitochondrial injury and then decrease the necroptosis of cardiomyocytes. These results suggest that PTPMT1 may be a new target for the treatment of radiation-induced heart disease.
    Keywords:  PTEN-like mitochondrial phosphatase; induced pluripotent stem cell-derived cardiomyocytes; mitochondrial injury; necroptosis; radiation-induced heart disease
    DOI:  https://doi.org/10.1152/ajpcell.00466.2022
  15. BMB Rep. 2023 May 09. pii: 5823. [Epub ahead of print]
    Selection of iPSCs without mtDNA deletion for autologous cell therapy in a patient with Pearson syndrome.
    Yeonmi Lee, Jongsuk Han, Sae-Byeok Hwang, Soon-Suk Kang, Hyeoung-Bin Son, Chaeyeon Jin, Jae Eun Kim, Beom Hee Lee, Eunju Kang.
      Screening for genetic defects in the cells should be examined for clinical application. The Pearson syndrome (PS) patient harbored nuclear mutations in the POLG and SSBP1 genes, which could induce systemic large-scale mitochondrial genome (mtDNA) deletion. We investigated iPSCs with mtDNA deletions in PS patient and whether deletion levels could be maintained during differentiation. The iPSC clones derived from skin fibroblasts (9% deletion) and blood mononuclear cells (24% deletion) were measured for mtDNA deletion levels. Of the 13 skin-derived iPSC clones, only 3 were found to be free of mtDNA deletions, whereas all blood-derived iPSC clones were found to be free of deletions. The iPSC clones with (27%) and without mtDNA deletion (0%) were selected and performed in vitro and in vivo differentiation, such as embryonic body (EB) and teratoma formation. After differentiation, the level of deletion was retained or increased in EBs (24%) or teratoma (45%) from deletion iPSC clone, while, the absence of deletions showed in all EBs and teratomas from deletion-free iPSC clones. These results demonstrated that non-deletion in iPSCs was maintained during in vitro and in vivo differentiation, even in the presence of nuclear mutations, suggesting that deletion-free iPSC clones could be candidates for autologous cell therapy in patients.
  16. Front Immunol. 2023 ;14 1138519
    Proteome changes in a human retinal pigment epithelial cell line during oxidative stress and following antioxidant treatment.
    R Scott Duncan, Andrew Keightley, Adam A Lopez, Conner W Hall, Peter Koulen.
      Age related macular degeneration (AMD) is the most common cause of blindness in the elderly. Oxidative stress contributes to retinal pigment epithelium (RPE) dysfunction and cell death thereby leading to AMD. Using improved RPE cell model systems, such as human telomerase transcriptase-overexpressing (hTERT) RPE cells (hTERT-RPE), pathophysiological changes in RPE during oxidative stress can be better understood. Using this model system, we identified changes in the expression of proteins involved in the cellular antioxidant responses after induction of oxidative stress. Some antioxidants such as vitamin E (tocopherols and tocotrienols) are powerful antioxidants that can reduce oxidative damage in cells. Alpha-tocopherol (α-Toc or αT) and gamma-tocopherol (γ-Toc or γT) are well-studied tocopherols, but signaling mechanisms underlying their respective cytoprotective properties may be distinct. Here, we determined what effect oxidative stress, induced by extracellularly applied tBHP in the presence and absence of αT and/or γT, has on the expression of antioxidant proteins and related signaling networks. Using proteomics approaches, we identified differential protein expression in cellular antioxidant response pathways during oxidative stress and after tocopherol treatment. We identified three groups of proteins based on biochemical function: glutathione metabolism/transfer, peroxidases and redox-sensitive proteins involved in cytoprotective signaling. We found that oxidative stress and tocopherol treatment resulted in unique changes in these three groups of antioxidant proteins indicate that αT and γT independently and by themselves can induce the expression of antioxidant proteins in RPE cells. These results provide novel rationales for potential therapeutic strategies to protect RPE cells from oxidative stress.
    Keywords:  gene ontology; oxidative stress; proteomics; retinal pigment epithelium (RPE) cells; tert-butyl hydroperoxide; tocopherol
    DOI:  https://doi.org/10.3389/fimmu.2023.1138519
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