Faculty Profiles - TOYOKUNI Shinya

Papers - TOYOKUNI Shinya

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BRCA1 haploinsufficiency interferes mitochondria under Fenton reaction-based carcinogenesis Reviewed International journal

Kong, Y; Mashimo, T; Imaoka, T; Toyokuni, S

CANCER SCIENCE Vol. 116 page： 648 - 648 2025.1

Homozygous slc25a20 zebrafish mutant reveals insights into carnitine-acylcarnitine translocase deficiency pathogenesis. Reviewed International journal Open Access

Hishida R, Ishiguro K, Yamanaka T, Toyokuni S, Matsui H

Molecular genetics and metabolism reports Vol. 41 page： 101165 2024.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Molecular Genetics and Metabolism Reports

The SLC25A20 gene encodes carnitine-acylcarnitine translocase (CACT), facilitating the transport of long-chain acylcarnitine required for energy production via β-oxidation into the mitochondria. Loss-of-function mutations in this gene lead to CACT deficiency, a rare autosomal recessive disorder of fatty acid metabolism characterized by severe symptoms including cardiomyopathy, hepatic dysfunction, rhabdomyolysis, hypoketotic hypoglycemia, and hyperammonemia, often resulting in neonatal mortality. Here, we utilized CRISPR/Cas9 gene editing to isolate slc25a20 mutant zebrafish. Homozygous mutants displayed significant lethality, with the majority succumbing before reaching maturity. However, we identified a notably rare homozygous individual that survived into adulthood, prompting a histological examination. Firstly, we observed adipose tissue accumulation at various sites in the homozygous mutant. The mutant heart exhibited hypertrophy, along with degenerated myocardial and muscle cells containing numerous eosinophilic nuclei. Additionally, we found no large oil droplet vacuoles in the mutant liver; however, the hepatocytes displayed numerous small vacuoles resembling lipid droplets. Iron deposition was evident in the spleen and parts of the liver. Overall, our slc25a20 zebrafish mutant displayed tissue pathologies analogous to human CACT deficiency, suggesting its potential as a pathological model contributing to the elucidation of pathogenesis and the improvement/development of therapies for CACT deficiency.

DOI： 10.1016/j.ymgmr.2024.101165

New era of plasma dentistry. Reviewed International journal

Sato K, Tanaka H, Okazaki Y, Hori M, Hibi H, Toyokuni S

Free radical research Vol. 58 ( 12 ) page： 868 - 874 2024.12

Language：English Publishing type：Research paper (scientific journal) Publisher：Free Radical Research

Plasma, which was coined by Irving Langmuir in 1928, is the fourth physical state after the solid/liquid/gas phases. Low-temperature plasma (LTP) is a contradictory condition that involves high energy with free radicals at near-body temperatures and was developed through engineering in the 1990’s. Research on LTP in engineering and medical fields has rapidly developed since the 2000’s. LTP can be applied through direct or indirect exposure, and there are advantages to both methods. In the medical field, LTP has been found to exert several effects, such as wound healing, hemostasis and anticancer effects, mainly based on different levels of oxidative stress. In the dental field, studies have been performed on LTP applications for general dental procedures, such as restorative, periodontal and prosthodontic procedures, and for oral cancer treatment. Many studies have demonstrated the effectiveness of LTP. Compared with other organs, the anatomical characteristic of the oral cavity is easy direct observation, which is highly advantageous for clinical applications. Due to its good accessibility and efficiency, plasma dentistry is expected to be applied to various dental applications in clinics in the near future.

DOI： 10.1080/10715762.2024.2446323

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PubMed

Deficiency in glutathione peroxidase 4 (GPX4) results in abnormal lens development and newborn cataract. Reviewed International journal Open Access

Wei Z, Hao C, Radeen KR, Hao Z, Kettimuthu K, Maner-Smith K, Toyokuni S, Fan X

Proceedings of the National Academy of Sciences of the United States of America Vol. 121 ( 48 ) page： e2407842121 2024.11

Language：English Publishing type：Research paper (scientific journal) Publisher：Proceedings of the National Academy of Sciences of the United States of America

The human lens is composed of a monolayer of lens epithelial cells (LECs) and elongated fibers that align tightly but are separated by the plasma membrane. The integrity of the lens plasma membrane is crucial for maintaining lens cellular structure, homeostasis, and transparency. Glutathione peroxidase 4 (GPX4), a selenoenzyme, plays a critical role in protecting against lipid peroxidation. This study aims to elucidate the role of GPX4 in lens plasma membrane stability during lens development using in vitro, ex vivo, and in vivo systems. Our findings reveal that GPX4 deficiency triggers lens epithelial apoptosis-independent but ferroptosis-mediated cell death. Blocking lens GPX4 activity during ex vivo culture induces lens opacification, LEC death, and disruption of lens fiber cell arrangement. Deletion of lens-specific Gpx4 results in significant unsaturated phospholipid loss and an increase in oxidized phospholipids. Consequently, lenses with Gpx4 deficiency exhibit massive disruption of lens fiber cell structure, significant loss of LECs via ferroptosis, and formation of newborn cataracts. Remarkably, administering the lipid peroxidation inhibitor, liproxstatin-1, to pregnant mothers at embryonic days 9.5 significantly prevents lipid peroxidation, LEC death, and lens developmental defects. Our study unveils the crucial role of GPX4 in lens development and transparency, and also provides a successful intervention approach to prevent lens developmental defects through lipid peroxidation inhibition.

DOI： 10.1073/pnas.2407842121

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PubMed

Low-temperature plasma as a strategy to achieve SDGs. Reviewed International journal Open Access

Tanaka H, Ishikawa K, Toyokuni S

Free radical research Vol. 58 ( 10 ) page： 594 - 595 2024.10

Glyburide confers neuroprotection against age-related macular degeneration (AMD) Reviewed International journal Open Access

Picard, E; Youale, J; Hyman, MJ; Xie, ED; Achiedo, S; Kaufmann, GT; Moir, J; Daruich, A; Crisanti, P; Torriglia, A; Polak, M; Behar-Cohen, F; Skondra, D; Berdugo, M

TRANSLATIONAL RESEARCH Vol. 272 page： 81 - 94 2024.10

Ferroptosis in health and disease. Reviewed International coauthorship International journal Open Access

Berndt C, Alborzinia H, Amen VS, Ayton S, Barayeu U, Bartelt A, Bayir H, Bebber CM, Birsoy K, Böttcher JP, Brabletz S, Brabletz T, Brown AR, Brüne B, Bulli G, Bruneau A, Chen Q, DeNicola GM, Dick TP, Distéfano A, Dixon SJ, Engler JB, Esser-von Bieren J, Fedorova M, Friedmann Angeli JP, Friese MA, Fuhrmann DC, García-Sáez AJ, Garbowicz K, Götz M, Gu W, Hammerich L, Hassannia B, Jiang X, Jeridi A, Kang YP, Kagan VE, Konrad DB, Kotschi S, Lei P, Le Tertre M, Lev S, Liang D, Linkermann A, Lohr C, Lorenz S, Luedde T, Methner A, Michalke B, Milton AV, Min J, Mishima E, Müller S, Motohashi H, Muckenthaler MU, Murakami S, Olzmann JA, Pagnussat G, Pan Z, Papagiannakopoulos T, Pedrera Puentes L, Pratt DA, Proneth B, Ramsauer L, Rodriguez R, Saito Y, Schmidt F, Schmitt C, Schulze A, Schwab A, Schwantes A, Soula M, Spitzlberger B, Stockwell BR, Thewes L, Thorn-Seshold O, Toyokuni S, Tonnus W, Trumpp A, Vandenabeele P, Vanden Berghe T, Venkataramani V, Vogel FCE, von Karstedt S, Wang F, Westermann F, Wientjens C, Wilhelm C, Wölk M, Wu K, Yang X, Yu F, Zou Y, Conrad M

Redox biology Vol. 75 page： 103211 2024.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Redox Biology

Ferroptosis is a pervasive non-apoptotic form of cell death highly relevant in various degenerative diseases and malignancies. The hallmark of ferroptosis is uncontrolled and overwhelming peroxidation of polyunsaturated fatty acids contained in membrane phospholipids, which eventually leads to rupture of the plasma membrane. Ferroptosis is unique in that it is essentially a spontaneous, uncatalyzed chemical process based on perturbed iron and redox homeostasis contributing to the cell death process, but that it is nonetheless modulated by many metabolic nodes that impinge on the cells’ susceptibility to ferroptosis. Among the various nodes affecting ferroptosis sensitivity, several have emerged as promising candidates for pharmacological intervention, rendering ferroptosis-related proteins attractive targets for the treatment of numerous currently incurable diseases. Herein, the current members of a Germany-wide research consortium focusing on ferroptosis research, as well as key external experts in ferroptosis who have made seminal contributions to this rapidly growing and exciting field of research, have gathered to provide a comprehensive, state-of-the-art review on ferroptosis. Specific topics include: basic mechanisms, in vivo relevance, specialized methodologies, chemical and pharmacological tools, and the potential contribution of ferroptosis to disease etiopathology and progression. We hope that this article will not only provide established scientists and newcomers to the field with an overview of the multiple facets of ferroptosis, but also encourage additional efforts to characterize further molecular pathways modulating ferroptosis, with the ultimate goal to develop novel pharmacotherapies to tackle the various diseases associated with – or caused by – ferroptosis.

DOI： 10.1016/j.redox.2024.103211

Growth promotion and disease tolerance in strawberry plants with plasma-activated Ringer’s lactate solution Reviewed International journal

Sakai K., Matsubara Y., Hashizume H., Tanaka H., Toyokuni S., Hori M.

Acta Horticulturae Vol. 3 ( 1404 ) page： 917 - 922 2024.9

Language：English Publishing type：Research paper (scientific journal) Publisher：Acta Horticulturae

Recently, plasma-activated solutions have been attempted on biotic regulations mainly in medical aspects. In this study, effect of plasma-activated Ringer’s lactate solution (PAL) on disease (anthracnose, Fusarium wilt) tolerance and antifungal function in strawberry plants was investigated. Runner-derived strawberry (Fragaria × ananassa Duch. ‘Benihoppe’) plants were treated with Fuji-γ-PAL and Strong PAL (×100, ×300 dilution) to leaves or roots. Then, plants were inoculated with Colletotrichum fructicola (MAFF306788, 105 cfu mL-1); causable pathogen of anthracnose, or Fusarium oxysporum f. sp. fragariae (NRF0903, 106 cfu mL-1); pathogen of Fusarium wilt. Increase in dry weight of shoots occurred in Strong PAL 100-treated plants. Incidence and severity in symptoms of anthracnose and Fusarium wilt were alleviated in most of the PAL-treated plants in both diseases. In this case, Strong-PAL showed relatively higher suppression effect than Fuji-γ-PAL in both diseases. As for antifungal aspects in vitro using Czapek-Doc medium, both PALs suppressed Fusarium propagation; Strong PAL showed higher suppression effect compared to Fuji-γ-PAL. On the other hand, Strong PAL 100-treated plants showed higher DPPH radical scavenging activity in leaves among the treatments. These findings suggest that PAL induce growth promotion and disease tolerance in strawberry plants, and these effects differ with the method of PAL treatment.

DOI： 10.17660/ActaHortic.2024.1404.125

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特集フェロトーシス(鉄依存性細胞死)--そのメカニズムの解明と,治療への応用フェロトーシス抵抗性と発がん International journal

前田勇貴, 豊國伸哉

医学のあゆみ Vol. 290 ( 2 ) page： 174 - 177 2024.7

Phototoxicity of low doses of light and influence of the spectral composition on human RPE cells Reviewed International journal Open Access

Françon, A; Delaunay, K; Jaworski, T; Lebon, C; Picard, E; Youale, J; Behar-Cohen, F; Torriglia, A

SCIENTIFIC REPORTS Vol. 14 ( 1 ) 2024.3

Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria. Reviewed International journal Open Access

Danyang Mi, Izumi Yanatori, Hao Zheng, Yingyi Kong, Tasuku Hirayama, Shinya Toyokuni

Free radical research Vol. 58 ( 4 ) page： 261 - 275 2024.3

Language：English Publishing type：Research paper (scientific journal)

Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Though direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

DOI： 10.1080/10715762.2024.2340711

Analysis of spontaneous pancreatic endocrine tumors in Gcggfp/gfp mice Reviewed International journal

Hori, M; Maeda, K; Imai, T; Hippo, Y; Toyokuni, S; Hayashi, Y

CANCER SCIENCE Vol. 115 page： 181 - 181 2024.3

Effect of aging and PARP inhibitor, olaparib on ovarian function with BRCA1 mutant model rats Reviewed International journal

Sonehara, R; Motooka, Y; Mashimo, T; Imaoka, T; Kajiyama, H; Toyokuni, S

CANCER SCIENCE Vol. 115 page： 170 - 170 2024.3

BRCA2 germline mutation promotes follicle development and induces diminished ovarian reserve Reviewed International journal

Tanaka, H; Motooka, Y; Maeda, Y; Mashimo, T; Kajiyama, H; Toyokuni, S

CANCER SCIENCE Vol. 115 page： 172 - 172 2024.3

Genomic distribution of 8-oxoguanines in the kidney genome of ferric nitrilotriacetate -treated mice Reviewed International journal

Akatsuka, S; Toyokuni, S

CANCER SCIENCE Vol. 115 page： 1279 - 1279 2024.3

Tracking BRCA1 haploinsufficiency focusing mitochondrial metabolism under Fenton reactionbased carcinogenesis Reviewed International journal

Kong, YY; Mashimo, T; Imaoka, T; Toyokuni, S

CANCER SCIENCE Vol. 115 page： 195 - 195 2024.3

Role of iron, oxygen and ferroptosis in tumor evolutionary biology Reviewed International journal

Toyokuni, S; Kong, YY; Luo, YG; Zheng, H; Motooka, Y; Imaoka, T; Akatsuka, S

CANCER SCIENCE Vol. 115 page： 907 - 907 2024.3

Involvement of iron-sulphur cofactors in regulation of mammalian THP-1 macrophage iron homeostasis and redox status Reviewed International journal

Lyu, QY; Toyokuni, S; Kouketsu, Y

CANCER SCIENCE Vol. 115 page： 908 - 908 2024.3

Epstein-Barr virus lytic gene BNRF1 promotes B-cell lymphomagenesis via IFI27 upregulation. Reviewed International journal Open Access

Sagou K, Sato Y, Okuno Y, Watanabe T, Inagaki T, Motooka Y, Toyokuni S, Murata T, Kiyoi H, Kimura H

PLoS pathogens Vol. 20 ( 2 ) page： e1011954 2024.2

Language：English Publishing type：Research paper (scientific journal) Publisher：Plos Pathogens

Epstein-Barr virus (EBV) is a ubiquitous human lymphotropic herpesvirus that is causally associated with several malignancies. In addition to latent factors, lytic replication contributes to cancer development. In this study, we examined whether the lytic gene BNRF1, which is conserved among gamma-herpesviruses, has an important role in lymphomagenesis. We found that lymphoblastoid cell lines (LCLs) established by BNRF1-knockout EBV exhibited remarkably lower pathogenicity in a mice xenograft model than LCLs produced by wild-type EBV (LCLs-WT). RNA-seq analyses revealed that BNRF1 elicited the expression of interferon-inducible protein 27 (IFI27), which promotes cell proliferation. IFI27 knockdown in LCLs-WT resulted in excessive production of reactive oxygen species, leading to cell death and significantly decreased their pathogenicity in vivo. We also confirmed that IFI27 was upregulated during primary infection in B-cells. Our findings revealed that BNRF1 promoted robust proliferation of the B-cells that were transformed by EBV latent infection via IFI27 upregulation both in vitro and in vivo.

DOI： 10.1371/journal.ppat.1011954

Open Access

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PubMed

Cold Atmospheric Pressure Plasma-Activated Liquids for Cancer Treatment Reviewed International journal

Miron, C; Hiromasa, T; Britun, N; Hashizume, H; Ishikawa, K; Du, LY; Yamakawa, T; Kurebayashi, Y; Kondo, T; Kondo, H; Kajiyama, H; Toyokuni, S; Mizuno, M; Hori, M

ADVANCES IN DIGITAL HEALTH AND MEDICAL BIOENGINEERING, VOL 3, EHB-2023 Vol. 111 page： 150 - 162 2024

Language：English Publishing type：Research paper (scientific journal) Publisher：Ifmbe Proceedings

Low-temperature plasma (LTP) is a promising tool that can assist in cancer treatment. Plasma-treated liquids have shown a selective cytotoxic effect on cancer cells attributed to reactive species formed in discharge, but this mechanism is not completely understood. In this study, the chemical compounds formed by plasma irradiation of Ringer’s lactate solutions and their effects on non-tumorigenic breast epithelial cells (MCF-10A) and breast cancer cells (MCF-7) were investigated. Among these compounds, glyceric acid increased the cell viability by more than two-fold compared to the control samples for MCF-10A and MCF-7 cells, whereas the tricarballylic acid had a pronounced cytotoxic effect on the cells when incubated with solutions of 0.6 mM to 50 mM concentrations. A good selectivity in killing the cancer cells was observed when the chemical compounds identified in plasma-treated liquids (such as ethyl acetate, glyceric acid, and tricarballylic acid) were used in a mixture solution of a certain concentration. The results show that the LTP-generated chemical compounds have both, stimulatory and inhibitory effects on cell viability, and the best selectivity is achieved only when these compounds are combined in a certain amount and have a synergistic effect, completely killing only the cancer cells.

DOI： 10.1007/978-3-031-62523-7_17

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Papers - TOYOKUNI Shinya