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Article ; Online: Glucose starvation causes ferroptosis-mediated lysosomal dysfunction.

Miki, Kenji / Yagi, Mikako / Kang, Dongchon / Kunisaki, Yuya / Yoshimoto, Koji / Uchiumi, Takeshi

iScience

2024 Volume 27, Issue 5, Page(s) 109735

Abstract: Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are ...

Abstract	Lysosomes, the hub of metabolic signaling, are associated with various diseases and participate in autophagy by supplying nutrients to cells under nutrient starvation. However, their function and regulation under glucose starvation remain unclear and are studied herein. Under glucose starvation, lysosomal protein expression decreased, leading to the accumulation of damaged lysosomes. Subsequently, cell death occurred via ferroptosis and iron accumulation due to DMT1 degradation. GPX4, a key factor in ferroptosis inhibition located on the outer membrane of lysosomes, accumulated in lysosomes, especially under glucose starvation, to protect cells from ferroptosis. ALDOA, GAPDH, NAMPT, and PGK1 are also located on the outer membrane of lysosomes and participate in lysosomal function. These enzymes did not function effectively under glucose starvation, leading to lysosomal dysfunction and ferroptosis. These findings may facilitate the treatment of lysosomal-related diseases.
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2024.109735
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Article: Correction: Mitochondrial dysfunction and impaired growth of glioblastoma cell lines caused by antimicrobial agents inducing ferroptosis under glucose starvation.

Miki, Kenji / Yagi, Mikako / Yoshimoto, Koji / Kang, Dongchon / Uchiumi, Takeshi

Oncogenesis

2022 Volume 11, Issue 1, Page(s) 64

Language	English
Publishing date	2022-10-19
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2674437-5
ISSN	2157-9024
ISSN	2157-9024
DOI	10.1038/s41389-022-00443-1
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Article: Mitochondrial dysfunction and impaired growth of glioblastoma cell lines caused by antimicrobial agents inducing ferroptosis under glucose starvation.

Miki, Kenji / Yagi, Mikako / Yoshimoto, Koji / Kang, Dongchon / Uchiumi, Takeshi

Oncogenesis

2022 Volume 11, Issue 1, Page(s) 59

Abstract: Glioblastoma is a difficult-to-cure disease owing to its malignancy. Under normal circumstances, cancer is dependent on the glycolytic system for growth, and mitochondrial oxidative phosphorylation (OXPHOS) is not well utilized. Here, we investigated the ...

Abstract	Glioblastoma is a difficult-to-cure disease owing to its malignancy. Under normal circumstances, cancer is dependent on the glycolytic system for growth, and mitochondrial oxidative phosphorylation (OXPHOS) is not well utilized. Here, we investigated the efficacy of mitochondria-targeted glioblastoma therapy in cell lines including U87MG, LN229, U373, T98G, and two patient-derived stem-like cells. When glioblastoma cells were exposed to a glucose-starved condition (100 mg/l), they rely on mitochondrial OXPHOS for growth, and mitochondrial translation product production is enhanced. Under these circumstances, drugs that inhibit mitochondrial translation, called antimicrobial agents, can cause mitochondrial dysfunction and thus can serve as a therapeutic option for glioblastoma. Antimicrobial agents activated the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 pathway, resulting in increased expression of heme oxygenase-1. Accumulation of lipid peroxides resulted from the accumulation of divalent iron, and cell death occurred via ferroptosis. In conclusion, mitochondrial OXPHOS is upregulated in glioblastoma upon glucose starvation. Under this condition, antimicrobial agents cause cell death via ferroptosis. The findings hold promise for the treatment of glioblastoma.
Language	English
Publishing date	2022-10-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2674437-5
ISSN	2157-9024
ISSN	2157-9024
DOI	10.1038/s41389-022-00437-z
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Article ; Online: Induction of glioblastoma cell ferroptosis using combined treatment with chloramphenicol and 2-deoxy-D-glucose.

Miki, Kenji / Yagi, Mikako / Noguchi, Naoki / Do, Yura / Otsuji, Ryosuke / Kuga, Daisuke / Kang, Dongchon / Yoshimoto, Koji / Uchiumi, Takeshi

Scientific reports

2023 Volume 13, Issue 1, Page(s) 10497

Abstract: Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose- ... ...

Abstract	Glioblastoma, a malignant tumor, has no curative treatment. Recently, mitochondria have been considered a potential target for treating glioblastoma. Previously, we reported that agents initiating mitochondrial dysfunction were effective under glucose-starved conditions. Therefore, this study aimed to develop a mitochondria-targeted treatment to achieve normal glucose conditions. This study used U87MG (U87), U373, and patient-derived stem-like cells as well as chloramphenicol (CAP) and 2-deoxy-D-glucose (2-DG). We investigated whether CAP and 2-DG inhibited the growth of cells under normal and high glucose concentrations. In U87 cells, 2-DG and long-term CAP administration were more effective under normal glucose than high-glucose conditions. In addition, combined CAP and 2-DG treatment was significantly effective under normal glucose concentration in both normal oxygen and hypoxic conditions; this was validated in U373 and patient-derived stem-like cells. 2-DG and CAP acted by influencing iron dynamics; however, deferoxamine inhibited the efficacy of these agents. Thus, ferroptosis could be the underlying mechanism through which 2-DG and CAP act. In conclusion, combined treatment of CAP and 2-DG drastically inhibits cell growth of glioblastoma cell lines even under normal glucose conditions; therefore, this treatment could be effective for glioblastoma patients.
MeSH term(s)	Humans ; Glioblastoma/drug therapy ; Ferroptosis ; Chloramphenicol/pharmacology ; Glucose ; Deoxyglucose/pharmacology
Chemical Substances	Chloramphenicol (66974FR9Q1) ; Glucose (IY9XDZ35W2) ; Deoxyglucose (9G2MP84A8W)
Language	English
Publishing date	2023-06-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-37483-5
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Article ; Online: iMPAQT reveals that adequate mitohormesis from TFAM overexpression leads to life extension in mice.

Igami, Ko / Kittaka, Hiroki / Yagi, Mikako / Gotoh, Kazuhito / Matsushima, Yuichi / Ide, Tomomi / Ikeda, Masataka / Ueda, Saori / Nitta, Shin-Ichiro / Hayakawa, Manami / Nakayama, Keiichi I / Matsumoto, Masaki / Kang, Dongchon / Uchiumi, Takeshi

Life science alliance

2024 Volume 7, Issue 7

Abstract: Mitochondrial transcription factor A, TFAM, is essential for mitochondrial function. We examined the effects of overexpressing ... ...

Abstract	Mitochondrial transcription factor A, TFAM, is essential for mitochondrial function. We examined the effects of overexpressing the
MeSH term(s)	Animals ; Mice ; Mice, Transgenic ; Muscle, Skeletal/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Longevity/genetics ; Mitochondrial Proteins/genetics ; Mitochondrial Proteins/metabolism ; Mitochondria/metabolism ; Mitochondria/genetics ; Male ; Metabolomics/methods ; Growth Differentiation Factor 15/genetics ; Growth Differentiation Factor 15/metabolism ; Gene Expression Regulation ; High Mobility Group Proteins
Chemical Substances	DNA-Binding Proteins ; Transcription Factors ; Tfam protein, mouse ; Mitochondrial Proteins ; Growth Differentiation Factor 15 ; High Mobility Group Proteins
Language	English
Publishing date	2024-04-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302498
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Article ; Online: Cardiomyocyte-specific deletion of the mitochondrial transporter Abcb10 causes cardiac dysfunction via lysosomal-mediated ferroptosis.

Do, Yura / Yagi, Mikako / Hirai, Haruka / Miki, Kenji / Fikahori, Yukina / Setoyama, Daiki / Yamamoto, Masatatsu / Furukawa, Tatsuhiko / Kunishaki, Yuya / Kang, Dongchon / Uchiumi, Takeshi

Bioscience reports

2024

Abstract: Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily ...

Abstract	Heart function is highly dependent on mitochondria, which not only produce energy but also regulate many cellular functions. Therefore, mitochondria are important therapeutic targets in heart failure. Abcb10 is a member of the ABC transporter superfamily located in the inner mitochondrial membrane and plays an important role in haemoglobin synthesis, biliverdin transport, antioxidant stress, and stabilization of the iron transporter mitoferrin-1. However, the mechanisms underlying the impairment of mitochondrial transporters in the heart remain poorly understood. Here we generated mice with cardiomyocyte-specific loss of Abcb10. The Abcb10 knockouts exhibited progressive worsening of cardiac fibrosis, increased cardiovascular risk markers and mitochondrial structural abnormalities, suggesting that the pathology of heart failure is related to mitochondrial dysfunction. As the mitochondrial dysfunction was observed early but mildly, other factors were considered. We then observed increased Hif1α expression, decreased NAD synthase expression, and reduced NAD+ levels, leading to lysosomal dysfunction. Analysis of ABCB10 knockdown HeLa cells revealed accumulation of Fe2+ and lipid peroxides in lysosomes, leading to ferroptosis. Lipid peroxidation was suppressed by treatment with iron chelators, suggesting that lysosomal iron accumulation is involved in ferroptosis. We also observed that Abcb10 knockout cardiomyocytes exhibited increased ROS production, iron accumulation, and lysosomal hypertrophy. Our findings suggest that Abcb10 is required for the maintenance of cardiac function and reveal a novel pathophysiology of chronic heart failure related to lysosomal function and ferroptosis.
Language	English
Publishing date	2024-04-24
Publishing country	England
Document type	Journal Article
ZDB-ID	764946-0
ISSN	1573-4935 ; 0144-8463
ISSN (online)	1573-4935
ISSN	0144-8463
DOI	10.1042/BSR20231992
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Zs.A 1676: Show issues

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bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Mitochondrial dysfunction-induced high hCG associated with development of fetal growth restriction and pre-eclampsia with fetal growth restriction.

Kiyokoba, Ryo / Uchiumi, Takeshi / Yagi, Mikako / Toshima, Takahiro / Tsukahara, Shigehiro / Fujita, Yasuyuki / Kato, Kiyoko / Kang, Dongchon

Scientific reports

2022 Volume 12, Issue 1, Page(s) 4056

Abstract: Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how ... ...

Abstract	Fetal growth restriction (FGR) and pre-eclampsia with fetal growth restriction (PE/FGR) are high-risk perinatal diseases that may involve high levels of human chorionic gonadotropin (hCG) and mitochondrial dysfunction. However, little is known about how these factors affect placental function. We investigated how mitochondrial dysfunction and high hCG expression affected placental function in unexplained FGR and PE/FGR. We observed elevated expression of hCGβ and growth differentiation factor 15 mRNA and protein levels in the placenta with both diseases. Likewise, antiangiogenic factors, such as Ang2, IP10, sFlt1, IL8, IL1B, and TNFα, were also upregulated at the mRNA level. In addition, the expression of COXI and COXII which encoded by mitochondrial DNA were significantly decreased in both diseases, suggesting that mitochondrial translation was impaired. Treatment with hCG increased Ang2, IP10, IL8, and TNFα mRNA levels in a dose-dependent manner via the p38 and JNK pathways. Mitochondrial translation inhibitors increased hCGβ expression through stabilization of HIF1α, and increased IL8 and TNFα mRNA expression. These results revealed that high expression of hCG due to mitochondrial translational dysfunction plays an important role in the pathogenesis of FGR and PE/FGR.
MeSH term(s)	Chemokine CXCL10/metabolism ; Chorionic Gonadotropin/metabolism ; Chorionic Gonadotropin, beta Subunit, Human/metabolism ; Female ; Fetal Growth Retardation/metabolism ; Humans ; Interleukin-8/genetics ; Interleukin-8/metabolism ; Mitochondria/metabolism ; Placenta/metabolism ; Pre-Eclampsia/genetics ; Pre-Eclampsia/metabolism ; Pregnancy ; RNA, Messenger/metabolism ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/metabolism ; Vascular Endothelial Growth Factor Receptor-1/metabolism
Chemical Substances	Chemokine CXCL10 ; Chorionic Gonadotropin ; Chorionic Gonadotropin, beta Subunit, Human ; Interleukin-8 ; RNA, Messenger ; Tumor Necrosis Factor-alpha ; FLT1 protein, human (EC 2.7.10.1) ; Vascular Endothelial Growth Factor Receptor-1 (EC 2.7.10.1)
Language	English
Publishing date	2022-03-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-022-07893-y
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Article ; Online: TFAM expression in brown adipocytes confers obesity resistance by secreting extracellular vesicles that promote self-activation.

Fujii, Masakazu / Setoyama, Daiki / Gotoh, Kazuhito / Dozono, Yushi / Yagi, Mikako / Ikeda, Masataka / Ide, Tomomi / Uchiumi, Takeshi / Kang, Dongchon

iScience

2022 Volume 25, Issue 9, Page(s) 104889

Abstract: The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure ... ...

Abstract	The occurrence of diet-induced obesity has been increasing worldwide and has become a major health concern. Mitochondria are densely distributed in brown adipose tissue and are involved in lipid consumption. Therefore, increasing energy expenditure through the activation of brown adipocytes may be a potential therapy for obesity. Our findings showed that mitochondrial transcription factor A (TFAM) homozygous transgenic (TgTg) mice had highly activated brown adipocytes and increased expression of oxidative phosphorylation, leading to resistance to obesity. Transplantation models of TFAM-expressing brown adipocytes could mimic the phenotype of TFAM TgTg mice, and proving their anti-obesity effect. We found that brown adipocytes secrete exosomes which enable self-activation in an autocrine and paracrine manner. The secretion was enhanced in TFAM TgTg brown adipocytes, resulting in a higher activation. These findings may lead to a promising treatment strategy for obesity through selective stimulation of exosome secretion.
Language	English
Publishing date	2022-08-10
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2022.104889
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Article ; Online: Improving lysosomal ferroptosis with NMN administration protects against heart failure.

Yagi, Mikako / Do, Yura / Hirai, Haruka / Miki, Kenji / Toshima, Takahiro / Fukahori, Yukina / Setoyama, Daiki / Abe, Chiaki / Nabeshima, Yo-Ichi / Kang, Dongchon / Uchiumi, Takeshi

Life science alliance

2023 Volume 6, Issue 12

Abstract: Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor ... ...

Abstract	Myocardial mitochondria are primary sites of myocardial energy metabolism. Mitochondrial disorders are associated with various cardiac diseases. We previously showed that mice with cardiomyocyte-specific knockout of the mitochondrial translation factor p32 developed heart failure from dilated cardiomyopathy. Mitochondrial translation defects cause not only mitochondrial dysfunction but also decreased nicotinamide adenine dinucleotide (NAD
MeSH term(s)	Mice ; Animals ; Nicotinamide Mononucleotide/metabolism ; Nicotinamide Mononucleotide/pharmacology ; NAD/metabolism ; Ferroptosis ; Heart Failure/prevention & control ; Mitochondria/metabolism
Chemical Substances	Nicotinamide Mononucleotide (1094-61-7) ; NAD (0U46U6E8UK)
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302116
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Article ; Online: Mitochondrial haplotype mutation alleviates respiratory defect of MELAS by restoring taurine modification in tRNA with 3243A > G mutation.

Ueda, Saori / Yagi, Mikako / Tomoda, Ena / Matsumoto, Shinya / Ueyanagi, Yasushi / Do, Yura / Setoyama, Daiki / Matsushima, Yuichi / Nagao, Asuteka / Suzuki, Tsutomu / Ide, Tomomi / Mori, Yusuke / Oyama, Noriko / Kang, Dongchon / Uchiumi, Takeshi

Nucleic acids research

2023 Volume 51, Issue 14, Page(s) 7480–7495

Abstract: The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) ... ...

Abstract	The 3243A > G in mtDNA is a representative mutation in mitochondrial diseases. Mitochondrial protein synthesis is impaired due to decoding disorder caused by severe reduction of 5-taurinomethyluridine (τm5U) modification of the mutant mt-tRNALeu(UUR) bearing 3243A > G mutation. The 3243A > G heteroplasmy in peripheral blood reportedly decreases exponentially with age. Here, we found three cases with mild respiratory symptoms despite bearing high rate of 3243A > G mutation (>90%) in blood mtDNA. These patients had the 3290T > C haplotypic mutation in addition to 3243A > G pathogenic mutation in mt-tRNALeu(UUR) gene. We generated cybrid cells of these cases to examine the effects of the 3290T > C mutation on mitochondrial function and found that 3290T > C mutation improved mitochondrial translation, formation of respiratory chain complex, and oxygen consumption rate of pathogenic cells associated with 3243A > G mutation. We measured τm5U frequency of mt-tRNALeu(UUR) with 3243A > G mutation in the cybrids by a primer extension method assisted with chemical derivatization of τm5U, showing that hypomodification of τm5U was significantly restored by the 3290T > C haplotypic mutation. We concluded that the 3290T > C is a haplotypic mutation that suppresses respiratory deficiency of mitochondrial disease by restoring hypomodified τm5U in mt-tRNALeu(UUR) with 3243A > G mutation, implying a potential therapeutic measure for mitochondrial disease associated with pathogenic mutations in mt-tRNAs.
MeSH term(s)	Humans ; MELAS Syndrome/genetics ; MELAS Syndrome/metabolism ; RNA, Transfer, Leu/metabolism ; Taurine ; Haplotypes ; Mutation ; DNA, Mitochondrial/genetics ; Mitochondrial Diseases/genetics
Chemical Substances	RNA, Transfer, Leu ; Taurine (1EQV5MLY3D) ; DNA, Mitochondrial
Language	English
Publishing date	2023-07-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad591
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Zs.A 1067: Show issues

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