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DOI： 10.1016/j.isci.2022.104889

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DOI： 10.15252/embj.2020105268

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DOI： 10.1038/s41598-017-15414-5

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DOI： 10.1093/cvr/cvx095

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DOI： 10.1093/nar/gks774

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DOI： 10.1111/j.1349-7006.2010.01828.x

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

Language：English   Publisher：Life Science Alliance  

Mitochondrial transcription factor A, TFAM, is essential for mitochondrial function. We examined the effects of overexpressing the TFAM gene in mice. Two types of transgenic mice were created: TFAM heterozygous (TFAM Tg) and homozygous (TFAM Tg/Tg) mice. TFAM Tg/Tg mice were smaller and leaner notably with longer lifespans. In skeletal muscle, TFAM overexpression changed gene and protein expression in mitochondrial respiratory chain complexes, with down-regulation in complexes 1, 3, and 4 and up-regulation in complexes 2 and 5. The iMPAQT analysis combined with metabolomics was able to clearly separate the metabolomic features of the three types of mice, with increased degradation of fatty acids and branched-chain amino acids and decreased glycolysis in homozygotes. Consistent with these observations, comprehensive gene expression analysis revealed signs of mitochondrial stress, with elevation of genes associated with the integrated and mitochondrial stress responses, including Atf4, Fgf21, and Gdf15. These found that mitohormesis develops and metabolic shifts in skeletal muscle occur as an adaptive strategy.

DOI： 10.26508/lsa.202302498

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Neurodegenerative diseases and other age-related disorders are closely associated with mitochondrial dysfunction. We previously showed that mice with neuron-specific deficiency of mitochondrial translation exhibit leukoencephalopathy because of demyelination. Reduced cholesterol metabolism has been associated with demyelinating diseases of the brain such as Alzheimer’s disease. However, the molecular mechanisms involved and relevance to the pathogenesis remained unknown. In this study, we show that inhibition of mitochondrial translation significantly reduced expression of the cholesterol synthase genes and degraded their sterol-regulated transcription factor, sterol regulatory element-binding protein 2 (Srebp2). Further-more, the phosphorylation of Pyk2 and Gsk3β was increased in the white matter of p32cKO mice. We observed that Pyk2 inhibitors reduced the phosphorylation of Gsk3β and that GSK3β inhibitors suppressed degradation of the transcription factor Srebp2. The Pyk2–Gsk3β axis is involved in the ubiquitination of Srebp2 and reduced expression of cholesterol gene. These results suggest that inhibition of mitochondrial translation may be a causative mechanism of neurodegenerative diseases of aging. Improving the mitochondrial translation or effectiveness of Gsk3β inhibitors is a potential therapeutic strategy for leukoencephalopathy.

DOI： 10.26508/lsa.202302423

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Language：English   Publisher：iScience  

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.

DOI： 10.1016/j.isci.2024.109735

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Language：English   Publisher：Bioscience reports  

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.

DOI： 10.1042/BSR20231992

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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+) levels, leading to impaired lysosomal acidification and autophagy. In this study, we investigated whether nicotinamide mononucleotide (NMN) administration, which compensates for decreased NAD+ levels, improves heart failure because of mitochondrial dysfunction. NMN administration reduced damaged lysosomes and improved autophagy, thereby reducing heart failure and extending the lifespan in p32cKO mice. We found that lysosomal damage due to mitochondrial dysfunction induced ferroptosis, involving the accumulation of iron in lysosomes and lipid peroxide. The ameliorative effects of NMN supplementation were found to strongly affect lysosomal function rather than mitochondrial function, particularly lysosome-mediated ferroptosis. NMN supplementation can improve lysosomal, rather than mitochondrial, function and prevent chronic heart failure.

DOI： 10.26508/lsa.202302116

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Language：Japanese   Publisher：Scientific Reports  

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.

DOI： 10.1038/s41598-023-37483-5

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Language：Japanese   Publisher：Cell Reports  

Nonalcoholic fatty liver disease (NAFLD) is a chronic metabolic disorder caused by overnutrition and can lead to nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). The transcription factor Forkhead box K1 (FOXK1) is implicated in regulation of lipid metabolism downstream of mechanistic target of rapamycin complex 1 (mTORC1), but its role in NAFLD-NASH pathogenesis is understudied. Here, we show that FOXK1 mediates nutrient-dependent suppression of lipid catabolism in the liver. Hepatocyte-specific deletion of Foxk1 in mice fed a NASH-inducing diet ameliorates not only hepatic steatosis but also associated inflammation, fibrosis, and tumorigenesis, resulting in improved survival. Genome-wide transcriptomic and chromatin immunoprecipitation analyses identify several lipid metabolism-related genes, including Ppara, as direct targets of FOXK1 in the liver. Our results suggest that FOXK1 plays a key role in the regulation of hepatic lipid metabolism and that its inhibition is a promising therapeutic strategy for NAFLD-NASH, as well as for HCC.

DOI： 10.1016/j.celrep.2023.112530

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

DOI： doi.org/10.1016/j.celrep.2023.112530

Publisher：Journal of Gastroenterology and Hepatology (Australia)  

Objective: IgG4-related sclerosing cholangitis (IgG4-SC) is recognized as a benign steroid-responsive disease; however, little is known about the risk of development of cancer in patients with IgG4-SC and about how to counter this risk. Design: We conducted a retrospective review of the data of 924 patients with IgG4-SC selected from a Japanese nationwide survey. The incidence, type of malignancy, and risk of malignancy in these patients were examined. Then, the standardized incidence ratio (SIR) of cancer in patients with IgG4-SC was calculated. Results: Relapse was recognized in 19.7% (182/924) of patients, and cancer development was noted in 15% (139/924) of patients. Multivariate analysis identified only relapse as an independent risk factor for the development of cancer. In most of these patients with pancreato-biliary cancer, the cancer developed within 8 years after the diagnosis of IgG4-SC. The SIR for cancer after the diagnosis of IgG4-SC was 12.68 (95% confidence interval [CI] 6.89–8.79). The SIRs of cancers involving the biliary system and pancreas were 27.35 and 18.43, respectively. The cumulative survival rate was significantly better in the group that received maintenance steroid treatment (MST) than in the group that did not; thus, MST influenced the prognosis of these patients. Conclusion: Among the cancers, the risk of pancreatic and biliary cancers is the highest in these patients. Because of the elevated cancer risk, surveillance after the diagnosis and management to prevent relapse are important in patients with IgG4-SC to reduce the risk of development of cancer.

DOI： 10.1111/jgh.16066

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Language：Japanese   Publisher：Japanese Cosmetic Science Society  

<p>It is well known that the generation of reactive oxygen species (ROS) is increased in aged cells, however, there have been no reports on ROS levels in replicative senescent normal human epidermal keratinocytes (NHEKs). In this study, we investigated the mechanism of increased ROS generation in replicative senescent NHEKs using long-term cultured NHEKs. We defined primary NHEKs cultured for 27 days as aged NHEKs since they express various senescence markers and have decreased proliferation, and compared them with young NHEKs cultured for 13 days that did not show any senescence traits. The number of mitochondria in aged NHEKs increased along with cell enlargement due to aging but the mitochondrial density per protein content was not significantly different from that of young NHEKs. However, the ability to produce ATP was significantly decreased in aged NHEKs compared to young NHEKs. On the other hand, the amount of superoxide that was produced by mitochondria was not significantly different between young and aged NHEKs, and the amount of Mn-SOD (superoxide dismutase), which catalyzes superoxide to hydrogen peroxide, was significantly increased in aged NHEKs compared to young NHEKs. In addition, when hydrogen peroxide was added to the culture medium of young and of aged NHEKs, the scavenging rate was unexpectedly higher in aged NHEKs than in young NHEKs. Furthermore, the amounts of hydroxyl radicals derived from hydrogen peroxide, and Fe²⁺, which catalyzes the reaction, were both higher in aged NHEKs than in young NHEKs. These results suggested that some hydrogen peroxide that had not been eliminated by catalase or glutathione peroxidase is converted to hydroxyl radicals by Fe²⁺, which may contribute to the increased generation of ROS in replicative senescent NHEKs.</p>

DOI： 10.11469/koshohin.47.6

CiNii Research

Language：Japanese   Publisher：日本香粧品学会  

長期継代培養によって複製老化した正常ヒト真皮線維芽細胞(NHEK)を用いてミトコンドリア量や抗酸化力を比較し、複製老化した細胞における活性酸素種(ROS)増大メカニズムを解析した。新生児包皮の表皮から得られた初代培養正常ヒト表皮角化細胞を培養し、培養日数13日間をyoung、27日間をagedとした。細胞内ATP量を測定した。その結果、agedでは同細胞数および同タンパク質量あたりyoungと比較して減少していることから、ミトコンドリア活性がagedで低下していることを示す結果が得られた。ミトコンドリアから発生するスーパーオキシドを過酸化水素に代謝するMn-SODのタンパク質量を検出した。その結果、agedにおいてyoungよりも同細胞数、同タンパク質量あたりMn-SOD量が増加していた。複製老化表皮角化細胞において、一部の過酸化水素が複製老化に伴って増加した二価の鉄イオンによってヒドロキシラジカルに変換され多量のROSが発生していることが示唆された。

Language：Japanese  

DOI： 10.14952/seikagaku.2022.940882

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Language：English  

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.

DOI： 10.1038/s41598-022-07893-y

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DOI： 10.1038/s41598-022-12528-3

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DOI： doi.org/10.1038/s41598-022-07893-y

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

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Other Link： https://doi.org/10.1016/j.isci.2020.101654

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DOI： 10.1016/j.celrep.2018.10.057

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DOI： 10.1038/s41389-017-0009-3

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DOI： 10.1016/j.ajhg.2017.08.015

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DOI： 10.1016/j.ebiom.2017.05.018

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DOI： 10.1016/j.jdermsci.2016.08.533

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DOI： 10.7150/jca.13207

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DOI： 10.18632/oncotarget.12117

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DOI： 10.1038/ncomms4634

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DOI： 10.1111/j.1872-034X.2012.01103.x

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DOI： 10.1042/BSR20120097

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DOI： 10.1042/BSR20120046

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DOI： 10.1016/j.mito.2012.02.004

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DOI： 10.1042/BJ20111728

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DOI： 10.1016/j.bbamem.2011.11.019

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DOI： 10.1093/nar/gkq305

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DOI： 10.1016/j.bbamem.2010.01.019

Event date： 2020.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Venue：横浜   Country：Japan  

老化に伴う多くの疾患はミトコンドリア機能、オートファジー機能, 血中NAD量低下などが関与すると考えられている。ミトコンドリア機能の特にATP産生能低下、活性酸素の増加による細胞障害が疾患の原因とされてきた。飢餓時の蛋白のリサイクリング、損傷蛋白質の除去を司る生体内維持機構としてオートファジーが重要であるが、このオートファジーも老化に伴う疾患に関与することが示唆されている。また老化に伴いNAD量が減少することが疾患の原因となる報告も多い。そこで我々はミトコンドリア機能低下によってNAD量が減少しオートファジー機構の特にリソソーム機能を抑制することが疾患に繋がることを見出しその詳細なメカニズムを解明した。
我々が作製したミトコンドリア機能不全マウス（p32cKO）の解析により、心筋特異的ノックアウトマウスは早期に拡張型心筋症を発症し約500日で死亡することがわかった。このノックアウトマウスの心筋では、(1)メタボローム解析よりNAD量が低下することを見出した。(2)細胞質に存在するNAD合成酵素(nmnat2)の発現が低下していた。(3)心筋特異的p32cKOマウスではオートファジー関連因子であるp62の発現亢進やLC3-IIの増加、局在変化を認めた。このことはオートファジー機能低下、特にリソソーム機能低下を伴うことが示唆された。(4)電子顕微鏡像によりミトコンドリア形態異常、及びリソソーム形態異常を認めた。リソソーム機能はリソソーム内の酸性化が重要であり、ATP依存的なv-ATPaseによりリソソーム内は酸性に保たれる。そこで、リソソーム機能に重要なATP産生は、ミトコンドリア機能に依存するNAD合成系と連関する可能性が考えられた。

Event date： 2020.9

Language：Japanese   Presentation type：Symposium, workshop panel (public)  

Country：Japan  

ミトコンドリアは老化に伴い機能が低下することが知られている。そのため、メタボリックシンドローム、神経変性疾患、心筋症、癌、などを発症すると考えられている。さらに老化に伴う疾患の原因として、オートファジー機能低下、ATP産生能低下、NAD量低下、あるいは活性酸素増加などによる細胞障害が推測されるが、その詳細な分子機構は明らかではない。
我々はミトコンドリアタンパク質p32の機能解析を行ってきた。p32はミトコンドリアのRNAとリボソームの会合に重要な役割を果たすシャペロンとして機能し、ミトコンドリア翻訳に関与することを見出してきた。さらに様々な臓器特異的p32ノックアウトマウスを作製し、臓器ごとに異なるフェノタイプを報告している。その中でも特に、心臓特異的p32ノックアウトマウス(p32cKO)においてオートファジーに変化を見出したためそのメカニズムについて詳しく解析した。
このp32cKOは、早期に拡張型心筋症を発症し約500日で死亡した。その死亡原因を突き止めるためにメタボローム解析を行った。するとp32cKO心臓組織においてNAD量が減少していた。最近の研究では老化に伴い生体内のNAD量が減少し、老化関連疾患を引き起こすと考えられている。p32cKOではNAD合成酵素の特にサルベージ経路の酵素発現が低下しており、その経路の酵素であるNmnatは酵素活性も低下していた。さらにオートファジー関連因子の発現量や形態の変化、リソソーム形態異常などが観察された。NAD合成酵素の一つであるNamptを阻害するとリソソーム活性が減少することもわかった。したがって、生体内NAD量とオートファジーの特にリソソーム機能には関連性があること、そしてミトコンドリア機能に依存していることについて報告したい。

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Type：Competition, symposium, etc.