{"title":"线粒体翻译失败通过 Pyk2-Gsk3β-Srebp2 轴抑制胆固醇基因的表达。","authors":"Takahiro Toshima, Mikako Yagi, Yura Do, Haruka Hirai, Yuya Kunisaki, Dongchon Kang, Takeshi Uchiumi","doi":"10.26508/lsa.202302423","DOIUrl":null,"url":null,"abstract":"<p><p>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). Furthermore, 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.</p>","PeriodicalId":18081,"journal":{"name":"Life Science Alliance","volume":"7 7","pages":""},"PeriodicalIF":3.3000,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11079605/pdf/","citationCount":"0","resultStr":"{\"title\":\"Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis.\",\"authors\":\"Takahiro Toshima, Mikako Yagi, Yura Do, Haruka Hirai, Yuya Kunisaki, Dongchon Kang, Takeshi Uchiumi\",\"doi\":\"10.26508/lsa.202302423\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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). Furthermore, 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.</p>\",\"PeriodicalId\":18081,\"journal\":{\"name\":\"Life Science Alliance\",\"volume\":\"7 7\",\"pages\":\"\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-05-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11079605/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Life Science Alliance\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.26508/lsa.202302423\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/1 0:00:00\",\"PubModel\":\"Print\",\"JCR\":\"Q1\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Life Science Alliance","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.26508/lsa.202302423","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/1 0:00:00","PubModel":"Print","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
Mitochondrial translation failure represses cholesterol gene expression via Pyk2-Gsk3β-Srebp2 axis.
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). Furthermore, 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.
期刊介绍:
Life Science Alliance is a global, open-access, editorially independent, and peer-reviewed journal launched by an alliance of EMBO Press, Rockefeller University Press, and Cold Spring Harbor Laboratory Press. Life Science Alliance is committed to rapid, fair, and transparent publication of valuable research from across all areas in the life sciences.