Mitoribosome protein translation signaling and survival mechanisms

线粒体核糖体蛋白翻译信号传导和生存机制

基本信息

  • 批准号:
    10714636
  • 负责人:
  • 金额:
    $ 72.73万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-30 至 2028-05-31
  • 项目状态:
    未结题

项目摘要

Abstract Defective mitochondrial function causes cellular damage and death under stress conditions. At the organismal level mitochondrial dysfunction occurs in mitochondrial diseases caused by genetic mutations, neurodegeneration, and with less severity during aging, damaging vulnerable tissues such as brain and skeletal muscle. Mitochondrial mutations cause failures that disrupt energy metabolism, including reductive/oxidative imbalances and inflammation that lead to tissue damage and eventually death. Mitochondrial defective cells depend on glycolysis for energy generation and, similar to mitochondrial disease patients, are vulnerable to stress conditions. The mechanisms that cause this cell damage and how mitochondrial defective cells can be protected against damage and death are largely unknown. This is important because there are no cures for mitochondrial diseases, and dysfunctional mitochondria is one of the hallmarks of aging or neurodegeneration. In genetic and chemical high throughput screens our laboratory has identified a subset of antibiotics, including tetracyclines, that target the mitoribosome protein translation, and rescue cell death and inflammation in cellular and mouse models of mitochondrial diseases. Tetracyclines-promoted cell survival depends on suppression of ER stress and Unfolded Protein Response (UPR) that is independent of the transcription factor ATF4. The mechanisms of how tetracycline-induced mitoribosome stalling/splitting protect against cell death in cellular and mouse pre-clinical models of mitochondrial diseases is unknown. We hypothesize that a signaling mechanism initiated at the stalled/split mitoribosome promotes cell survival in the context of mitochondrial defective cells and human disease mutations. The main goal of this application is to identify the signaling and cellular mechanisms caused by stalled and split mitoribosomes that promote cell survival and determine the efficacy in cellular and mouse models of mitochondrial diseases. We propose 1) to determine the initial signaling mechanism at the partial stalled/split mitoribosome that promotes survival in mitochondrial disease mutant cells, focusing on MALSU splitting factor and additional proteins associated at the mitoribosome; 2) to analyze the components downstream of the stalled/split mitoribosome that promote survival in mitochondrial disease mutant cells, focusing on components that link the stalled/split mitoribosome to ER stress IRE1a and UPR responses and 3) to analyze the effects of tetracycline analogs in Ndufs4 KO mice, a mitochondrial complex I deficient mouse model, focusing on the effects tetracyclines on fitness, survival and modulation of mitoribosome signaling/ER stress and suppression of brain and skeletal muscle immune inflammation in Ndufs4 KO mice. The outcomes of this application will determine the regulatory and signaling mechanisms that are initiated by the stalled/split mitoribosome in conditions of defective mitochondrial disease mutations. These mechanisms will advance our understanding of mitoribosome protein translation and signaling mechanisms that protect cell damage in the context of mitochondrial dysregulation and diseases.
摘要

项目成果

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Pere Puigserver其他文献

Pere Puigserver的其他文献

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{{ truncateString('Pere Puigserver', 18)}}的其他基金

Regulatory mechanisms of mitochondrial cristae biogenesis and thermogenic function
线粒体嵴生物发生和产热功能的调节机制
  • 批准号:
    10716595
  • 财政年份:
    2023
  • 资助金额:
    $ 72.73万
  • 项目类别:
Mitochondrial Protein Translation Signaling and Survival Mechanisms
线粒体蛋白翻译信号和生存机制
  • 批准号:
    10462235
  • 财政年份:
    2021
  • 资助金额:
    $ 72.73万
  • 项目类别:
Metabolic and Bioenergetic Control in Mitochondrial Diseases
线粒体疾病的代谢和生物能控制
  • 批准号:
    9926273
  • 财政年份:
    2017
  • 资助金额:
    $ 72.73万
  • 项目类别:
Metabolic and epigenetic dependencies in melanomas during metastasis and targeted-drug resistance
黑色素瘤转移和靶向药物耐药过程中的代谢和表观遗传依赖性
  • 批准号:
    10599853
  • 财政年份:
    2014
  • 资助金额:
    $ 72.73万
  • 项目类别:
Metabolic Vulnerabilities in Melanoma Tumors
黑色素瘤的代谢脆弱性
  • 批准号:
    8760634
  • 财政年份:
    2014
  • 资助金额:
    $ 72.73万
  • 项目类别:
Metabolic and epigenetic dependencies in melanomas during metastasis and targeted-drug resistance
黑色素瘤转移和靶向药物耐药过程中的代谢和表观遗传依赖性
  • 批准号:
    10369725
  • 财政年份:
    2014
  • 资助金额:
    $ 72.73万
  • 项目类别:
Energy Expenditure and Metabolic Effects through Brown/Beige Adipose Clk2 Kinase
棕色/米色脂肪 Clk2 激酶的能量消耗和代谢效应
  • 批准号:
    9902407
  • 财政年份:
    2011
  • 资助金额:
    $ 72.73万
  • 项目类别:
Insulin Signaling and Metabolic Effects through CLK2 Kinase
CLK2 激酶的胰岛素信号传导和代谢效应
  • 批准号:
    8638955
  • 财政年份:
    2011
  • 资助金额:
    $ 72.73万
  • 项目类别:
Insulin Signaling and Metabolic Effects through CLK2 Kinase
CLK2 激酶的胰岛素信号传导和代谢效应
  • 批准号:
    8448785
  • 财政年份:
    2011
  • 资助金额:
    $ 72.73万
  • 项目类别:
Insulin Signaling and Metabolic Effects through CLK2 Kinase
CLK2 激酶的胰岛素信号传导和代谢效应
  • 批准号:
    8242706
  • 财政年份:
    2011
  • 资助金额:
    $ 72.73万
  • 项目类别:

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