AMP-activated protein kinase and adenylate kinase prevent the ATP catastrophe and cytotoxic protein aggregation
AMP-activated protein kinase and adenylate kinase prevent the ATP catastrophe and cytotoxic protein aggregation
复制标题
AMP 激活的蛋白激酶和腺苷酸激酶可防止 ATP 灾难和细胞毒性蛋白聚集
DOI：
10.1101/801738
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Yoshida Satoshi
中科院分区：
文献类型：
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作者：
Takaine Masak;Imamura Hiromi;Yoshida Satoshi
ATP是所有生命中化学能的主要来源，在真核细胞中维持在几毫摩尔。然而，这种高而稳定的ATP浓度的机制和生理相关性仍不清楚。我们在此证明，腺苷酸活化蛋白激酶（AMPK）和腺苷酸激酶（ADK）合作，以维持细胞ATP水平，而不管葡萄糖浓度。ATP还原酵母突变体的单细胞成像显示，这些突变体中的ATP浓度反复经历随机和短暂的ATP耗竭，这诱导了内源蛋白和致病蛋白（如亨廷顿蛋白和α-突触核蛋白）的细胞毒性聚集。此外，ATP减少突变体中ATP水平的药理学升高阻止了α-突触核蛋白聚集体的积累及其细胞毒性。细胞毒性聚集体的清除依赖于蛋白酶体，蛋白酶体活性与AMPK或ADK协同抵抗蛋白毒性应激。目前的结果提供了第一个证据表明，细胞ATP稳态确保蛋白质稳态，并揭示了细胞ATP浓度的随机波动有助于细胞毒性蛋白质聚集，这意味着AMPK和ADK是预防蛋白质病，如神经退行性疾病的重要因素。
ATP is the main source of chemical energy in all life and is maintained at several millimolar in eukaryotic cells. However, the mechanisms responsible for and physiological relevance of this high and stable concentration of ATP remain unclear. We herein demonstrate that AMP-activated protein kinase (AMPK) and adenylate kinase (ADK) cooperate to maintain cellular ATP levels regardless of glucose concentrations. Single cell imaging of ATP-reduced yeast mutants revealed that ATP concentrations in these mutants underwent stochastic and transient depletion of ATP repeatedly, which induced the cytotoxic aggregation of endogenous proteins and pathogenic proteins, such as huntingtin and α-synuclein. Moreover, pharmacological elevations in ATP levels in an ATP-reduced mutant prevented the accumulation of α-synuclein aggregates and its cytotoxicity. The removal of cytotoxic aggregates depended on proteasomes, and proteasomal activity cooperated with AMPK or ADK to resist proteotoxic stresses. The present results provide the first evidence to show that cellular ATP homeostasis ensures proteostasis and revealed that stochastic fluctuations in cellular ATP concentrations contribute to cytotoxic protein aggregation, implying that AMPK and ADK are important factors that prevent proteinopathies, such as neurodegenerative diseases.