ATP is the major source of chemical energy in all life and maintained at several millimolar in eukaryotic cells. However, the underlying mechanism and physiological relevance of such high and stable concentrations of ATP remain unclear. Here we show that AMP-activated protein kinase (AMPK) and adenylate kinase (ADK) cooperate to maintain cellular ATP level regardless of glucose concentrations. Single cell imaging of ATP revealed that ATP concentrations in these mutants underwent stochastic and

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... ransient depletion of ATP repeatedly, inducing formation of cytotoxic aggregation of endogenous proteins and pathogenic proteins such as huntingtin and α-synuclein. Moreover, pharmacological elevation of ATP level in an ATP-reduced mutant prevented accumulation of α-synuclein aggregation and its cytotoxicity. Removal of the cytotoxic aggregates depends on proteasome, and proteasomal activity cooperates with AMPK or ADK to resist proteotoxic stresses. Our findings provided the first evidence that cellular ATP homeostasis ensures proteostasis and revealed that stochastic fluctuation of cellular ATP concentration could contribute for cytotoxic protein aggregation, implying that AMPK and ADK are important factors that prevent proteinopathy such as neurodegenerative diseases.