AMP-activated protein kinase and adenylate kinase prevent ATP catastrophe and cytotoxic protein aggregation

Abstract

ATP at millimolar levels has recently been implicated in the solubilization of cellular proteins. However, the significance of this high ATP level under physiological conditions and the mechanisms that maintain ATP remain unclear. We herein demonstrated that AMP-activated protein kinase (AMPK) and adenylate kinase (ADK) cooperated to maintain cellular ATP levels regardless of glucose levels. Single cell imaging of ATP-reduced yeast mutants revealed that ATP levels in these mutants repeatedly underwent stochastic and transient depletion, which induced the cytotoxic aggregation of endogenous proteins and pathogenic proteins, such as huntingtin and -synuclein. Moreover, pharmacological elevations in ATP levels in an ATP-reduced mutant prevented the accumulation of -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 study is the first to demonstrate that cellular ATP homeostasis ensures proteostasis and revealed that suppressing the high volatility of cellular ATP levels prevented cytotoxic protein aggregation, implying that AMPK and ADK are important factors that prevent proteinopathies, such as neurodegenerative diseases.