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

ABSTRACT

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.