High and stable ATP levels prevent aberrant intracellular protein aggregation in yeast

Elife. 2022 Apr 19;11:e67659. doi: 10.7554/eLife.67659.

Abstract

Adenosine triphosphate (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 underwent stochastic and transient depletion, which promoted 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 present study demonstrates 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.

Keywords: AMPK; ATP; S. cerevisiae; adenylate kinase; cell biology; homeostasis; proteostasis; yeast.

Plain language summary

Cells use a chemical called adenosine triphosphate (ATP) as a controllable source of energy. Like a battery, each ATP molecule contains a specific amount of energy that can be released when needed. Cells just need enough ATP to survive, but most cells store a lot more than they need. It is unclear why cells keep so much ATP, or whether this excess ATP has any other purpose. To answer these questions, Takaine et al. identified mutants of the yeast Saccharomyces cerevisiae that had low levels of ATP, and studied how these cells differ from normal yeast The results showed that, in S. cerevisiae cells with lower and variable levels of ATP, proteins stick together, forming clumps. Proteins are molecules that perform diverse roles, keeping cells alive. When they clump together, they stop working and can cause cells to die. Further experiments showed that reducing the levels of ATP just for a short time increased the rate at which proteins stick together. Taken together, Takaine et al.’s results suggest that ATP plays a role in stopping proteins from sticking together, explaining why cells may store excess ATP, since it could aid survival. Protein clumps, also called aggregates, are a key feature of various illnesses, including neurodegenerative diseases such as Alzheimer’s. Takaine et al. provide a possible cause for why proteins aggregate in these diseases, which may be worth further study.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Adenosine Triphosphate / metabolism
  • Adenylate Kinase / metabolism
  • Protein Aggregates*
  • Saccharomyces cerevisiae* / genetics
  • Saccharomyces cerevisiae* / metabolism
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism

Substances

  • Protein Aggregates
  • alpha-Synuclein
  • Adenosine Triphosphate
  • AMP-Activated Protein Kinases
  • Adenylate Kinase

Grant support

The funders had no role in study design, data collection, and interpretation, or the decision to submit the work for publication.