2. Academic Validation
  3. Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress

Genetically encoded manipulation of ATP/ADP ratio in human cells uncovers proteomic and physiological signatures of energy stress

  • Cell Chem Biol. 2026 May 21;33(5):683-698.e7. doi: 10.1016/j.chembiol.2026.03.004.
Alex E Ekvik 1,  Megan M Kober 1,  Denis V Titov 2
Affiliations

Affiliations

  • 1 Department of Metabolic Biology & Nutrition, University of California, Berkeley, Berkeley, CA, USA.
  • 2 Department of Metabolic Biology & Nutrition, University of California, Berkeley, Berkeley, CA, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA, USA; Department of Molecular & Cell Biology, University of California, Berkeley, Berkeley, CA, USA. Electronic address: [email protected].
PMID: 41980778 DOI: 10.1016/j.chembiol.2026.03.004
Abstract

The ability of cells to power energy-demanding processes depends on maintaining the ATP hydrolysis reaction a billion-fold away from equilibrium. Cells respond to alterations in the energy state by sensing changes in the ratio of ATP, ADP, AMP, and inorganic phosphate levels. A key barrier to understanding how this happens is a lack of tools for direct manipulation of the energy state in living cells. Here, we introduce ATPGobble-a genetically encoded tool that hydrolyzes ATP in vivo. ATPGobble increases the metabolic rate, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK in human cells. We performed a systematic analysis of proteome and phosphoproteome changes caused by ATPGobble, and found that it remodels Cytoskeleton, cell cycle, and translation machinery. Our results establish ATPGobble as a powerful new tool for dissecting the regulatory roles of energy state in living cells.

Keywords

AMPK; ATP; ATP/ADP ratio; F1 ATPase; cell fitness; energy status; energy stress; genetically encoded tools; phosphoproteomics; proteomics.

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