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ATPGobble: a tool to modify ATP/ADP ratio in human cells

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 changes in energy state by sensing changes in ATP, ADP, AMP, and inorganic phosphate. A key barrier to a better understanding of the maintenance of energy homeostasis is a lack of tools for direct manipulation of energy state in living cells. Here, we report the development of ATPGobble–a genetically encoded tool for controlling cellular ATP hydrolysis rate. We validated ATPGobble by showing that it doubles the energy demand, decreases [ATP]/[ADP] and [ATP]/[AMP] ratios, and activates AMPK activity in human cells. We then used ATPGobble to systematically characterize the proteome and phosphoproteome changes caused by direct manipulation of the energy state. Our results establish ATPGobble as a powerful approach for dissecting the regulatory roles of energy state in human cells, opening new opportunities to study how cellular energy state governs physiology, stress responses, and disease processes.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Retinal Pigment Epithelium Cell Line, Epithelial Cell

DISEASE(S): Disease Free

SUBMITTER: Alex Ekvik

LAB HEAD: Denis V Titov

PROVIDER: PXD066979 | Pride | 2026-04-13

REPOSITORIES: Pride

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			Action	DRS
	17jan25_Ekvick_30spd_10_S4-C1_1_10670.d.zip	Other
	17jan25_Ekvick_30spd_11_S4-C3_1_10672.d.zip	Other
	17jan25_Ekvick_30spd_13_S4-C4_1_10673.d.zip	Other
	17jan25_Ekvick_30spd_14_S4-C5_1_10674.d.zip	Other
	17jan25_Ekvick_30spd_1_S4-B7_1_10664.d.tar	Other

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Project description:This model is from the article: Analyzing the functional properties of the creatine kinase system with multiscale 'sloppy' modeling. Hettling H, van Beek JH PLoS Comput Biol.2011 Aug;7(8):e1002130. PMEDID, Abstract: In this study the function of the two isoforms of creatine kinase (CK; EC 2.7.3.2) in myocardium is investigated. The 'phosphocreatine shuttle' hypothesis states that mitochondrial and cytosolic CK plays a pivotal role in the transport of high-energy phosphate (HEP) groups from mitochondria to myofibrils in contracting muscle. Temporal buffering of changes in ATP and ADP is another potential role of CK. With a mathematical model, we analyzed energy transport and damping of high peaks of ATP hydrolysis during the cardiac cycle. The analysis was based on multiscale data measured at the level of isolated enzymes, isolated mitochondria and on dynamic response times of oxidative phosphorylation measured at the whole heart level. Using 'sloppy modeling' ensemble simulations, we derived confidence intervals for predictions of the contributions by phosphocreatine (PCr) and ATP to the transfer of HEP from mitochondria to sites of ATP hydrolysis. Our calculations indicate that only 15±8% (mean±SD) of transcytosolic energy transport is carried by PCr, contradicting the PCr shuttle hypothesis. We also predicted temporal buffering capabilities of the CK isoforms protecting against high peaks of ATP hydrolysis (3750 µM*s(-1)) in myofibrils. CK inhibition by 98% in silico leads to an increase in amplitude of mitochondrial ATP synthesis pulsation from 215±23 to 566±31 µM*s(-1), while amplitudes of oscillations in cytosolic ADP concentration double from 77±11 to 146±1 µM. Our findings indicate that CK acts as a large bandwidth high-capacity temporal energy buffer maintaining cellular ATP homeostasis and reducing oscillations in mitochondrial metabolism. However, the contribution of CK to the transport of high-energy phosphate groups appears limited. Mitochondrial CK activity lowers cytosolic inorganic phosphate levels while cytosolic CK has the opposite effect. This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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ATPGobble: a tool to modify ATP/ADP ratio in human cells

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