Subcellular Systems Observe Onsager Reciprocity

Abstract The complexity of prokaryotic and, exceedingly, of eukaryotic cells, challenges the implemen-tation of methodologies to determine causality and quantify intracellular dynamics. Although stochastic thermodynamics can be used to effectively quantify the dynamics of single proteins or complexes, there is no statistical approach to generalize subcellular microstates to deter-mine the macrostates of a whole cell. Onsager reciprocity, a coupling between thermody-namic flows, has not been used systematically to quantify and establish causality among cel-lular dynamics. A prototypical thermodynamic profile of the cell is formulated as a model sys-tem to enable representation of its dynamics as force-driven thermodynamic flows. The ex-planatory potential of the methodology of thermodynamic reciprocity is demonstrated on mo-lecular mechanisms in which coupling between internal fluxes has been evident. Its predictive potential is then tested against mechanisms wherein coupling is unacknowledged, ruling out reciprocity between the contractile ring of the bacterial ortholog of tubulin that facilitates the separation of dividing Escherichia coli cells, and the bacterial actin ortholog, which polymer-izes along the cell walls. In contrast, reciprocity is identified, albeit with a large margin of error, between the actomyosin ring that facilitates the division of fission yeast cells and treadmilling longitudinal microtubules. Directly pertinent to the definition of the cell's prototypical thermody-namic profile, the reciprocity that was suggested between AMP-regulated kinase (AMPK) and mechanistic target of rapamycin (mTORC1) in the regulation of the cell cycle is confirmed. These findings support wider implementation of thermodynamic reciprocity to quantify and es-tablish causal relationships among cellular dynamics.