Abstract
Regulatory dynamics of energy metabolism in living cells entails a coordinated response of multiple enzyme networks that operate under non-equilibrium conditions. Here we show that mitochondrial dysfunctions associated with the aging process significantly modify nonlinear dynamical signatures in free radical generation/removal, thereby altering energy metabolism in liver cells. We support our data with a plausible biochemical mechanism for modified bioenergetics that involves uncoupling protein-2 that is up-regulated in aged cells as an adaptive response to mitigate increased oxidative stress. Combining high spatial and temporal resolution imaging and bio-energetic measurements, our work provides experimental support to the hypothesis that mitochondria manifest nonlinear dynamical behavior for efficiently regulating energy metabolism in intact cells, and any partial or complete reduction in this behavior would contribute to organ dysfunctions including the aging process and other disease processes.
Highlights
Unable to provide a realistic picture since they ignored physiologically relevant regulatory cross-talks between mitochondria and cytosol/nucleus
We observed that young liver cells manifest nonlinear dynamics for efficiently regulating reactive oxygen species (ROS) generation/removal machinery and that these regulatory correlations in free radical dynamics are diminished in aged cells, suggesting that the aging process modulates chemical dynamics in liver cell energy metabolism
As can be seen clearly, young cells display larger dispersion than aged cells even in their resting metabolic status, and this becomes more pronounced during substrate metabolism
Summary
On the other hand lifespan measurements at the whole animal level may indicate specific conditions (such as calorie restriction) in which lifespan can be increased or decreased, but they do not give any clue on the cellular mechanism involved in the aging process per se It is, imperative to develop strategies to probe single-cell responses that can report the mitochondrial dynamics in relation to other relevant metabolic networks in living cells rather than in isolated conditions. It is possible to dissect single cell responses under controlled perturbations, and one can obtain mechanistic insights into the complex dynamics of metabolic networks in living cells With this motivation we sought to ask how the aging process contributes to modifications in subtle dynamics in metabolic networks and how these modifications determine the overall cellular responses during normal substrate metabolism and under oxidative stress. Our data demonstrate for the first time that similar physiologically relevant nonlinear dynamical features are operative at the level of single cells for efficient regulation of energy metabolism
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