“Futile Cycling” in Physiologic Control Systems: A Price Paid for Fine Control

Rachana, Krishna; Prakash, Elapulli

doi:10.1152/advan.00010.2005

Cited by 3 publications

(1 citation statement)

References 3 publications

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“…As mentioned in the last section, new theories are also suggesting that calcium cycling could also be a thermogenic mechanism [200]. Another way to view it is that futile cycling is a price paid for fine control of metabolism [219]. Indeed, the link between uncoupling and lifespan has been investigated, and it is complex, but there is evidence that it can enhance lifespan in some models [220].…”

Section: Dissipation In and Out Of The Goldilocks Zone-controlling Li...mentioning

confidence: 99%

Informing the Cannabis Conjecture: From Life’s Beginnings to Mitochondria, Membranes and the Electrome—A Review

Nunn,

Guy,

Bell

2023

IJMS

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Before the late 1980s, ideas around how the lipophilic phytocannabinoids might be working involved membranes and bioenergetics as these disciplines were “in vogue”. However, as interest in genetics and pharmacology grew, interest in mitochondria (and membranes) waned. The discovery of the cognate receptor for tetrahydrocannabinol (THC) led to the classification of the endocannabinoid system (ECS) and the conjecture that phytocannabinoids might be “working” through this system. However, the how and the “why” they might be beneficial, especially for compounds like CBD, remains unclear. Given the centrality of membranes and mitochondria in complex organisms, and their evolutionary heritage from the beginnings of life, revisiting phytocannabinoid action in this light could be enlightening. For example, life can be described as a self-organising and replicating far from equilibrium dissipating system, which is defined by the movement of charge across a membrane. Hence the building evidence, at least in animals, that THC and CBD modulate mitochondrial function could be highly informative. In this paper, we offer a unique perspective to the question, why and how do compounds like CBD potentially work as medicines in so many different conditions? The answer, we suggest, is that they can modulate membrane fluidity in a number of ways and thus dissipation and engender homeostasis, particularly under stress. To understand this, we need to embrace origins of life theories, the role of mitochondria in plants and explanations of disease and ageing from an adaptive thermodynamic perspective, as well as quantum mechanics.

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Section: Dissipation In and Out Of The Goldilocks Zone-controlling Li...mentioning

confidence: 99%

Informing the Cannabis Conjecture: From Life’s Beginnings to Mitochondria, Membranes and the Electrome—A Review

Nunn,

Guy,

Bell

2023

IJMS

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A Whole-Body Model for Glycogen Regulation Reveals a Critical Role for Substrate Cycling in Maintaining Blood Glucose Homeostasis

Morgan²,

Abby

et al. 2011

PLoS Comput Biol

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Timely, and sometimes rapid, metabolic adaptation to changes in food supply is critical for survival as an organism moves from the fasted to the fed state, and vice versa. These transitions necessitate major metabolic changes to maintain energy homeostasis as the source of blood glucose moves away from ingested carbohydrates, through hepatic glycogen stores, towards gluconeogenesis. The integration of hepatic glycogen regulation with extra-hepatic energetics is a key aspect of these adaptive mechanisms. Here we use computational modeling to explore hepatic glycogen regulation under fed and fasting conditions in the context of a whole-body model. The model was validated against previous experimental results concerning glycogen phosphorylase a (active) and glycogen synthase a dynamics. The model qualitatively reproduced physiological changes that occur during transition from the fed to the fasted state. Analysis of the model reveals a critical role for the inhibition of glycogen synthase phosphatase by glycogen phosphorylase a. This negative regulation leads to high levels of glycogen synthase activity during fasting conditions, which in turn increases substrate (futile) cycling, priming the system for a rapid response once an external source of glucose is restored. This work demonstrates that a mechanistic understanding of the design principles used by metabolic control circuits to maintain homeostasis can benefit from the incorporation of mathematical descriptions of these networks into “whole-body” contextual models that mimic in vivo conditions.

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