The metabolic implications of intracellular circulation

Abstract

Two views currently dominate research into cell function and regulation. Model I assumes that cell behavior is quite similar to that expected for a watery bag of enzymes and ligands. Model II assumes that three-dimensional order and structure constrain and determine metabolite behavior. A major problem in cell metabolism is determining why essentially all metabolite concentrations are remarkably stable (are homeostatic) over large changes in pathway fluxes-for convenience, this is termed the [s] stability paradox. For muscle cells, ATP and O 2 are the most perfectly homeostatic, even though O2 delivery and metabolic rate correlate in a 1:1 fashion. In total, more than 60 metabolites are known to be remarkably homeostatic in differing metabolic states. Several explanations of [s] stability are usually given by traditional model I studies-none of which apply to all enzymes in a pathway, and all of which require diffusion as the means for changing enzyme-substrate encounter rates. In contrast, recent developments in our understanding of intracellular myosin, kinesin, and dyenin motors running on actin and tubulin tracks or cables supply a mechanistic basis for regulated intracellular circulation systems with cytoplasmic streaming rates varying over an approximately 80-fold range (from 1 to >80 m ؋ sec ؊1 ). These new studies raise a model II hypothesis of intracellular perfusion or convection as a primary means for bringing enzymes and substrates together under variable metabolic conditions. In this view, change in intracellular perfusion rates cause change in enzyme-substrate encounter rates and thus change in pathway fluxes with no requirement for large simultaneous changes in substrate concentrations. The ease with which this hypothesis explains the [s] stability paradox is one of its most compelling features. Two Models and Research Approaches in Cell Metabolism and RegulationI t is a rule of thumb in biology that many physiological and molecular functions are the sum of individual processes linked in sequence; in isolation, many such individual processes have no clear functions at all. How such systems are designed and regulated have presented perplexing problems to both biochemists and physiologists. Integrated function is often evaluated by comparing changes in flux through the pathway per se with changes in concentrations of substrates and products of individual enzyme reactions within the pathway. Two guiding paradigms or frameworks (for convenience we will term them model I and model II) have guided these evaluations. Although rarely stated, the implicit assumptions in model I studies are that simple ''solution chemistry'' rules apply to the cell͞tissue as a whole, that changes in rates of enzyme-substrate or protein-ligand interactions are generally diffusion dominated, and that cell behavior can thus be considered to be similar to that expected for a watery bag of organic materials. For model II studies, the starting point is structure-the microanatomy of the inside of the cell. These studies recognize ...

Batchelor Prize Lecture Fluid dynamics at the scale of the cell

“…This phenomenon is similar to that which occurs in the microfluidic 'herringbone micromixer' (Stroock et al 2002) in which diagonal grooves in the channel deflect the flow from its primary downstream direction, but in the case of Chara the flow is not chaotic. Computations show that there can be enhanced uptake of nutrients from the surrounding medium and more rapid mixing within the vacuole, providing support for the notion mentioned above (Hochachka 1999) that homeostasis is enhanced by streaming.…”

“…One extreme view is that the flows per se have no useful function, but are simply an inevitable by-product of nanoscale transport (Pickard 1974). Counter to this is the view that streaming can promote mixing in the cell and thereby help maintain homeostasis (Hochachka 1999). This debate prompted us to investigate the flows quantitatively and to consider their implications for transport and metabolism within cells.…”

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