Two research paths for probing the roles of oxygen in metabolic regulation

Hochachka, Peter W.

doi:10.1590/s0100-879x1999000600001

Cited by 7 publications

(13 citation statements)

References 43 publications

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“…Given that enzymes are structurally localized and not free to readily diffuse about and that substrates are also relatively restricted compared with simple solutions, workers in this area (41,57,58) consider diffusion by itself to be an inadequate, inefficient, and minimally regulatable means of delivering carbon substrates and O 2 to appropriate enzyme targets in the cell under the variable conditions and rates that are required in vivo. Instead, an intracellular circulation or convection system is proposed as an elegantly simple ''assist'' mechanism providing for the efficient bringing together of substrates (including O 2 ) and enzymes under varying metabolic conditions.…”

Section: Model Ii: Explaining the [S] Stability Paradox With Intracelmentioning

confidence: 99%

“…decrease in the velocity of mitochondrial movement (63), presumably coincident with a large drop in O 2 consumption caused by the same kind of manipulation (64). Except for a few recent analyses (41,57,58), the metabolic implications of such intracellular convection systems have been completely overlooked (or ignored). However, the idea of intracellular convection as a means for increasing enzyme-substrate encounter rates with increasing tissue work is quite compelling.…”

Section: Model Ii: Explaining the [S] Stability Paradox With Intracelmentioning

confidence: 99%

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The metabolic implications of intracellular circulation

Hochachka

1999

Proc. Natl. Acad. Sci. U.S.A.

133

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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 ...

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Section: Model Ii: Explaining the [S] Stability Paradox With Intracelmentioning

confidence: 99%

Section: Model Ii: Explaining the [S] Stability Paradox With Intracelmentioning

confidence: 99%

The metabolic implications of intracellular circulation

Hochachka

1999

Proc. Natl. Acad. Sci. U.S.A.

133

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“…LDH-A is one of the glycolytic enzymes with a HIF-1α site. The HIF-1α pathway is activated at oxygen saturation lower than 5% (1 kPa), and although pO 2 in the atmosphere is around 20 kPa, the normal pO 2 in most tissues ranges between 6.7 and 9.3 kPa (Iyer et al , 1998; Hochachka, 1999; Semenza, 2001). …”

Section: Discussionmentioning

confidence: 99%

Anoxia- and hypoxia-induced expression of LDH-A* in the Amazon Oscar, Astronotus crassipinis

et al. 2011

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Adaptation or acclimation to hypoxia occurs via the modulation of physiologically relevant genes, such as erythropoietin, transferrin, vascular endothelial growth factor, phosphofructokinase and lactate dehydrogenase A. In the present study, we have cloned, sequenced and examined the modulation of the LDH-A gene after an Amazonian fish species, Astronotus crassipinis (the Oscar), was exposed to hypoxia and anoxia. In earlier studies, we have discovered that adults of this species are extremely tolerant to hypoxia and anoxia, while the juveniles are less tolerant. Exposure of juveniles to acute hypoxia and anoxia resulted in increased LDH-A gene expression in skeletal and cardiac muscles. When exposed to graded hypoxia juveniles show decreased LDH-A expression. In adults, the levels of LDH-A mRNA did not increase in hypoxic or anoxic conditions. Our results demonstrate that, when given time for acclimation, fish at different life-stages are able to respond differently to survive hypoxic episodes.

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“…Given these constraints, several workers (Wheatley, 2003;Wheatley and Clegg, 1994;Hochachka, 1999b) consider diffusion by itself to be an inadequate, inefficient and minimally regulatable means of delivering carbon substrates and oxygen to appropriate enzyme targets in the cell under the variable conditions and rates that are required in vivo. Instead, we favor an hypothesis -almost demanded by the rules imposed by a structured and ordered internal milieu -of an intracellular convection or perfusion system as an elegantly simply resolution of the problem of how substrates (including O2) and enzymes are brought together.…”

Section: The Model II Approach Intracellular Structure Needs An Intramentioning

confidence: 99%

Intracellular convection, homeostasis and metabolic regulation

Hochachka

2003

Journal of Experimental Biology

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In its historic definition, the term homeostasis refers to the constancy of the internal milieu in the face of external perturbations; the latter in principle may be caused by extracellular factors, or in the case we shall consider, by change in intracellular biological function. Of all the tissues in the vertebrate body, skeletal muscle displays the special quality of being able to routinely sustain very large changes in work and metabolic rates. Compared to the 1.5-to 2-fold differences in metabolic rates between resting and activated states, which is common to many tissues (liver and brain, to mention two), skeletal muscles in most animals must be able to sustain up to, or even more than, 100-fold changes in ATP turnover rates. Amongst vertebrate endotherms, the highest muscle metabolic rate (in the range of 600·µmol·ATP·g -1 ·min -1 ) appears to be that of hummingbird breast muscle during hovering flight, which is a rate over 500 times muscle RMR (Suarez, 1992;Suarez et al., 1990Suarez et al., , 1991. During muscle ischemia, hypoxemia or hypoxia, the metabolism of muscle, like that of many other tissues under conditions of oxygen lack, may need to sustain a suppression of metabolism even below resting rates (Hochachka and Guppy, 1987), thus extending even further the enormous range between the lowest and highest sustainable ATP turnover rates of this remarkable tissue.Current popular interpretations of such large scale differences in steady state energy turnover are regulated assume cybernetic feedback control circuitry. The standard

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Two research paths for probing the roles of oxygen in metabolic regulation

Cited by 7 publications

References 43 publications

The metabolic implications of intracellular circulation

The metabolic implications of intracellular circulation

Anoxia- and hypoxia-induced expression of LDH-A* in the Amazon Oscar, Astronotus crassipinis

Intracellular convection, homeostasis and metabolic regulation

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