The oxygen dependence of cellular energy metabolism

Wilson, David F.; Erecińska, Maria; Drown, C.; Silver, Ian A.

doi:10.1016/0003-9861(79)90375-8

Cited by 333 publications

(107 citation statements)

References 19 publications

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“…While, as for complexes I and III, the flux is formulated to drive the system toward thermodynamic equilibrium, additional multiplicative factors have been included in order to successfully reproduce the observed data. The factor 1=ð1 þ k O2 =½O 2 Þ is included in equation 9 to account for the observed dependence of the rates of oxygen consumption and ATP generation on oxygen concentration [6,[19][20][21]26,27]. It will be shown that the factor [cytC(red) 2þ ]/ cytC tot is found to provide better fits to the observed data than are possible without it.…”

Section: Synopsismentioning

confidence: 99%

A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

Beard¹

2005

PLoS Comp Biol

106

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A computational model for the mitochondrial respiratory chain that appropriately balances mass, charge, and free energy transduction is introduced and analyzed based on a previously published set of data measured on isolated cardiac mitochondria. The basic components included in the model are the reactions at complexes I, III, and IV of the electron transport system, ATP synthesis at F 1 F 0 ATPase, substrate transporters including adenine nucleotide translocase and the phosphate-hydrogen co-transporter, and cation fluxes across the inner membrane including fluxes through the K þ /H þ antiporter and passive H þ and K þ permeation. Estimation of 16 adjustable parameter values is based on fitting model simulations to nine independent data curves. The identified model is further validated by comparison to additional datasets measured from mitochondria isolated from rat heart and liver and observed at low oxygen concentration. To obtain reasonable fits to the available data, it is necessary to incorporate inorganic-phosphatedependent activation of the dehydrogenase activity and the electron transport system. Specifically, it is shown that a model incorporating phosphate-dependent activation of complex III is able to reasonably reproduce the observed data. The resulting validated and verified model provides a foundation for building larger and more complex systems models and investigating complex physiological and pathophysiological interactions in cardiac energetics.

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Section: Synopsismentioning

confidence: 99%

A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

Beard¹

2005

PLoS Comp Biol

106

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“…Increases in dissolved oxygen have been shown to increase cellular ATP levels, perhaps through increased cellular metabolism. 75,76 In contrast to fibroblasts, 71 primary osteoblasts, 77 primary chondrocytes, 34 and human MSCs, 32 primary SMG cells exhibit poor viability when exposed to methacrylate-based chain-addition polymerization reactions (Fig. 1B).…”

Section: Resultsmentioning

confidence: 99%

Development of Poly(Ethylene Glycol) Hydrogels for Salivary Gland Tissue Engineering Applications

Shubin

Felong

Graunke

et al. 2015

Tissue Engineering Part A

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More than 40,000 patients are diagnosed with head and neck cancers annually in the United States with the vast majority receiving radiation therapy. Salivary glands are irreparably damaged by radiation therapy resulting in xerostomia, which severely affects patient quality of life. Cell-based therapies have shown some promise in mouse models of radiation-induced xerostomia, but they suffer from insufficient and inconsistent gland regeneration and accompanying secretory function. To aid in the development of regenerative therapies, poly(ethylene glycol) hydrogels were investigated for the encapsulation of primary submandibular gland (SMG) cells for tissue engineering applications. Different methods of hydrogel formation and cell preparation were examined to identify cytocompatible encapsulation conditions for SMG cells. Cell viability was much higher after thiol-ene polymerizations compared with conventional methacrylate polymerizations due to reduced membrane peroxidation and intracellular reactive oxygen species formation. In addition, the formation of multicellular microspheres before encapsulation maximized cell-cell contacts and increased viability of SMG cells over 14-day culture periods. Thiol-ene hydrogel-encapsulated microspheres also promoted SMG proliferation. Lineage tracing was employed to determine the cellular composition of hydrogel-encapsulated microspheres using markers for acinar (Mist1) and duct (Keratin5) cells. Our findings indicate that both acinar and duct cell phenotypes are present throughout the 14 day culture period. However, the acinar:duct cell ratios are reduced over time, likely due to duct cell proliferation. Altogether, permissive encapsulation methods for primary SMG cells have been identified that promote cell viability, proliferation, and maintenance of differentiated salivary gland cell phenotypes, which allows for translation of this approach for salivary gland tissue engineering applications.

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“…3A), showing that cytochrome c counteracts partially the inhibitory effects of NO. This situation is akin to the known relationship between the levels of cytochrome c reduction and oxygen concentration (26,27).…”

Section: Effects Of No In State 3 and State 4 Respirationmentioning

confidence: 97%

On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide

Antunes

Boveris

Cadenas

2004

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

169

128

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The detailed molecular mechanism for the reversible inhibition of mitochondrial respiration by NO has puzzled investigators: The rate constants for the binding of NO and O 2 to the reduced binuclear center Cu B͞a3 of cytochrome oxidase (COX) are similar, and NO is able to dissociate slowly from this center whereas O 2 is kinetically trapped, which altogether seems to favor the complex of COX with O 2 over the complex of COX with NO. Paradoxically, the inhibition of COX by NO is observed at high ratios of O 2 to NO (in the 40 -500 range) and is very fast (seconds or faster). In this work, we used simple mathematical models to investigate this paradox and other important biological questions concerning the inhibition of COX by NO. The results showed that all known features of the inhibition of COX by NO can be accounted for by a direct competition between NO and O 2 for the reduced binuclear center Cu B͞a3 of COX. Besides conciliating apparently contradictory data, this work provided an explanation for the so-called excess capacity of COX by showing that the COX activity found in tissues actually is optimized to avoid an excessive inhibition of mitochondrial respiration by NO, allowing a moderate, but not excessive, overlap between the roles of NO in COX inhibition and in cellular signaling. In pathological situations such as COX-deficiency diseases and chronic inflammation, an excessive inhibition of the mitochondrial respiration is predicted.mitochondrial respiration ͉ mathematical model ͉ cytochrome-oxidasedeficiency diseases ͉ inflammation ͉ excess capacity of cytochrome oxidase T he paradigm that the respiratory chain is regulated by ADP and O 2 was recently updated to include the reversible inhibition of cytochrome oxidase (COX) by nitric oxide (NO) (1-6). The physiological role and the detailed molecular mechanism of this inhibition, as well as the reason for the apparent excess content of COX compared with other mitochondrial complexes, are fundamental questions of mitochondrial biochemistry that remain unsolved. Concerning the mechanism, the problem is particularly puzzling because the known characteristics of COX inhibition by NO are difficult to conciliate with the available kinetic rate constants for this inhibition. On the one hand, COX is inhibited rapidly, within a time scale of seconds, with half-inhibition of respiration attained at O 2 ͞NO ratios in the 40-500 range (4, 7), which apparently indicates that the interaction of COX with NO is stronger than that of COX with O 2 and very fast. On the other hand, the rate constants for the binding of O 2 and NO with the fully reduced binuclear center (Cu B ͞a 3 ) of COX are similar [1.4 ϫ 10 8 (8) and 4 ϫ 10 7 to 1 ϫ 10 8 M Ϫ1 ⅐s Ϫ1 (9, 10), respectively] and NO dissociates slowly from this center (0.01-0.13 s Ϫ1 ) (11, 12), whereas the apparent dissociation rate constant of O 2 with COX is virtually zero because, during the initial steps of reduction of oxygen by COX, oxygen is kinetically trapped (8). Accordingly, several investigators have noticed th...

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The oxygen dependence of cellular energy metabolism

Cited by 333 publications

References 19 publications

A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

A Biophysical Model of the Mitochondrial Respiratory System and Oxidative Phosphorylation

Development of Poly(Ethylene Glycol) Hydrogels for Salivary Gland Tissue Engineering Applications

On the mechanism and biology of cytochrome oxidase inhibition by nitric oxide

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