Intracellular diffusion gradients of O2 and ATP

Jones, Dean P.

doi:10.1152/ajpcell.1986.250.5.c663

Cited by 267 publications

(151 citation statements)

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“…In the olfactory bulb, for example, where capillary density is high, intercapillary differences and 'Krogh cylinders' are small. Parpaleix 21 Because of the lower fraction of free water within cells as compared with extracellular space, higher viscosity within the cells and diffusional barriers imposed by proteins, diffusion coefficients for small molecules such as oxygen are considerably smaller intracellularly 21 than extracellularly. In cardiomyocytes, an intracellular oxygen gradient of only 2 mm Hg has been determined over a wide range of extracellular pO 2 .…”

Section: Relevant Basic Numbers Of Oxygen and Glucose Delivery To Thementioning

confidence: 99%

The Oxygen Paradox of Neurovascular Coupling

Leithner

Royl

2013

J Cereb Blood Flow Metab

113

100

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The coupling of cerebral blood flow (CBF) to neuronal activity is well preserved during evolution. Upon changes in the neuronal activity, an incompletely understood coupling mechanism regulates diameter changes of supplying blood vessels, which adjust CBF within seconds. The physiologic brain tissue oxygen content would sustain unimpeded brain function for only 1 second if continuous oxygen supply would suddenly stop. This suggests that the CBF response has evolved to balance oxygen supply and demand. Surprisingly, CBF increases surpass the accompanying increases of cerebral metabolic rate of oxygen (CMRO 2 ). However, a disproportionate CBF increase may be required to increase the concentration gradient from capillary to tissue that drives oxygen delivery. However, the brain tissue oxygen content is not zero, and tissue pO 2 decreases could serve to increase oxygen delivery without a CBF increase. Experimental evidence suggests that CMRO 2 can increase with constant CBF within limits and decreases of baseline CBF were observed with constant CMRO 2 . This conflicting evidence may be viewed as an oxygen paradox of neurovascular coupling. As a possible solution for this paradox, we hypothesize that the CBF response has evolved to safeguard brain function in situations of moderate pathophysiological interference with oxygen supply. Keywords: brain; CMRO 2 ; functional hyperemia; neurovascular coupling; oxygen A quick glance at basic numbers of oxygen and glucose delivery to the brain and cerebral energy metabolism suggests that the most delicate function of cerebral blood flow (CBF) is the delivery of sufficient amounts of oxygen to the tissue where the oxygen reserve is so low that ATP production declines almost immediately once blood flow ceases. Therefore, the intuitive explanation for the rapid and large CBF response to neuronal activation is the supply of the additional oxygen needed. Experimental observations of large CBF responses accompanying small increases of cerebral metabolic rate of oxygen (CMRO 2 ), however, have cast doubt on this intuitive assumption. A number of alternative hypotheses may reconcile the seemingly conflicting findings: (1) A small increase of CMRO 2 may only be possible with a large increase in CBF due to physical limitations of oxygen delivery. Journal of Cerebral Blood(2) The large CBF response may be necessary to ensure oxygen delivery to the areas most distant from blood supply. (3) The large CBF response may not be necessary in its full extent but may have evolved as a safety mechanism ensuring sufficient oxygen supply in situations where oxygen delivery to the brain is impaired. (4) The large CBF response may be necessary for reasons other than oxygen delivery.In this opinion paper, we discuss studies on brain energy metabolism and neurovascular coupling. Based on the available evidence, we hypothesize that the surprisingly large CBF response to neuronal activation has evolved as a safety mechanism for oxygen delivery. To support this hypothesis, we first review basic facts on ...

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Section: Relevant Basic Numbers Of Oxygen and Glucose Delivery To Thementioning

confidence: 99%

The Oxygen Paradox of Neurovascular Coupling

Leithner

Royl

2013

J Cereb Blood Flow Metab

113

100

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“…2 ATP synthesis is ablated, and most cells undergo apoptosis soon after anoxia exposure. [3][4][5] Cells exposed to hypoxia, or reduced oxygen levels, on the other hand, are able to maintain normal ATP synthesis and survive. 5,6 However, as cells replicate in a hypoxic environment, they reduce the oxygen supply even further and generate levels of local anoxia.…”

Section: Oxygen Homeostasis and Hifmentioning

confidence: 99%

Mitochondrial complex III regulates hypoxic activation of HIF

2008

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Decreases in oxygen levels are observed in physiological processes, such as development, and pathological situations, such as tumorigenesis and ischemia. In the complete absence of oxygen (anoxia), mammalian cells are unable to generate sufficient energy for survival, so a mechanism for sensing a decrease in the oxygen level (hypoxia) before it reaches a critical point is crucial for the survival of the organism. In response to decreased oxygen levels, cells activate the transcription factors hypoxiainducible factors (HIFs), which lead to metabolic adaptation to hypoxia, as well as to generate new vasculature to increase oxygen supply. How cells sense decreases in oxygen levels to regulate HIF activation has been hotly debated. Emerging evidence indicates that reactive oxygen species (ROS) generated by mitochondrial complex III are required for hypoxic activation of HIF. This review examines the current knowledge about the role of mitochondrial ROS in HIF activation, as well as implications of ROS-level regulation in pathological processes such as cancer. Oxygen Homeostasis and HIF Maintaining oxygen homeostasis is critical for survival and proper function of cells and organisms. 1 Reduced oxygen levels (hypoxia) initiates proper placental and vascular development. Hypoxia also has a causal role in pathological conditions such as ischemia-related diseases and cancer. A complete absence of oxygen (anoxia) results in cell death. 2 ATP synthesis is ablated, and most cells undergo apoptosis soon after anoxia exposure. 3-5 Cells exposed to hypoxia, or reduced oxygen levels, on the other hand, are able to maintain normal ATP synthesis and survive. 5,6 However, as cells replicate in a hypoxic environment, they reduce the oxygen supply even further and generate levels of local anoxia. Therefore, cells must respond quickly to decreasing oxygen levels before reaching an anoxic state (Figure 1).Mammalian cells respond to hypoxia by activating broadaction transcription factors named hypoxia-inducible factors, or HIFs, which are expressed by virtually all cells of the body. 7-9 Three members of the HIF family exist, named HIF1, HIF2 and HIF-3. 10-13 HIFs bind to hypoxia-responsive elements, consensus sequences in the promoter region of more than one hundred genes, activating the transcription of genes that allow the cell to adapt to and survive in the hypoxic environment. 14,15 Genes regulated by HIFs include glucose transporter that allow the cells to efficiently import glucose to continue generating ATP despite reduced nutrient availability; and genes that reorganize the microenvironment to bring in oxygen, such as vascular endothelial growth factor, which stimulates formation of new blood vessels. [16][17][18] Importantly for tumorigenesis, HIF also turns on genes such as insulin-like growth factor 2,19 which induces cellular survival and proliferation, as well as those that promote tumor invasion and migration, such as matrix metalloproteinase-2. 20 These factors contribute to tumor growth and invasion and metastasis, im...

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“…These values are thought to reflect cytosolic levels. Whether significant oxygen gradients exist between the cytosol and the mitochondria has been the subject of conflicting reports, but recent evidence suggests these gradients are small (reviewed in Jones, 1986;Wittenberg & Wittenberg, 1989;Tamura et al, 1989 Different organs show different responses to changes in oxygen supply. In heart, increasing oxygen supply above the physiological level results in a small increase in oxygen consumption but the mechanism of this stimulation is unclear (Oguro et al, 1973).…”

Section: Control By Oxygenmentioning

confidence: 99%

Control of respiration and ATP synthesis in mammalian mitochondria and cells

Brown

1992

Biochemical Journal

555

304

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We have seen that there is no simple answer to the question ‘what controls respiration?’ The answer varies with (a) the size of the system examined (mitochondria, cell or organ), (b) the conditions (rate of ATP use, level of hormonal stimulation), and (c) the particular organ examined. Of the various theories of control of respiration outlined in the introduction the ideas of Chance & Williams (1955, 1956) give the basic mechanism of how respiration is regulated. Increased ATP usage can cause increased respiration and ATP synthesis by mass action in all the main tissues. Superimposed on this basic mechanism is calcium control of matrix dehydrogenases (at least in heart and liver), and possibly also of the respiratory chain (at least in liver) and ATP synthase (at least in heart). In many tissues calcium also stimulates ATP usage directly; thus calcium may stimulate energy metabolism at (at least) four possible sites, the importance of each regulation varying with tissue. Regulation of multiple sites may occur (from a teleological point of view) because: (a) energy metabolism is branched and thus proportionate regulation of branches is required in order to maintain constant fluxes to branches (e.g. to proton leak or different ATP uses); and/or (b) control over fluxes is shared by a number of reactions, so that large increases in flux requires stimulation at multiple sites because each site has relatively little control. Control may be distributed throughout energy metabolism, possibly due to the necessity of minimizing cell protein levels (see Brown, 1991). The idea that energy metabolism is regulated by energy charge (as proposed by Atkinson, 1968, 1977) is misleading in mammals. Neither mitochondrial ATP synthesis nor cellular ATP usage is a unique function of energy charge as AMP is not a significant regulator (see for example Erecinska et al., 1977). The near-equilibrium hypothesis of Klingenberg (1961) and Erecinska & Wilson (1982) is partially correct in that oxidative phosphorylation is often close to equilibrium (apart from cytochrome oxidase) and as a consequence respiration and ATP synthesis are mainly regulated by (a) the phosphorylation potential, and (b) the NADH/NAD+ ratio. However, oxidative phosphorylation is not always close to equilibrium, at least in isolated mitochondria, and relative proximity to equilibrium does not prevent the respiratory chain, the proton leak, the ATP synthase and ANC having significant control over the fluxes. Thus in some conditions respiration rate correlates better with [ADP] than with phosphorylation potential, and may be relatively insensitive to mitochondrial NADH/NAD+ ratio.(ABSTRACT TRUNCATED AT 400 WORDS)

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Intracellular diffusion gradients of O2 and ATP

Cited by 267 publications

References 0 publications

The Oxygen Paradox of Neurovascular Coupling

The Oxygen Paradox of Neurovascular Coupling

Mitochondrial complex III regulates hypoxic activation of HIF

Control of respiration and ATP synthesis in mammalian mitochondria and cells

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