Carbon Monoxide Specifically Inhibits Cytochrome C Oxidase of Human Mitochondrial Respiratory Chain

Alonso, J.R.; Cardellach, Francesc; López, Sònia; Casademont, Jordi; Miró, Òscar

doi:10.1034/j.1600-0773.2003.930306.x

Cited by 218 publications

(135 citation statements)

References 44 publications

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“…These findings may have particular clinical significance as most of the tetrazoles, thiazoles, and 1,2,3-triazoles identified in this paper are reversible inhibitors of mitochondrial respiration. The reversibility of mitochondrial inhibition by these compounds is very important because irreversible inhibitors, such as carbon monoxide, azide, and rotenone, are wellknown metabolic poisons (16)(17)(18). In addition, many of the heterocycles described herein have low reported toxicities (19)(20)(21)(22).…”

Section: Resultsmentioning

confidence: 99%

Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration

Barile

Herrmann

Tyvoll

et al. 2012

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

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Platelets are important mediators of blood coagulation that lack nuclei, but contain mitochondria. Although the presence of mitochondria in platelets has long been recognized, platelet mitochondrial function remains largely unaddressed. On the basis of a small amount of literature that suggests platelet mitochondria are functional, we hypothesized that the inhibition of platelet mitochondria disrupts platelet function and platelet-activated blood coagulation. To test this hypothesis, members of the tetrazole, thiazole, and 1,2,3-triazole families of small molecule heterocycles were screened for the ability to inhibit isolated mitochondrial respiration and coagulation of whole blood. The families of heterocycles screened were chosen on the basis of the ability of the heterocycle family to inhibit a biomimetic model of cytochrome c oxidase (CcO). The strength of mitochondrial inhibition correlates with each compound's ability to deter platelet stimulation and platelet-activated blood clotting. These results suggest that for this class of molecules, inhibition of blood coagulation may be occurring through a mechanism involving mitochondrial inhibition. Platelets are directly involved in a number of functions necessary for clotting, including recognition of vascular lesions, triggering activation of the coagulation cascade, and activation of other platelets. The platelet membrane serves as a scaffold for clot formation, and platelets are involved in the activation and cocatalysis of reactions involving many of the soluble clotting factors (1). Like red blood cells, platelets lack nuclei and consequently are unable to replace damaged proteins encoded in the nuclear genome. However, unlike red blood cells, platelets contain actively metabolizing mitochondria (2). Some hints as to the role these mitochondria play in platelet function have been elucidated (3). Along with glycogen granules, platelet mitochondria provide energy that is needed at least indirectly for platelet aggregation and secretion of procoagulant molecules (4). More direct evidence of a role for mitochondria in coagulation rests on observations that changes in the permeability of mitochondrial membranes are linked to changes in coagulation activity (5, 6). These facts imply that inhibition of platelet mitochondrial function should have an inhibitory effect upon platelet-activated blood coagulation.Experimental investigation led to the discovery of three families of small molecule heterocycles that reversibly inhibit mitochondrial respiration and attenuate platelet-activated blood coagulation. These three families of compounds comprise unique examples of a class of anticoagulants proposed to inhibit blood clotting through a mitochondrial mechanism (Fig. 1).The discovery of these particular families of platelet inhibitory molecules occurred after initial work from the Collman laboratory related to biomimetic modeling of cytochrome c oxidase (CcO). CcO is the terminal enzyme in the electron transport chain that catalyzes the four-electron reduction of O 2...

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Section: Resultsmentioning

confidence: 99%

Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration

Barile

Herrmann

Tyvoll

et al. 2012

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

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“…One such a toxicant is carbon monoxide (CO), which is found at levels that are 2.8-fold higher in SS smoke than in MS smoke (Committee on Passive Smoking, 1986). CO inhibits the mitochondrial respiratory chain by interfering with the cytochrome c oxidase (Alonso et al, 2003) and may affect sperm motility by altering mitochondria functions and reducing the energy stores needed for motility. Ex vivo studies have shown that fully mature sperm are not susceptible to CO (Makler et al, 1993), indicating that CO may affect the acquisition of sperm motility in the epididymis.…”

Section: Discussionmentioning

confidence: 99%

Differential sensitivity of male germ cells to mainstream and sidestream tobacco smoke in the mouse

Polyzos

Schmid

Piña-Guzmán

et al. 2009

Toxicology and Applied Pharmacology

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Cigarette smoking in men has been associated with increased chromosomal abnormalities in sperm and with increased risks for spontaneous abortions, birth defects and neonatal death.Little is known, however, about the reproductive consequences of paternal exposure to secondhand smoke. We used a mouse model to investigate the effects of paternal exposure to sidestream (SS) smoke, the main constituent of second-hand smoke, on the genetic integrity and function of sperm, and to determine whether male germ cells were equally sensitive to mainstream (MS) and SS smoke. A series of sperm DNA quality and reproductive endpoints were investigated after exposing male mice for two weeks to MS or SS smoke. Our results indicated that: (i) only SS smoke significantly affected sperm motility; (ii) only MS smoke induced DNA strand breaks in sperm; (iii) both MS and SS smoke increased sperm chromatin structure abnormalities; and (iv) MS smoke affected both fertilization and the rate of early embryonic development, while SS smoke affected fertilization only. These results show that MS and SS smoke have differential effects on the genetic integrity and function of sperm and provide further evidence that male exposure to second-hand smoke, as well as direct cigarette smoke, may diminish a couple's chance for a successful pregnancy and the birth of a healthy baby.

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“…CO also combines with cytochrome A and A3 to cause direct poisoning effects, and decreases in levels of cytochrome C oxidase inhibit mitochondrial metabolism, leading to cellular respiratory dysfunction. 13 Furthermore, CO-mediated brain damage associated with free radicals has been noticed. CO binds to platelet heme proteins, causing the release of nitric oxide.…”

Section: Mechanisms Causing Brain Damage After Co Exposurementioning

confidence: 99%

The Role of MR Imaging in Assessment of Brain Damage from Carbon Monoxide Poisoning: A Review of the Literature

Beppu

2013

American Journal of Neuroradiology

105

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SUMMARY:The aim of this article is to review how MR imaging and associated imaging modalities provide clinicopathologic information on brain damage after carbon monoxide poisoning. Initially, many authors documented typical findings of conventional MR imaging in the gray matter structures such as the globus pallidus and in various regions of cerebral white matter. The focus of investigation has since shifted to observation of cerebral white matter areas that are more frequently detected on MR imaging and are more responsible for chronic symptoms than the gray matter. DWI has dramatically contributed to the ability to quantitatively assess cerebral white matter damage. Subsequently, DTI has enabled more sensitive evaluation than DWI and can demonstrate progressive pathologic changes in the early stage, allowing prediction of chronic conditions. In addition, MR spectroscopy reveals changes in metabolite levels, offering quantitative clinicopathologic information on brain damage after carbon monoxide poisoning.ABBREVIATIONS: CO ϭ carbon monoxide; CWM ϭ cerebral white matter; DNS ϭ delayed neuropsychiatric sequelae; FA ϭ fractional anisotropy; GP ϭ globus

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Carbon Monoxide Specifically Inhibits Cytochrome C Oxidase of Human Mitochondrial Respiratory Chain

Cited by 218 publications

References 44 publications

Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration

Inhibiting platelet-stimulated blood coagulation by inhibition of mitochondrial respiration

Differential sensitivity of male germ cells to mainstream and sidestream tobacco smoke in the mouse

The Role of MR Imaging in Assessment of Brain Damage from Carbon Monoxide Poisoning: A Review of the Literature

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