Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins

Brand, Martin D.; Affourtit, Charles; Esteves, Telma C.; Green, Katherine; Lambert, Adrian J.; Miwa, Soichi; Pakay, Julian L.; Parker, Nadeene

doi:10.1016/j.freeradbiomed.2004.05.034

Cited by 944 publications

(674 citation statements)

References 105 publications

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“…the role of UCP3 may be to increase uncoupling and commensurate O 2 consumption, even during state 4 conditions, thereby minimizing ROS production. This is supported by a more recent hypothesis for the main, ancestral function of UCP2 and UCP3, that being to cause mild uncoupling and so diminish mitochondrial superoxide production [21].…”

Section: Introductionmentioning

confidence: 61%

Possible role of avian uncoupling protein in down‐regulating mitochondrial superoxide production in skeletal muscle of fasted chickens

et al. 2006

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Little is known about the precise physiological roles of uncoupling protein 1 (UCP1) homologs (UCP2, UCP3, avian UCP) whose levels are up-regulated during fasting. UCPs in skeletal muscle are thought to play a role in the regulation of lipids as fuel substrates, and/or in controlling the production of reactive oxygen species (ROS). The aim of this investigation, using skeletal muscle from fasted chickens, was to examine alterations in the expression of genes encoding for avian UCP and key enzymes relevant to lipid flux across the mitochondrial b-oxidation pathway. We also clarified whether an increase in avUCP content could be associated with altered ROS production by mitochondria. Transcription levels of avUCP and CPT-I genes were increased 7.7-and 9.5-fold after a 24 h fast and slightly diminished but remained about 5.0-and 7.7-fold higher than baseline levels, respectively, after 48 h of fasting. In contrast, members of the b-oxidation pathway, LCAD and 3HADH, were gradually up-regulated from 12 to 48 h of fasting. This suggests that processes involved in the transfer and oxidation of fatty acids are up-regulated differently during the initial stage of fasting. Analysis of ROS production by lucigenin-derived chemiluminescence showed that the FFA-sensitive portion of carboxyatractyloside-upregulated ROS production was greater in skeletal muscle mitochondria from 24 h-fasted chickens compared with control, which leads us to postulate that ROS production is potentially down-regulated by UCP. The possible involvement of a backlog of fatty acid for oxidation, observed in chickens after a 24 h fast, in a transmembrane gradient of free non-oxidized fatty acids is also discussed.

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Section: Introductionmentioning

confidence: 61%

Possible role of avian uncoupling protein in down‐regulating mitochondrial superoxide production in skeletal muscle of fasted chickens

et al. 2006

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“…The generation of mitochondrial ROS (mtROS) is correlated with levels of Δ Ψ m or ETC activity,21, 22 and ETC‐deficient ρ0 cells are incapable of producing mtROS 4, 9, 10, 11. Our results agree with these previous findings in that the ROS levels measured with H 2 DCFDA were significantly lower in the MDA/ρ0 cells compared with the control cells, where strong fluorescence was observed in the intracellular organelles (Figs 6a, S4a; [−]).…”

Section: Resultsmentioning

confidence: 99%

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

et al. 2016

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Mitochondria are multifunctional organelles; they have been implicated in various aspects of tumorigenesis. In this study, we investigated a novel role of the basal electron transport chain (ETC) activity in cell proliferation by inhibiting mitochondrial replication and transcription (mtR/T) using pharmacological and genetic interventions, which depleted mitochondrial DNA/RNA, thereby inducing ETC deficiency. Interestingly, mtR/T inhibition did not decrease ATP levels despite deficiency in ETC activity in different cell types, including MDA‐MB‐231 breast cancer cells, but it severely impeded cell cycle progression, specifically progression during G2 and/or M phases in the cancer cells. Under these conditions, the expression of a group of cell cycle regulators was downregulated without affecting the growth signaling pathway. Further analysis suggested that the transcriptional network organized by E2F1 was significantly affected because of the downregulation of E2F1 in response to ETC deficiency, which eventually resulted in the suppression of cell proliferation. Thus, in this study, the E2F1‐mediated ETC‐dependent mechanism has emerged as the regulatory mechanism of cell cycle progression. In addition to E2F1, FOXM1 and BMYB were also downregulated, which contributed specifically to the defects in G2 and/or M phase progression. Thus, ETC‐deficient cancer cells lost their growing ability, including their tumorigenic potential in vivo. ETC deficiency abolished the production of reactive oxygen species (ROS) from the mitochondria and a mitochondria‐targeted antioxidant mimicked the deficiency, thereby suggesting that ETC activity signaled through ROS production. In conclusion, this novel coupling between ETC activity and cell cycle progression may be an important mechanism for coordinating cell proliferation and metabolism.

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“…The toxicity of H 2 O 2 can be partly explained by increased lipid peroxidation resulting in HNE production but this is less likely to occur under conditions of signaling by H 2 O 2 . Although it has been demonstrated that low HNE can cause an increase in O 2 ·− production by neutrophils while higher concentrations of HNE inhibit (232), other studies have shown that HNE can activate uncoupling proteins and thereby decrease mitochondrial ROS production (233,234). Thus, the relationship between HNE and H 2 O 2 in terms of signaling versus oxidative injury requires further examination.…”

Section: E Future Of Hne Signaling Studiesmentioning

confidence: 95%

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

Forman

Fukuto

Miller

et al. 2008

Archives of Biochemistry and Biophysics

219

165

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During the past several years, major advances have been made in understanding how reactive oxygen species (ROS) and nitrogen species (RNS) participate in signal transduction. Identification of the specific targets and the chemical reactions involved still remains to be resolved with many of the signaling pathways in which the involvement of reactive species has been determined. Our understanding is that ROS and RNS have second messenger roles. While cysteine residues in the thiolate (ionized) form found in several classes of signaling proteins can be specific targets for reaction with H 2 O 2 and RNS, better understanding of the chemistry, particularly kinetics, suggests that for many signaling events in which ROS and RNS participate, enzymatic catalysis is more likely to be involved than non-enzymatic reaction. Due to increased interest in how oxidation products, particularly lipid peroxidation products, also are involved with signaling, a review of signaling by 4-hydroxy-2-nonenal (HNE) is included. This article focuses on the chemistry of signaling by ROS, RNS, and HNE and will describe reactions with selected target proteins as representatives of the mechanisms rather attempt to comprehensively review the many signaling pathways in which the reactive species are involved. Keywords signaling; glutathione; thioredoxin; oxidants; reactive oxygen species; thiols; peroxide; nitric oxide; peroxynitrite; 4-hydroxynonenal; cysteine; hydrogen peroxide; protein tyrosine phosphatase; reactive nitrogen species; eNOS; iNOS; nNOS; soluble guanylate cyclase; cGMP; tyrosine nitration; fatty acid nitration; NO-heme; NO-metal complexes; nitrite; protein kinase C; ERK; JNK; p38MAPK; tyrosine kinase receptors; calcium OVERVIEW OF SIGNALING BY REACTIVE SPECIESUnderstanding of the roles of reactive oxygen species (ROS), reactive nitrogen species (RNS) and the lipid peroxidation product, 4-hydroxy-2-nonenal (HNE) in signaling has evolved rapidly during the last decade. This has been markedly helped by identification of the specific targets in signaling pathways. In previous reviews, we defined how ROS, H 2 O 2 in particular,

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Mitochondrial superoxide: production, biological effects, and activation of uncoupling proteins

Cited by 944 publications

References 105 publications

Possible role of avian uncoupling protein in down‐regulating mitochondrial superoxide production in skeletal muscle of fasted chickens

Possible role of avian uncoupling protein in down‐regulating mitochondrial superoxide production in skeletal muscle of fasted chickens

Linkage of E2F1 transcriptional network and cell proliferation with respiratory chain activity in breast cancer cells

The chemistry of cell signaling by reactive oxygen and nitrogen species and 4-hydroxynonenal

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