Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage

Indo, Hiroko P.; Davidson, Mercy M.; Yen, Hsiu-Chuan; Suenaga, Shigeaki; Tomita, Kazuo; Nishii, Takeshi; Higuchi, Masahiro; Koga, Yasutoshi; Ozawa, Toshihiko; Majima, Hideyuki J.

doi:10.1016/j.mito.2006.11.026

Cited by 445 publications

(282 citation statements)

References 56 publications

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“…This impairment of the electron transport system can increase mitochondrial ROS generation leading to oxidative damage of mtDNA [45]. In good agreement with these previous findings, we detected several times higher levels of 8-oxoG in mtDNA isolated from antimycin A-exposed cells than those from untreated cells.…”

Section: Discussionsupporting

confidence: 92%

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Pázmándi

Agod

Kumar

et al. 2014

Free Radical Biology and Medicine

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Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells, Free Radical Biology and Medicine, http://dx.doi.org/10.1016/j. freeradbiomed. 2014.09.028 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.www.elsevier.com/locate/freeradbiomed Abbreviations: 7-AAD, 7-aminoactinomycin-D; 8-oxoG, 8-oxo-7,8-dihydroguanine; 8-oxodG, 8-oxo-7,8-dihydro-2'- well as increased TNF-Į and IL-8 production from the cells. These effects were more apparent when pDCs were exposed to oxidatively modified mtDNA. Neither native nor oxidized mtDNA molecules were able to induce interferon (IFN)-Į secretion from pDCs unless they formed a complex with human cathelicidin LL-37, an antimicrobial peptide.Interestingly, simultaneous administration of a Toll-like receptor (TLR)9 antagonist abrogated the effects of both native and oxidized mtDNAs on human pDCs. In a murine model, oxidized mtDNA also proved a more potent activator of pDCs compared to the native form, except for induction of IFN-Į production. Collectively, we demonstrate here for the first time that elevated levels of 8-oxoG bases in the extracellular mtDNA induced by oxidative stress increase the immunostimulatory capacity of mtDNA on pDCs. 3 HighlightsWe compared the immunostimulatory capacity of native and oxidized mtDNA on pDCs.8-Oxoguanin-containing mtDNA has a greater capacity to activate primary human pDCs.In vivo, oxidized mtDNA also proved a more potent activator of pDC than native mtDNA.

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Section: Discussionsupporting

confidence: 92%

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Pázmándi

Agod

Kumar

et al. 2014

Free Radical Biology and Medicine

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“…Other cybrid experiments indicated that the generation of mitochondrial ROS is increased depending on the deletion amount, but displayed no threshold effect because elevated mitochondrial ROS production was even detectable in cells with a relatively low amount of 16% of the common deletion (Peng et al, 2006, Indo et al, 2007. UV-induced programmed cell death was increased in cybrids harbouring amounts of the 4977 bp deletion up to 80% leading to the suggestion that large scale deletion sensitize a cell to undergo apoptosis (Schoeler et al, 2006;Liu et al, 2007).…”

Section: Discussionmentioning

confidence: 99%

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

Meißner

Bruse

Mohamed

et al. 2008

Experimental Gerontology

144

119

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It has been suggested that deletions of mitochondrial DNA (mtDNA) are important players with regard to the ageing process. Since the early 1990s, the 4977 bp deletion has been studied in various tissues, especially in postmitotic tissues with high energy demand. Unfortunately, some of these studies included less than 10 subjects, so the aim of our study was to quantify reliable the deletion amount in nine different regions of human brain, heart and skeletal muscle in a cohort of 92 individuals. The basal ganglia contain the highest deletion amounts with values up to 2.93% and differences in deletion levels between early adolescence and older ages were up to three orders of magnitude. Values in frontal lobe were on average an order of magnitude lower, but lowest in cerebellar tissue where the amount was on average only 5 x 10 -3 of the basal ganglia. The deletion started to accumulate in iliopsoas muscle early in the fourth decade of life with values between 0.00019% and 0.0035% and was highest in a 102 year-old woman with 0.14%. In comparison to skeletal muscle, the overall abundance in heart muscle of the left ventricle was only one third. The best linear logarithmic correlation between amount of the deletion and age was found in substanta nigra with r=0.87 (p<0.0005) followed by anterior wall of the left ventricle (r=0.82; p<0.0005). With regard to mitochondrial DNA damage, we propose to use the 4977 bp deletion as an ideal biomarker to discriminate between physiological ageing and accelerated ageing. The biological meaning of mitochondrial deletions in the process of ageing is under discussion, but there is experimental evidence that large-scale deletions impair the oxidative phosphorylation in single cells and sensitize these cells to undergo apoptosis.

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“…Consequently, it is possible that these organelles are involved in the process of carcinogenesis through alterations in cell metabolism and cell death pathways (Pilkington et al, 2008). Cancer cells show alterations in mtDNA, in oxidative phosphorylation and in energetic metabolism, all triggered by a pro-oxidative change (Indo et al, 2007). The "respiratory damage" in cancer cells predicts low coupling efficiency in electron transfer at the inner membrane of mitochondria and, consequently, greater loss of electrons, leading to the formation of more O 2  − (Pelicano et al, 2003).…”

Section: Mitochondria and Reactive Oxygen Species (Ros)mentioning

confidence: 99%

Oxidative Therapy Against Cancer

Miguel¹,

Cordero²

2012

Oxidative Stress and Diseases

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Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage

Cited by 445 publications

References 56 publications

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

Oxidative modification enhances the immunostimulatory effects of extracellular mitochondrial DNA on plasmacytoid dendritic cells

The 4977bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: A useful biomarker or more?

Oxidative Therapy Against Cancer

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