The effect of long-term inhibition of mitochondrial protein synthesis on the oxidation capacity of mitochondria for NADH-linked substrates

Kroon, A.M.; Holtrop, Marijke; Fries, Hella; Melis, Trudi E.; Bogert, Coby Van den

doi:10.1016/0006-291x(85)91066-6

Cited by 9 publications

(7 citation statements)

References 10 publications

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“…, which preferentially inhibits mitochondrial protein synthesis, may cause overgeneration of reactive oxygen species by specifically blocking the synthesis of the enzyme complexes involved in the electron transport chain (53,54). To test this notion, we determined the levels of superoxide at 0, 12, and 24 h of doxycycline stimulation.…”

Section: Doxycycline-induced Overgeneration Of Superoxide Resulted Inmentioning

confidence: 99%

“…However, several report showed that H 2 O 2 -induced NF-B activation is highly cell typedependent, which may reflect difference in ROS metabolism (74). Tetracycline is known for preferential inhibition of mitochondrial protein synthesis and decreases the level of cytochrome c oxidase, the key components of electron transport chain (53,54). It was thought that the reduction of the synthesis of cytochrome c oxidase may lead to a disruption of electron transport function and lead to electron leakage from the respiratory chain to O 2 , thus resulting elevated levels of superoxide radicals.…”

Section: Discussionmentioning

confidence: 99%

“…However, the mechanism by which doxycycline induces apoptosis remains unclear. Kroon and co-workers (53,54) showed that tetracycline acts as an anticancer agent by preferentially inhibiting mitochondrial protein synthesis, including cytochrome c oxidase, the key components of electron transport chain, and decrease of its synthesis may lead to a disruption of electron transport function and lead to electron leakage from the respiratory chain to O 2 , thus resulting elevated levels of superoxide radicals.…”

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confidence: 99%

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Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-κB

Fujioka

Schmidt

Sclabas

et al. 2004

Journal of Biological Chemistry

128

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Both pro-and antiapoptotic activities of NF-B transcription factor have been observed; however, less is known about the mechanism by which NF-B induces apoptosis. To elucidate how NF-B regulates proapoptotic signaling, we performed functional analyses using wild-type, ikk1؊/؊ , ikk2 ؊/؊ , rela ؊/؊ murine fibroblasts, MDAPanc-28/Puro, MDAPanc-28/IB␣M, and HCT116/p53 ؉/؉ and HCT116/p53 ؊/؊ cells with investigational anticancer agent doxycycline as a superoxide inducer for generating apoptotic stimulus. In this report, we show that doxycycline increased superoxide generation and subsequently activated NF-B, which in turn up-regulated p53 expression and increased the stability and DNA binding activity of p53. Consequently, NF-Bdependent p53 activity induced the expression of p53-regulated genes PUMA and p21 waf1 as well as apoptosis. Importantly, lack of RelA, IKK, and p53 as well as expression of a dominant negative IB␣ (IB␣M) inhibited NF-B-dependent p53 activation and apoptosis. The doxycycline-induced NF-B activation was not inhibited in HCT116/p53 ؊/؊ cells. Our results demonstrate that NF-B plays an essential role in activation of wild-type p53 tumor suppressor to initiate proapoptotic signaling in response to overgeneration of superoxide. Thus, these findings reveal a mechanism of NF-B-regulated proapoptotic signaling.

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Section: Doxycycline-induced Overgeneration Of Superoxide Resulted Inmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-κB

Fujioka

Schmidt

Sclabas

et al. 2004

Journal of Biological Chemistry

128

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“…Tetracycline has been shown to reduce both complex I respiration rate and cytochrome c oxidase (COI) activity (van den Bogert et al. , 1985; Kroon et al ., 1985). An alternative, or additional, explanation for the reduced ADP:O ratio is that the antibiotic caused differential mitochondrial proton leak (Brand, 2000).…”

Section: Discussionmentioning

confidence: 99%

Tetracycline treatment influences mitochondrial metabolism and mtDNA density two generations after treatment in Drosophila

Ballard

Melvin

2007

Insect Molecular Biology

106

104

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Tetracycline is commonly used to clear Wolbachia from infected insects. Studies then compare specific biochemical and/or life-history traits between infected and uninfected individuals with the same genetic background. We investigated the potential for tetracycline to influence mitochondrial efficiency and mitochondrial (mt)DNA density two generations after treatment in Drosophila simulans. We observed that antibiotic treatment resulted in a decline in inorganic phosphate incorporated into ATP per mole of oxygen consumed (ADP:O ratio). Further, tetracycline treatment caused a significant increase in mtDNA density in naturally Wolbachia-uninfected but not in naturally Wolbachia-infected lines suggesting a dosage effect. These data suggest that the current practice of comparing Wolbachia-infected and Wolbachia-uninfected insects two generations after tetracycline treatment needs to be re-evaluated.

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“…Kroon and colleagues (16,17) showed that tetracycline preferentially inhibited mitochondrial protein synthesis in cancer cells, including cytochrome c oxidase, the key component of the electron transport chain. Our previous report showed that doxycycline induces superoxide formation, suggesting that decreased synthesis of mitochondrial protein disrupts electron transport function and results in electron leakage from the respiratory chain to O 2 , thus elevating levels of superoxide radicals (18).…”

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confidence: 99%

Function of Polo-like Kinase 3 in NF-κB-mediated Proapoptotic Response

Li¹,

Niu

Uwagawa³

et al. 2005

Journal of Biological Chemistry

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RelA, the p65 subunit of NF-B transcription factors, plays a key role in regulation of antiapoptotic and proapoptotic responses. However, the downstream target genes regulated by RelA-NF-B in the initiation of proapoptotic signaling were not identified. We previously showed that RelA-NF-B functioned as a proapoptotic factor by activating the p53-signaling pathway in response to doxycycline-induced superoxide. In the present study, we demonstrate that the ability of doxycycline/superoxide to induce expression of polo-like kinase 3 (Plk3) depends on NF-B activity. We

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The effect of long-term inhibition of mitochondrial protein synthesis on the oxidation capacity of mitochondria for NADH-linked substrates

Cited by 9 publications

References 10 publications

Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-κB

Stabilization of p53 Is a Novel Mechanism for Proapoptotic Function of NF-κB

Tetracycline treatment influences mitochondrial metabolism and mtDNA density two generations after treatment in Drosophila

Function of Polo-like Kinase 3 in NF-κB-mediated Proapoptotic Response

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