Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis

Higuchi, Masahiro; Proske, Rita J.; Yeh, Edward T.H.

doi:10.1038/sj.onc.1202485

Cited by 114 publications

(87 citation statements)

References 30 publications

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“…23 In contrast, in OPCs, at the TNF-a concentrations analyzed, no cell death was observed, and there was significantly higher MitoSOX staining than in controls. This phenomenon was accompanied by a significant decrease in the activity of complex I compared with its activity under control conditions.…”

Section: Discussionmentioning

confidence: 84%

“…In addition, TNF-a has already been shown to increase superoxide levels in leukemia cells. 23 In the current study, mitochondrial superoxide anion levels in oligodendrocyte progenitors were determined using the O 2 À -sensitive mitochondrial probe MitoSOX. We found that mitochondrial superoxide anion levels were indeed significantly increased in TNF-a-treated OPCs compared with controls ( Figure 4a).…”

Section: Resultsmentioning

confidence: 99%

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Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

et al. 2014

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Mitochondrial defects, affecting parameters such as mitochondrial number and shape, levels of respiratory chain complex components and markers of oxidative stress, have been associated with the appearance and progression of multiple sclerosis. Nevertheless, mitochondrial physiology has never been monitored during oligodendrocyte progenitor cell (OPC) differentiation, especially in OPCs challenged with proinflammatory cytokines. Here, we show that tumor necrosis factor alpha (TNF-a) inhibits OPC differentiation, accompanied by altered mitochondrial calcium uptake, mitochondrial membrane potential, and respiratory complex I activity as well as increased reactive oxygen species production. Treatment with a mitochondrial uncoupler (FCCP) to mimic mitochondrial impairment also causes cells to accumulate at the progenitor stage. Interestingly, AMP-activated protein kinase (AMPK) levels increase during TNF-a exposure and inhibit OPC differentiation. Overall, our data indicate that TNF-a induces metabolic changes, driven by mitochondrial impairment and AMPK activation, leading to the inhibition of OPC differentiation.

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Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

et al. 2014

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“…Under aerobic conditions, the respiratory chain is a potent source of free radicals (Pryor, 1982;Buttke and Sandstrom, 1994;Slater et al, 1995) and data from different experimental systems indicate that complex I impairment may lead to enhanced ROS production (Pitkanen and Robinson, 1996;Higuchi et al, 1998;Seaton et al, 1998;Barrientos and Moraes, 1999). Moreover, apoptosis may occur when the amount of ROS produced in the mitochondria cannot be handled by radical-scavenging intracellular antioxidants.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells

Cariati¹,

Zancai²,

Righetti³

et al. 2003

Oncogene

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In the search for retinoids active against Burkitt's lymphoma (BL), we found that the arotinoid mofarotene (Ro 40-8757) induced strong antiproliferative and apoptotic responses in most established BL cell lines as well as in primary BL cells. Ro 40-8757-induced apoptosis is associated with mitochondrial membrane depolarization, activation of caspase-3 and -9, and enhanced production of reactive oxygen species. These effects were related to a transient drop in intracellular ATP content, probably favored by a downregulation of NADH dehydrogenase subunit-1, a component of the mitochondrial respiratory chain (MRC) Complex I. Inhibition of MRC with thenoyltrifluoroacetone suppressed both the ATP recovery and apoptosis, confirming that the effects of Ro 40-8757 are mediated by changes in mitochondrial function. Compared to EBV-negative lines, EBV-carrying BLs were more resistant to Ro 40-8757-induced apoptosis. EBV infection and ectopic LMP-1 expression increased the resistance of BL cells to Ro 40-8757-induced apoptosis, probably through bcl-2 upregulation. Finally, we also show that 2-methoxyoestradiol, an inhibitor of the scavenger enzymes superoxide dismutases, enhanced Ro 40-8757-mediated apoptosis. These findings provide the rationale for evaluating the clinical efficacy of Ro 40-8757 in BL patients and suggest that the combination of Ro 40-8757 with inhibitors of scavenger enzymes may be a promising therapeutic approach for this aggressive lymphoma.

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“…apoptosis-inducing factor, which induce apoptosis (7,50,51). Once cells are stimulated by TNF-␣, rapid LMP and membrane permeability transition have been observed (52,53). To test whether the LMP lies on the TNF-␣-induced cell death pathway in OLGs, we stained OLGs with a mitochondrion-selective, mitochondrial membrane potential-dependent dye, MitoTracker (54,55), with or without TNF-␣ treatment.…”

Section: Fig 2 Effects Of Ngf On Tnf-induced Olg Cell Deathmentioning

confidence: 99%

Nerve Growth Factor Protects Oligodendrocytes from Tumor Necrosis Factor-α-induced Injury through Akt-mediated Signaling Mechanisms

Takano¹,

Hisahara²,

Namikawa³

et al. 2000

Journal of Biological Chemistry

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Inhibition of mitochondrial respiratory chain complex I by TNF results in cytochrome c release, membrane permeability transition, and apoptosis

Cited by 114 publications

References 30 publications

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

Tumor necrosis factor-α impairs oligodendroglial differentiation through a mitochondria-dependent process

Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells

Nerve Growth Factor Protects Oligodendrocytes from Tumor Necrosis Factor-α-induced Injury through Akt-mediated Signaling Mechanisms

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