Mitochondrial Complex I Inhibitor Rotenone Induces Apoptosis through Enhancing Mitochondrial Reactive Oxygen Species Production*

By Nianyu Li, K. Ragheb, G. Lawler, J. Sturgis, Bartek Rajwa, J. Melendez, J. Paul Robinson. Journal of Biological Chemistry, 2003

1,359 citations recorded by the source corpus.

Inhibition of mitochondrial respiratory chain complex I by rotenone had been found to induce cell death in a variety of cells. However, the mechanism is still elusive. Because reactive oxygen species (ROS) play an important role in apoptosis and inhibition of mitochondrial respiratory chain complex I by rotenone was thought to be able to elevate mitochondrial ROS production, we investigated the relationship between rotenone-induced apoptosis and mitochondrial reactive oxygen species. Rotenone was able to induce mitochondrial complex I substrate-supported mitochondrial ROS production both in isolated mitochondria from HL-60 cells as well as in cultured cells. Rotenone-induced apoptosis was confirmed by DNA fragmentation, cytochrome c release, and caspase 3 activity. A quantitative correlation between rotenone-induced apoptosis and rotenone-induced mitochondrial ROS production was identified. Rotenone-induced apoptosis was inhibited by treatment with antioxidants (glutathione, N-acetylcysteine, and vitamin C). The role of rotenone-induced mitochondrial ROS in apoptosis was also confirmed by the finding that HT1080 cells overexpressing magnesium superoxide dismutase were more resistant to rotenone-induced apoptosis than control cells. These results suggest that rotenone is able to induce apoptosis via enhancing the amount of mitochondrial reactive oxygen species production.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/da8b3bc9ba81e9303de96dd72adc97de10f582d9

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Citations in the corpus

• Oxidative stress in the placenta (2004, background): “Inhibition of METC complex I with rotenone caused apoptosis in HL60, a leukemia cell, and in HT1080, a fibrosarcoma cell, via ROS generation showing a functional effect of superoxide generation (Li et al. 2003).”
• Autophagy proteins regulate innate immune response by inhibiting NALP3 inflammasome-mediated mitochondrial DNA release (2010, neutral): “2c ), indicative of more mitochondrial production of reactive oxygen species (ROS) and mitochondrial dysfunctio”
• The sites and topology of mitochondrial superoxide production (2010, background): “Conversely, many studies report that rotenone increases ROS production in cells (Barrientos and Moraes, 1999; Li et al., 2003; Nakamura et al., 2001; Siraki et al., 2002).”
• Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling (2009, background): “Rotenone is a well known inhibitor of electron transfer from complex I to ubiquinone of the electron transport chain (25), resulting in ROS accumulation (26).”
• Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS) (2011, methodology): “Although rotenone has been shown to both increase and decrease mitochondrial ROS production in a variety of cell types (Li et al., 2003; Thompson et al., 2007),”
• Calcium, ATP, and ROS: a mitochondrial love-hate triangle. (2004, background): “Although other inhibitors of complex I are known to enhance its ROS generation (108, 197), it is not known whether this is the case for NO Ca(2) .”
• INHIBITION OF MITOCHONDRIAL TRANSLATION AS A THERAPEUTIC STRATEGY FOR HUMAN ACUTE MYELOID LEUKEMIA (2011, background): “Respiratory chain inhibitors such as rotenone and Na azide have been previously shown to induce rapid increases in ROS generation leading to cell death (Li et al., 2003; Park et al., 2007; Turrens and Boveris, 1980).”