Mitochondrial Complex II Can Generate Reactive Oxygen Species at High Rates in Both the Forward and Reverse Reactions*
By Casey L Quinlan, A. Orr, I. Perevoshchikova, Jason R. Treberg, B. Ackrell, M. Brand. Journal of Biological Chemistry, 2012
618 citations recorded by the source corpus.
Background: Complex II is not considered a significant contributor to mitochondrial ROS production. Results: Complex II generates ROS in both the forward reaction, from succinate, and the reverse reaction, from the reduced ubiquinone pool. Conclusion: Occupancy and reduction state of the flavin dictate its ROS producing behavior. Significance: Based on the maximum rates observed, complex II may be a contributor to physiological ROS production. Respiratory complex II oxidizes succinate to fumarate as part of the Krebs cycle and reduces ubiquinone in the electron transport chain. Previous experimental evidence suggested that complex II is not a significant contributor to the production of reactive oxygen species (ROS) in isolated mitochondria or intact cells unless mutated. However, we find that when complex I and complex III are inhibited and succinate concentration is low, complex II in rat skeletal muscle mitochondria can generate superoxide or H2O2 at high rates. These rates approach or exceed the maximum rates achieved by complex I or complex III. Complex II generates these ROS in both the forward reaction, with electrons supplied by succinate, and the reverse reaction, with electrons supplied from the reduced ubiquinone pool. ROS production in the reverse reaction is prevented by inhibition of complex II at either the ubiquinone-binding site (by atpenin A5) or the flavin (by malonate), whereas ROS production in the forward reaction is prevented by malonate but not by atpenin A5, showing that the ROS from complex II arises only from the flavin site (site IIF). We propose a mechanism for ROS production by complex II that relies upon the occupancy of the substrate oxidation site and the reduction state of the enzyme. We suggest that complex II may be an important contributor to physiological and pathological ROS production.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/aaed40ad6c7eea68c0f8567b8be67b69fb2ce146
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Citations in the corpus
- ROS homeostasis and metabolism: a dangerous liason in cancer cells (2016, background): “The combined use of pro-oxidizing treatment and antioxidant inhibition is expected to cause severe oxidative stress and severe cytotoxicity Cell Death and Disease consequence of electron leakage during mitochondrial respiration using nicotinamide adenine dinucleotide (reduced form) (NADH) and FADH.1”
- Mitochondrial electron transport chain, ROS generation and uncoupling (Review) (2019, background): “ROS are exclusively produced in the matrix, because the flavoprotein is located on the matrix side of the inner mitochondrial membrane (56).”