Mitochondrial respiratory chain complex I and II (Complex I/II)

Mitochondrial respiratory chain complexes I and II are essential components of the electron transport chain located in the inner mitochondrial membrane. Complex I (NADH:ubiquinone oxidoreductase) utilizes a flavin mononucleotide (FMN) cofactor to initiate electron transfer from NADH, while Complex II (succinate dehydrogenase) utilizes a flavin adenine dinucleotide (FAD) cofactor to transfer electrons from succinate (Hirst, J. Annu Rev Biochem, 2013; Cecchini, G. Crit Rev Biochem Mol Biol, 2003). These complexes are primary sites for the generation of reactive oxygen species (ROS) and are critical for maintaining the cellular energy balance through ATP production (Brand, M. D. Biochem Soc Trans, 2010). Dysfunction in these complexes is linked to a variety of conditions, including mitochondrial DNA disorders, neurodegenerative diseases like Parkinson's, and metabolic syndromes (Koopman, W. J. et al. N Engl J Med, 2012). In oncology, these complexes are targeted to disrupt the metabolic flexibility of cancer cells, with drugs like metformin and IACS-010759 acting as inhibitors that can interact with the flavin-containing subunits (Wheaton, W. W. et al. Nat Cell Biol, 2014; Molina, J. R. et al. Nat Med, 2018). However, targeting these complexes carries significant risks, such as lactic acidosis and systemic toxicity due to their fundamental role in cellular respiration (Owen, M. R. et al. Biochem J, 2000).

Other names

NADH:ubiquinone oxidoreductaseSuccinate dehydrogenaseNADH dehydrogenaseSuccinate-ubiquinone oxidoreductaseETC Complex IETC Complex II

Inhibition of electron transfer at the flavin-containing subunits (FMN in Complex I and FAD in Complex II) of the mitochondrial respiratory chain, leading to decreased ATP production and altered cellular redox state (Hirst, J. Annu Rev Biochem, 2013; Cecchini, G. Crit Rev Biochem Mol Biol, 2003).