Complex II of the respiratory chain (RC) recently emerged as a prominent regulator of cell death. In both cancer cells as well as neurodegenerative diseases, mutations in subunits have been found along with other genetic alterations indirectly affecting this complex. Anticancer compounds were developed that target complex II and cause cell death in a tumor-specific way. Our mechanistic understanding of how complex II is activated for cell death induction has recently been made clearer in recent studies, the results of which are covered in this review. This protein assembly is specifically activated for cell death via the dissociation of its SDHA and SDHB subunits from the membrane-anchoring proteins through pH change or mitochondrial Ca(2+) influx. The SDH activity contained in the SDHA/SDHB subcomplex remains intact and then generates, in an uncontrolled fashion, excessive amounts of reactive oxygen species (ROS) for cell death. Future studies on this mitochondrial complex will further elucidate it as a target for cancer treatments and reveal its role as a nexus for many diverse stimuli in cell death signaling.

Division of Experimental Medicine Imperial College London Hammersmith Campus Du Cane Road London W12 0NN UK

Institute of Biotechnology Academy of Sciences of the Czech Republic Prague 142 20 Czech Republic

Institute of Biotechnology Academy of Sciences of the Czech Republic Prague 142 20 Czech Republic; School of Medical Science Griffith Health Institute Griffith University Southport Qld 4222 Australia

School of Medical Science Griffith Health Institute Griffith University Southport Qld 4222 Australia

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Mitochondrial complex II and reactive oxygen species in disease and therapy

Ubiquinone-binding site mutagenesis reveals the role of mitochondrial complex II in cell death initiation