The physics of normal and impaired mitochondrial electron transfer

The mitochondrial electron transport chain (ETC) produces most of our bodies’ energy in the form of ATP. Within the ETC, complex II, also known as succinate dehydrogenase (SDH), plays a unique role in that it converts succinate to fumarate as part of the Krebs cycle while simultaneously feeding energetic electrons to the ETC. The electrons travel along a chain of three Fe-S clusters in subunit B (SDHB) before entering the membranous domain containing a heme group and ubiquinone, which ultimately transports them to complex III. Some SDHB mutations in the form of amino acid replacements trigger aggressive growth of certain cancers, such as paraganglioma and pheochromocytoma. We will discuss our collaborative experimental and theoretical program, which includes measurements of human tissue and cell lines, and calculations of normal and mutated electron tunneling rates using Marcus theory. Our preliminary results suggest that some mutations disrupt SDHB electron pathways, causing many electrons to fail to reach their ubiquinone target and instead spill out to generate reactive oxygen species that increase tumorigenicity.