Date of Completion
Complex II, Succinate:quionone Oxidoreductase, Cardiolipin, Mitochondria, Model Membranes, Nanodisc
Dr. Nathan Alder
Dr. Debra A. Kendall
Dr. Carolyn M. Teschke
Field of Study
Doctor of Philosophy
Mitochondrial respiratory Complex II, also referred to as succinate dehydrogenase (SDH) and succinate: ubiquinone oxidoreductase (SQR), is a critical control point central to cellular energy metabolism as it links the Tricarboxylic Acid (TCA) Cycle and the electron transport chain (ETC). Complex II oxidizes succinate to fumarate as part of the TCA Cycle and passes these electrons through a series of redox centers to a membrane-bound ubiquinone molecule as part of the OXPHOS system to generate cellular energy. It is composed of four subunits, two of which form a soluble catalytic dimer (SdhA/SdhB) and two of which compose a membrane-anchoring dimer (SdhC/SdhD). As the smallest complex of the OXPHOS system, Complex II is often overlooked, but dysfunction of the complex has been implicated in various neurodegenerative diseases, tumorigenic states, and the aging process. As Complex II is a membrane-bound enzyme, model membrane systems such as liposomes and discoidal bilayer nanoparticles (termed nanodiscs) are necessary to study the enzyme in solution. The first part of this thesis investigates the relationship between Complex II and the characteristic mitochondrial membrane phospholipid, cardiolipin (CL) by substituting the lipids present in the nanodisc system. The studies presented here support that CL is necessary for efficient Complex II activity and inter-dimer stability, also decreasing the reactive oxygen species formation by the complex. In addition, the presence of various types of CL in the membrane enhance to differing levels the dehydration and packing in the interfacial region of the bilayer. The second part of this thesis focuses on the assembly of holoenzyme Complex II. First, Complex II membrane subunits can form dynamic interactions with each other as well as with homologs found in the mitochondrial inner membrane, possibly revealing a novel regulatory mechanism within the organelle. Second, soluble Helix I of the SdhC membrane subunit is largely involved in modulating and recognizing the correct interaction between the membrane and catalytic dimers. Overall, Complex II assembly and activity prove to be dynamic processes that require regulation by the surrounding lipid, namely cardiolipin, and protein environments.
Schwall, Christine T., "Investigation of the Assembly, Activity, and Lipid Dependence of Mitochondrial Respiratory Complex II via Model Membrane Systems" (2014). Doctoral Dissertations. 517.