Targeting Alzheimer's disease neuronal mitochondria as a therapeutic approach

The mitochondrial electron transport chain is a key biochemical pathway responsible for the generation of adenosine triphosphate (ATP). In this process, respiratory complexes catalyze electron transfer reactions that are coupled to proton pumping across the inner mitochondrial membrane. The charge and pH gradient across the membrane drives ATP generation. The first component of the respiratory chain, complex I, plays a central role by contributing up to ∼40% of total proton-motive force generation. Complex I is a major producer of the reactive oxygen species that are detrimental to biomolecules when present in excess quantities and is also host to a large number of point mutations, which cause mitochondrial dysfunction, leading to a number of disease conditions. In this chapter, we briefly discuss the structure and function of complex I, with a focus on computational approaches to study its function and druggability.