FIG. 4.

Aβ and the mitochondria. During homeostatic conditions, proteins that are encoded by nuclear genes and synthesized on cytoplasmic ribosomes are directed for import into mitochondria by their mitochondrial targeting sequences (MTS). In the presence of an electrochemical gradient, proteins are imported, first through the outer mitochondrial membrane by the outer mitochondrial transferase (TOM) and second, to the mitochondrial matrix by the inner mitochondrial transferase (TIM). To ensure a constant electrochemical gradient, mitochondria rely on the electron transport chain (ETC), which generates not only the cellular energy source in the form of ATP but also a small amount of oxidants that can damage proximal mitochondrial proteins. To prevent damage accumulation, the Lon protease quickly removes these oxidized proteins. However, during Alzheimer's disease, Aβ accumulates within the mitochondrial cristae (irrespective of the electrochemical gradient) and blocks the import of mitochondrial-targeted proteins. This, in turn, decreases the cell's ability to generate ATP. In an exaggeration of the dysregulation that can occur during aging, mitochondrial proteins may undergo increased oxidation in Alzheimer's mitochondria, which may surpass the degradation capacity of Lon and, ultimately, cause loss of mitochondrial function. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars