Mitochondrial targets of Aβ. Aβ associated with mitochondria may be deposited at several locations. Although not present exclusively on the outer mitochondrial membrane, Aβ that might be present at that site might influence the interaction of multiple cytosolic proteins (including those of the bcl2 family) with mitochondria, as well as affect the receptor binding of cargo targeted for import into the organelle via the TOM import machinery impeding mitochondrial entry to neosynthesised nuclear-encoded proteins such as subunits of the electron transport chain (ETC) complex IV (CIV). In the intramembrane space, Aβ might affect the functions of both the inner and outer mitochondrial membrane by multiple mechanisms including modulating their permeability. In the mitochondrial matrix, Aβ might interact with important components of metabolic or antioxidant mechanisms. The interaction of Aβ with the inner mitochondrial membrane would bring it into contact with respiratory chain complexes with the potential for myriad effects on cellular metabolism. Thus, Aβ affects the activity of several enzymes, such as pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (α-KGDH), decreasing NADH reduction, and the ETC enzyme CIV, reducing the amount of hydrogen that is translocated from the matrix to the intermembrane space, thus impairing the mitochondrial membrane potential (MMP). The dysfunction of the ETC leads to a decreased CV activity and so to a lower ATP synthesis, in addition to increasing reactive oxygen species (ROS) production. ROS negatively influences presequence P (PreP) activity, blocking Aβ degradation, exacerbating mitochondrial Aβ presence. Moreover, ROS induce peroxidation of several mitochondrial macromolecules, such as mitochondrial DNA (mtDNA) and mitochondrial lipids, additionally impairing mitochondrial function. Aβ binds NAD+ pocket in ABAD, blocking its activity and inducing further ROS production. Aβ also influences mitochondrial dynamic, by improving Fis1 presence and activity, thus increasing mitochondrial fragmentation (fission protein: Fis1; fusion proteins: Mfn1/2 and OPA1). Furthermore, Aβ binding to cyclophilin D (CypD) enhances the protein translocation to the inner membrane, favouring the opening of the mitochondrial permeability transition pore, formed by ANT and VDAC. Calcium storage in mitochondria is impaired, altering neuronal function; calcium is exported to the cytosol, as well as other apoptotic factors (ProAp) such as cytochrome c, apoptosis-inducing factor, Smac/DIABLO, endonuclease G, and procaspases, activating cellular apoptosis. IMM: inner mitochondrial membrane, IMS: intermembrane space, OMM: outer mitochondrial membrane.
