Fig. 4.

Interaction of proteins in neurodegenerative diseases and mitochondria. The accumulation of mitochondrial DNA mutations may induce ROS production and cause oxidative damage in aged tissues. In AD, age-related production of ROS and decreased ATP levels may contribute to the production of Aβ peptides. Aβ peptides enter mitochondria, induce free radicals, decrease cytochrome oxidase activity, and inhibit ATP generation. In AD brains, APP is transported to outer mitochondrial membranes, blocks the import of nuclear cytochrome oxidase proteins to mitochondria, and may be responsible for decreased cytochrome oxidase activity. In AD neurons (from AD patients, AD transgenic mice, APP cells), Aβ is found in the mitochondrial matrix and binds to ABAD, produces free radicals, and causes mitochondrial dysfunction. The N-terminal portion of ApoE4 is associated with mitochondria, induces free radicals, and causes oxidative damage. Gamma secretase complex proteins, such as presenilins, APH, and nicastrin, were found in the mitochondria and may contribute to Aβ production and free radical generation. In HD neurons, mutant Htt binds to the outer mitochondrial membrane and induces free radical production. H₂O₂may also interrupt with calcium uptake. In PD neurons, mutant proteins of α-synuclein, parkin, PINK1, and DJ1 are associated with mitochondria and cause mitochondrial dysfunction. Complex I activity is inhibited in PD neurons. In ALS, mutant SOD1 is localized in the inner and outer mitochondrial membranes and matrix, and induces free radical production and oxidative damage. Impairment of complexes II and IV are associated with ALS. Frataxin (a gene product in Freidriech ataxia) is a mitochondrial protein responsible for heme biosynthesis and the formation of iron-sulfur clusters. In Freidriech ataxia, mutant frataxin facilitates the accumulation of iron in mitochondria and induces free radicals