Research Paper Volume 8, Issue 8 pp 1718—1734

Figure 9. Model describing how metformin induces Aβ aggregates formation and mitochondrial dysfunction. Metformin increases BACE1 production that stimulates APP processing and Aβ production at cell membrane level. Metformin stabilizes small Aβ aggregates that could be internalized. TOM40 pore mediates the mitochondrial internalization of Aβ and APP. The whole APP can block TOM40 channel and the small Aβ can be imported in the inner membrane where affects the Complex I (C I) of the respiratory chain. Small Aβ aggregates displace the binding of HKI with mitochondrial VDAC1 leading to its oligomerization and the formation of large pores that are capable to change permeability and mediate the cytochrome C release. All these coexistent events lead to mitochondrial dysfunction and neuronal apoptosis.