Figure 1. Impaired amyloid‐β (Aβ) degradation due to the decreased activity of pitrilysin metallopeptidase 1 (PITRM1) contributes to Aβ accumulation in the mitochondria, leading to neuronal death.

The presence of Aβ within the mitochondria affects several aspects of mitochondrial function. Interaction of Aβ with the outer mitochondrial membrane (OMM) impairs the transport of nuclear‐encoded mitochondrial proteins, such as subunits of the respiratory chain complexes, into the organelle via the translocase of the outer membrane (TOM) import machinery. Insufficient PITRM1 impairs the degradation of mitochondrial targeting sequences (MTS) cleaved from the imported proteins by the mitochondrial processing peptidase (MPP), further disturbing the import of proteins into the mitochondria. Respiratory chain dysfunction leads to decreased ATP synthesis in addition to increased reactive oxygen species (ROS) production. Finally, Aβ reduces proton translocation from the matrix to the intermembrane space, thus impairing the mitochondrial membrane potential (MMP).