Amyloid-β in mitochondrial disease: mutation in a human metallopeptidase links amyloidotic neurodegeneration with mitochondrial processing

Abstract

There is increasing evidence that common molecular pathways in neurons are closely linked with mitochondrial function and that mitochondrial dysfunction is connected to various forms of neurodegenerative diseases. For instance, mitochondria are involved in amyloid‐β (Aβ) deposition in Alzheimer's disease, although the exact molecular pathways remain largely unknown. Brunetti et al (2015) in this issue of EMBO Molecular Medicine provide a novel link between Aβ accumulation and mitochondria. A pathogenic mutation in a Norwegian family in the mitochondrial metallopeptidase PITRM1 is found to underlie a novel mitochondrial neurodegenerative phenotype associated with Aβ accumulation.

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).