Role of PITRM1 in Mitochondrial Dysfunction and Neurodegeneration

Dario Brunetti,Daniele Ghezzi,Carlo Viscomi,Laurence A Bindoff,Alessia Catania,Michela Deleidi,Massimo Zeviani

doi:10.3390/biomedicines9070833

Abstract

Mounting evidence shows a link between mitochondrial dysfunction and neurodegenerative disorders, including Alzheimer Disease. Increased oxidative stress, defective mitodynamics, and impaired oxidative phosphorylation leading to decreased ATP production, can determine synaptic dysfunction, apoptosis, and neurodegeneration. Furthermore, mitochondrial proteostasis and the protease-mediated quality control system, carrying out degradation of potentially toxic peptides and misfolded or damaged proteins inside mitochondria, are emerging as potential pathogenetic mechanisms. The enzyme pitrilysin metallopeptidase 1 (PITRM1) is a key player in these processes; it is responsible for degrading mitochondrial targeting sequences that are cleaved off from the imported precursor proteins and for digesting a mitochondrial fraction of amyloid beta (Aβ). In this review, we present current evidence obtained from patients with PITRM1 mutations, as well as the different cellular and animal models of PITRM1 deficiency, which points toward PITRM1 as a possible driving factor of several neurodegenerative conditions. Finally, we point out the prospect of new diagnostic and therapeutic approaches.

Highlights

Mitochondrial dysfunction, whether primary or secondary, is increasingly recognized as a hallmark of neurodegeneration [1] and a wide body of literature provides evidence of impaired mitochondrial function as a cause rather than a consequence of neurodegeneration [2,3,4]
Mitochondrial protein homeostasis is key for the maintenance of energetic efficiency and for protein quality control, and its impairment has been associated with human disease and neurodegeneration [89]
We collected substantial evidence suggesting that the mitochondrial peptidase pitrilysin metallopeptidase 1 (PITRM1) plays an important role in cellular proteostasis

Summary

Introduction

Mitochondrial dysfunction, whether primary or secondary, is increasingly recognized as a hallmark of neurodegeneration [1] and a wide body of literature provides evidence of impaired mitochondrial function as a cause rather than a consequence of neurodegeneration [2,3,4]. A potential role for PITRM1 in AD is fostered by studies showing that increased expression and activity of neuronal mPreP significantly reduced the mitochondrial Aβ load, and improved mitochondrial function, and synaptic plasticity and strength, in AD mouse models, and prevented the development of impaired spatial learning and memory. This enhancement of PITRM1 activity provided a new therapeutic option for the treatment of AD [56,60]. Pharmacological attempts using this approach have, so far, been unsuccessful [62] and therapeutic modulators of PITRM1 remain to be identified

Genetic Variants in Human PITRM1

Mouse Models

A PITRM1 Mutant Dog

Cellular Models of PITRM1 Impairment

Findings

Conclusions