| 2016 |
PITRM1 is a mitochondrial matrix enzyme responsible for degrading mitochondrial targeting sequences (MTS) cleaved from imported precursor proteins and for digesting the mitochondrial fraction of amyloid-beta (Aβ). A homozygous missense mutation (p.Arg183Gln) reduces its proteolytic activity, resulting in Aβ accumulation in patient fibroblasts, skeletal muscle, and a yeast model. Heterozygous Pitrm1+/- mice develop progressive ataxia with brain Aβ-positive amyloid deposits, providing direct mechanistic evidence that PITRM1 loss impairs Aβ clearance leading to amyloidotic neurodegeneration. |
In vitro peptidase activity assay, patient fibroblast and skeletal muscle analysis, yeast complementation model, heterozygous mouse model with neuropathology |
EMBO molecular medicine |
High |
26697887
|
| 2018 |
A novel PITRM1 missense mutation (p.T931M) reduces PITRM1 protein levels by ~95% and specifically impairs cleavage of peptides ≥40 amino acids, demonstrating that the length of the substrate peptide is a determinant of PITRM1 enzymatic activity, with longer peptides being preferentially affected by this variant. |
Whole exome/genome sequencing, quantitative peptide cleavage activity assays in patient cells and yeast model |
Journal of medical genetics |
Medium |
29764912
|
| 2020 |
PITRM1 deficiency in human iPSC-derived cortical neurons strongly induces the mitochondrial unfolded protein response (UPRmt) and enhances mitochondrial clearance (mitophagy). PITRM1-knockout cerebral organoids spontaneously develop AD-like pathology including amyloid precursor protein and Aβ accumulation, tau pathology, protein aggregates, and neuronal cell death, establishing that impaired mitochondrial presequence processing triggers proteotoxic stress and UPRmt as an early protective response. |
PITRM1-knockout human iPSC-derived cortical neurons and cerebral organoids, single-cell RNA sequencing, immunohistochemistry for Aβ/tau/aggregates |
Molecular psychiatry |
High |
32632204
|
| 2021 |
Increasing neuronal PITRM1 expression/activity in aged AD transgenic mice (up to 19–24 months) re-established mitochondrial respiration, suppressed reactive oxygen species, improved synaptic function, and reduced synapse loss. Loss of PITRM1 proteolytic activity (catalytic mutant) abolished these rescue effects and resulted in Aβ accumulation, demonstrating that PITRM1 proteolytic activity is specifically required for mitochondrial Aβ clearance and protection of mitochondrial and synaptic function. |
Transgenic mouse model overexpressing PITRM1 or proteolytic-dead PITRM1 in cortical neurons; mitochondrial respiration assay, ROS measurement, synaptic function assessment, Aβ quantification |
Aging cell |
High |
33951271
|
| 2021 |
An in-frame 6-bp deletion in canine PITRM1 (loss of two N-terminal residues) causes severe mitochondrial respiratory chain deficiency in brain tissue, Aβ accumulation, and lethal epilepsy. Yeast modeling of the mutation confirmed impaired growth and reduced respiration capacity, establishing that the N-terminal domain of PITRM1 is required for proper protein function and mitochondrial respiratory integrity. |
Homozygosity mapping, genome sequencing, mitochondrial respiratory chain enzyme activity assay in brain tissue, yeast complementation model |
Human genetics |
Medium |
33835239
|
| 2023 |
PITRM1 dysfunction causes accumulation of mitochondrial targeting sequences (MTS), which dissipates mitochondrial membrane potential and triggers feedback inhibition of the mitochondrial processing peptidase (MPP), impairing maturation of Frataxin. Pharmacological activation of PPARG by pioglitazone upregulates both IDE and PITRM1 protein levels, restoring presequence processing, Frataxin maturation, and mitochondrial function in patient fibroblasts. |
MTS accumulation assay, mitochondrial membrane potential measurement, MPP activity assay, Frataxin maturation western blot, pharmacological treatment with pioglitazone in patient vs. control fibroblasts |
Frontiers in pharmacology |
Medium |
37576821
|
| 2009 |
Mouse Pitrm1 expression is upregulated in response to loss of the Gli3 transcription factor and is expressed in Pax3-positive myoblast progenitors, dermomyotome, and developing muscles. Pitrm1 expression is regulated downstream of hedgehog signaling in the developing limb, placing it in the Shh/Gli3 pathway during embryonic development. |
In situ hybridization in Gli3, Shh null, and Ptch1 conditional mutant mouse limbs; co-expression with Pax3 lineage marker |
Developmental dynamics |
Low |
19877269
|