PITRM1

PreP is an Zn²⁺-dependent and ATP-independent metalloprotease, it does not select substrates on the basis of post-translational modifications or embedded degradation tags.^[7][8][9] Instead, it uses a negatively charged catalytic chamber to engulf substrates peptides of up to ~65 residues while excluding larger, folded proteins.^[10][11] It primarily localizes to the mitochondrial matrix, and cuts a range of peptides into recyclable fragments.^[12][13] The substrates of PreP are vital to proteostasis, as they can insert to mitochondrial membranes, disrupting electrical potential and uncoupling respiration.^[14][15] Thus deletion of PRTRM1 leads to a delayed growth phenotype.^[16][17] Notabley, PreP degrades several functionally relevant Aβ species, the aggregates of which are toxic to the neuron and play a key role in AD pathogenesis.^[18][10][19]

PreP is the Aβ-degrading protease in mitochondria. Immune-depletion of PreP in brain mitochondria prevents degradation of mitochondrial Aβ, and PreP activity is found diminished in AD patients.^[4] It has been reported that the loss of PreP activity is due to methionine oxidation and this study provides a rational basis for therapeutic intervention in conditions characterized by excessive oxidation of PreP.^[20] A recent study also suggests that PreP regulates islet amyloid polypeptide in beta cells.^[21] Two siblings carrying a homozygous PITRM1 missense mutation (c.548G>A, p.Arg183Gln) were reported to be associated with an autosomal recessive, slowly progressive syndrome. Clinical features include mental retardation, spinocerebellar ataxia, cognitive decline and psychosis.^[22] A mouse model hemizygous for PITRM1 displayed progressive ataxia which was suggested to be linked to brain degenerative lesions, including accumulation of Aβ‐positive amyloid deposits. Recently, two brothers from a consanguineous family presenting with childhood-onset recessive cerebellar pathology were shown to carry a homozygous mutation in PITRM1 (c.2795C>T, p.T931M). This mutation resulted in 95% reduction in PITRM1 protein.^[23] PITRM1 knockdown was shown to lead to reduced levels of mature Frataxin protein,^[24] a protein that when deficient causes Friedreich's ataxia, and may be implicated in pathology in patients carrying PITRM1 mutations.

PITRM1 has been shown to interact with the following proteins: CCL22, CGB2, DDX41, DEFB104A, HDHD3, MRPL12, NDUFV2, PRDX6, PRKCSH, RARS2, RIF1, SUCLG2, TEKT3, TERF2, and VAPB.^[25]