{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPITRM1, also known as the mitochondrial presequence protease or PreP, is a matrix metallopeptidase that plays a critical role in maintaining mitochondrial proteostasis. It achieves this by degrading mitochondrial targeting sequences cleaved from imported precursor proteins as well as other unstructured peptides, including amyloid‐β. This dual proteolytic function is essential for preventing the toxic accumulation of peptides within mitochondria, which can impair oxidative phosphorylation and lead to increased reactive oxygen species production."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDetailed enzymological characterization of PITRM1 has revealed that its proteolytic efficiency is sensitive to both genetic mutations and redox modifications. Mutations such as the arginine-to-glutamine substitution (R183Q) markedly decrease the enzyme’s catalytic rate without affecting substrate binding, suggesting that precise charge interactions in the active region are vital for its function. In addition, studies demonstrate that oxidative modifications, which can be partly reversed by mitochondrial repair enzymes like methionine sulfoxide reductase A, further compromise PITRM1 activity. Together, these findings indicate that both genetic and environmental factors can modulate PITRM1 function, ultimately impacting mitochondrial precursor processing."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nPerturbations in PITRM1’s proteolytic capability have significant physiological consequences, particularly in the context of neurodegeneration. Reduced PITRM1 activity, as observed in various genetic models and patient-derived cells, is linked to the accumulation of amyloid‐β within mitochondria, activation of the mitochondrial unfolded protein response, and enhanced mitochondrial clearance. These events collectively contribute to neuronal stress, synaptic dysfunction, and ultimately neurodegeneration associated with Alzheimer’s disease and related disorders. Moreover, experimental upregulation of PITRM1 in aged Alzheimer’s disease mouse models has been shown to restore mitochondrial respiration, decrease oxidative stress, and preserve synaptic integrity. These findings underscore the therapeutic potential of modulating PITRM1 activity to counteract amyloid‐β toxicity and maintain mitochondrial function."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Catarina Moreira Pinho, Behnosh F Björk, Nyosha Alikhani, et al. 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