PITRM1 is a zinc-dependent metalloendopeptidase localized to the mitochondrial matrix that degrades peptides 5–65 residues in length, with preference for cleavage after small polar residues and before basic residues. It degrades mitochondrial transit peptides after their removal from precursor proteins and also degrades unstructured peptides including amyloid-beta (Aβ) 40 and 42, functioning as a highly efficient protease toward these substrates. PITRM1 deficiency induces mitochondrial proteotoxic stress and activates the mitochondrial unfolded protein response (UPRmt) 1. Loss-of-function mutations cause a progressive neurological syndrome featuring cerebellar ataxia, cognitive decline, and psychotic episodes 2. In cerebral organoids derived from PITRM1-knockout induced pluripotent stem cells, spontaneous Alzheimer's disease–like pathology develops over time, including protein aggregates, tau pathology, and neuronal cell death 1. Mutations impairing PITRM1 catalytic activity, such as R183Q identified in amyloidogenic neuropathy, reduce hydrolysis rates while maintaining substrate binding 3. PITRM1 also protects against alpha-synuclein-mediated mitochondrial toxicity 4. Clinically, increasing neuronal PITRM1 expression in advanced-age Alzheimer's disease mouse models restores mitochondrial respiration, suppresses reactive oxygen species, and preserves synaptic function even in the context of substantial amyloid pathology 5, suggesting that augmenting PITRM1 function may represent a therapeutic strategy for slowing Alzheimer's disease progression.