PISD (phosphatidylserine decarboxylase) is a mitochondrial enzyme that catalyzes the conversion of phosphatidylserine to phosphatidylethanolamine (PtdEtn) in the inner mitochondrial membrane 1. This conversion is central to phospholipid metabolism and interorganelle trafficking of phosphatidylserine 2. The enzyme undergoes autocatalytic self-processing to generate its active heteromeric form 3. PISD dysfunction impairs mitochondrial function, as evidenced by fragmented mitochondrial networks, decreased oxidative phosphorylation, and increased metabolic stress sensitivity in patient fibroblasts 1. Phosphatidylethanolamine synthesized by PISD is essential for autophagosome biogenesis; restoring PISD-dependent PE production enhances autophagy and tau clearance in tauopathy neurons 4. Additionally, PISD regulates the mitochondrial permeability transition pore through interaction with SPG7, controlling necroptosis pathways 5. Biallelic PISD variants cause a spectrum of mitochondrial diseases ranging from skeletal dysplasia with short stature and spondyloepimetaphyseal dysplasia to multisystem disorders affecting eyes, ears, bones, and brain 36. These pathogenic variants impair enzyme autoprocessing or catalytic activity, resulting in mitochondrial dysfunction 1. PISD dysregulation is implicated in Alzheimer's disease and other neurodegenerative conditions 2.