PLD6 (phospholipase D family member 6) is a dual-function enzyme with distinct phospholipase and nuclease activities that plays critical roles in mitochondrial dynamics and reproductive biology. As a phospholipase, PLD6 uses cardiolipin as substrate to generate phosphatidic acid (PA), which facilitates mitochondrial fusion through interaction with proteins like NME3 and mitofusins 1. This PA production is essential for maintaining mitochondrial homeostasis, with PLD6 depletion causing mitochondrial fragmentation and metabolic dysfunction 2. PLD6's mitochondrial fusion activity is regulated by the ubiquitin-proteasome system, specifically through FEM1B-mediated degradation controlled by TOM20 3. In reproductive contexts, PLD6 exhibits endonuclease activity crucial for piRNA biogenesis during spermatogenesis, where it processes piRNA precursors to maintain genome stability in germline cells. Beyond its established roles, emerging evidence suggests PLD6 functions as an oncogenic factor in colorectal cancer by promoting mitochondrial metabolic reprogramming that activates Wnt/β-catenin signaling 2. PLD6 also contributes to podocyte function and protection against lipid nephrotoxicity through cardiolipin metabolism 4. Genetic variants affecting PLD6 expression are associated with testis weight regulation and may influence reproductive efficiency across mammalian species 5.