PRSS55 is a testis-specific serine protease essential for male fertility through multiple mechanisms. Primary function: PRSS55 localizes to sperm mitochondria and regulates branched-chain amino acid (BCAA) metabolism by interacting with BCKDK and BCKDHA, thereby controlling energy homeostasis and ATP production critical for sperm function 1. Mechanism: The protein stabilizes ADAM3, a membrane protein required for sperm migration through the uterotubal junction and zona pellucida binding 2. PRSS55 also activates type II muscle myosin, facilitating cytoskeleton organization and sperm structural differentiation 3. Disease relevance: Prss55 knockout mice exhibit severe astheno/teratozoospermia with morphological defects in sperm head, neck, midpiece, and tail, alongside impaired mitochondrial function and decreased electron transfer chain expression 3. Critically, a novel homozygous mutation (c.575C>T [p.A192V]) in PRSS55 causes human male infertility with similar morphological sperm defects 4. Clinical significance: The mutation reduces PRSS55 protein concentration and alters conformation 4. Human PRSS55 can functionally rescue mouse Prss55 knockout fertility when properly localized intracellularly, establishing a validated contraceptive research model 5. These findings position PRSS55 as a promising therapeutic target for genetic male infertility treatment 1.