Atp6ap2, also known as the prorenin receptor (PRR), is an accessory subunit of V-ATPase. It plays a crucial role in multiple signaling pathways, including Wnt/β-catenin signaling, and is involved in maintaining cellular homeostasis, regulating pH in extracellular space and intracellular compartments, and participating in autophagy [2,8].

In osteoclast (OC)-lineage cells, conditional KO (cKO) of Atp6ap2 in OCs leads to trabecular bone loss due to increased osteoclastogenesis and activity, as bone formation rates remain normal. The absence of Atp6ap2 reduces basal levels of Wnt/β-catenin pathway proteins in OCs [1].

In OB-lineage cells, cKO of Atp6ap2 reduces trabecular bone formation and bone mass, impairs β-catenin signaling, and affects the distribution of LRP6/β-catenin and N-cadherin/β-catenin protein complexes at the cell membrane [3].

In cardiomyocytes, knockdown of Atp6ap2 deteriorates heart function by compromising autophagic flux and activating NLRP3 inflammasome [5].

In pancreatic β cells and insulinoma cells, Atp6ap2 is robustly expressed, and its knockdown in insulinoma-derived cells decreases cell viability [4].

In breast cancer cells, Atp6ap2 is overexpressed and promotes cancer progression, and its decline in senescent breast cancer cells triggers pH dysregulation [6,7].

In the renal nephron, nephron-specific Atp6ap2 knockout increases urinary excretion of fatty acids and decreases renal cortical megalin expression [9].

In conclusion, Atp6ap2 is essential for maintaining normal physiological functions in various tissues. Studies using KO/CKO mouse models have revealed its critical role in bone homeostasis, heart function, pancreatic cell viability, cancer progression, and renal function. Understanding Atp6ap2 functions through these models provides insights into the mechanisms of related diseases and potential therapeutic targets.