Mitochondrial localization of nitric oxide synthase in partially differentiated urothelial cells of urinary bladder lesions

In urothelium, nitric oxide (NO) produced by NO synthase (NOS) plays various roles during disease processes. Because diseases influence the expression of uroplakins, the main urothelial differentiation-related proteins, we compared their expression and localization with that of inducible NOS (iNOS) in bladder outlet obstruction caused by benign prostatic hyperplasia and in noninvasive urothelial neoplasms (papilloma, low-grade, and high-grade papillary carcinoma). In all cases, we found areas with terminal and areas with partial cell differentiation. Terminally differentiated urothelium was uroplakin positive and NOS negative. Areas of partial differentiation contained superficial cells with altered apical surface morphology and with no or weak uroplakin staining. These areas showed elevated iNOS staining. By immunoelectron microscopy, it was demonstrated for the first time that iNOS was localized in mitochondria of urothelial cells that show partial differentiation. These results suggest that various urinary bladder lesions alter the normal differentiation pathway of urothelial superficial cells, which induces the expression of NOS in mitochondria of partially differentiated cells.