Different regulatory systems operate in the midpiece and principal piece of the mammalian sperm flagellum.

In mammalian sperm, the flagellar midpiece and principal piece contain different signalling molecules and ion channels. For example, the soluble adenylyl cyclase (sAC), which is required for activation of motility, is restricted to the midpiece, while the plasma membrane calcium channels CatSper1 and CatSper2, which are required for hyperactivation of motility, are restricted to the principal piece. The midpiece and principal piece are partially separated by a barrier called the annulus, yet despite this and the differential distribution of signalling molecules, they normally appear to work together to produce a wave that propagates smoothly down the tail. Under certain circumstances, however, the two segments can act independently. This is the case for sperm of Ste5Jcs l mutant mice, which swim with stiff midpieces but vigorously-beating principal pieces, due apparently to a defect in the mitochondria.