Molecular mechanisms regulating the mitochondrial targeting of microsomal cytochrome P450 enzymes

Cytochrome P450 enzymes (CYPs) are a superfamily of monooxygenases found in almost all living organisms. CYPs are predominantly localized in the endoplasmic reticulum membranes as integral membrane proteins, where they metabolize a variety of endogenous and xenobiotic compounds. CYPs also reside in other subcellular compartments, including the plasma membranes and mitochondria. CYP localization in mitochondria is regulated in one of two ways: (1) direct targeting of inherent CYPs with canonical mitochondrial signals in their protein sequence after synthesis in the cytosol or (2) mitochondrial localization of microsomal CYPs after processing of the NH(2)-terminal region. Microsomal CYPs targeted to mitochondria demonstrate conventional or altered catalytic activities using electrons provided by the mitochondrial electron transport system. Mechanisms of microsomal CYP targeting to mitochondria, regulation of localization, and the implications of these in drug metabolism are described in the present review.