Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria: the concept of chimeric signals

Abstract

Summary Targeting signals are critical for proteins to find their specific cellular destination. Signals for protein targeting to the endoplasmic reticulum (ER), mitochondria, peroxisome and nucleus are distinct and the mechanisms of protein translocation across these membrane compartments also vary markedly. Recently, however, a number of proteins have been shown to be present in multiple cellular sites such as mitochondria and ER, cytosol and mitochondria, plasma membrane and mitochondria, and peroxisome and mitochondria suggesting the occurrence of multimodal targeting signals in some cases. Cytochrome P450 monooxygenases (CYPs), which play crucial roles in pharmacokinetics and pharmacodynamics of drugs and toxins, are the prototype of bimodally targeted proteins. Several members of family 1, 2 and 3 CYPs have now been reported to be associated with mitochondria and plasma membrane in addition to the ER. This review highlights the mechanisms of bimodal targeting of CYP1A1, 2B1, 2E1 and 2D6 to mitochondria and ER. The bimodal targeting of these proteins is driven by their N-terminal signals which carry essential elements of both ER targeting and mitochondria targeting signals. These multimodal signals have been termed chimeric signals appropriately to describe their dual targeting property. The cryptic mitochondrial targeting signals of CYP2B1, 2D6, 2E1 require activation by PKA or PKC mediated phosphorylation at sites immediately flanking the targeting signal, and/or membrane anchoring regions. The cryptic mitochondria targeting signal of CYP1A1 requires activation by endoproteolytic cleavage by a cytosolic endoprotease, which exposes the mitochondrial signal. This review discusses both mechanisms of bimodal targeting and toxicological consequences of mitochondria targeted CYP proteins.

Differential Expression of Human Cytochrome P450 Enzymes from the CYP3A Subfamily in the Brains of Alcoholic Subjects and Drug-Free Controls

“…Although cross-contamination may have occurred between subcellular fractions during sample processing, distinct patterns of expression were seen in the two fractions arguing against the hypothesis that apparent P450 expression in mitochondrial and soluble fractions was due to contamination with microsomes. Importantly, it is now recognized that many "microsomal" P450s are also expressed in mitochondria, cytosol, and plasma membrane (Neve and Ingelman-Sundberg, 2008;Avadhani et al, 2011). Import into the mitochondrion involves an initial transit through the cytosol, which may explain the cytosolic localization of CYP3A4 in the present study, given the clear signal observed in the mitochondrial fraction.…”

The cytochrome P450 genesis locus: the origin and evolution of animal cytochrome P450s

“…endoplasmic reticulum and mitochondrial targeting, including CYP1A [79,80] and CYP2E1 [79,81]. Vertebrate CYP11A and CYP11B/11C are ohonologues that duplicated during 2R (table 1).…”

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Importantly, CYPs are mainly located in the ER membranes, although some CYPs could be also found in mitochondria (Avadhani et al. 2011; Knockaert et al. 2011).…”