UCP2, a mitochondrial protein regulated at multiple levels

Abstract

An ever-increasing number of studies highlight the role of uncoupling protein 2 (UCP2) in a broad range of physiological and pathological processes. The knowledge of the molecular mechanisms of UCP2 regulation is becoming fundamental in both the comprehension of UCP2-related physiological events and the identification of novel therapeutic strategies based on UCP2 modulation. The study of UCP2 regulation is a fast-moving field. Recently, several research groups have made a great effort to thoroughly understand the various molecular mechanisms at the basis of UCP2 regulation. In this review, we describe novel findings concerning events that can occur in a concerted manner at various levels: Ucp2 gene mutation (single nucleotide polymorphisms), UCP2 mRNA and protein expression (transcriptional, translational, and protein turn-over regulation), UCP2 proton conductance (ligands and post-transcriptional modifications), and nutritional and pharmacological regulation of UCP2.

Fig. 1

Transcriptional regulation of human Ucp2 gene. Schematic representation of the transcription factor binding sites and of their relative transcription factors/regulatory proteins involved in the regulation of human Ucp2 transcription. The positions of transcription factor binding sites represent nucleotide positions relative to the transcription start site. TRE thyroid hormone response elements, E-box helix–loop–helix protein binding sites, PPARs peroxisomal proliferators-activated receptors, SREBPs sterol response element binding proteins, TRs thyroid hormone receptors, PGC-1 PPARgamma coactivator-1, RSBEs repressive SMAD binding elements. The −866G>A polymorphism is shown. The symbols plus or minus in the transcription factor binding sites indicate activation or repression of Ucp2 transcription, respectively

Fig. 2

Translational regulation of UCP2. Schematic representation of the various regulatory regions of the UCP2 mRNA. The specific complementary sites of miRNA-133a and miRNA-15a in the 5′-untranslated region (5′-UTR), in the UCP2 coding sequence (UCP2 cds), and in the 3′-untranslated region (3′-UTR) of the UCP2 mRNA (NM_003355) are represented on the basis of UCP2 mRNA sequence analysis performed using NCBI-Nucleotide web site (http://www.ncbi.nlm.nih.gov/nuccore). The position of the UCP2 exons and of the Ala55Val polymorphism are shown. uORF upstream open reading frame, hnRNP K heterogeneous nuclear ribonucleoprotein K

Fig. 3

Post-translational and proton conductance activity regulation of UCP2. The overall molecular events involved in the regulation of the uncoupling activity of UCP2 are represented. The UCP2-mediated cycling hypothesis is shown. Unsaturated fatty acids (uFA) flip-flop along their interleaflet concentration gradient (1), and the subsequent backward transport of the anionic deprotonated uFA⁻ is ensured by UCP2 (2). SSG glutathionylation, ROS reactive oxygen species, PNs purine nucleotides, QH ₂ ubiquinol

Fig. 4

Summary of the overall molecular mechanisms of UCP2 regulation described in the text and their relationship with the velocity of execution. The symbols plus or minus indicate activation or repression of UCP2, respectively