The regulation and turnover of mitochondrial uncoupling proteins

Abstract

Uncoupling proteins (UCP1, UCP2 and UCP3) are important in regulating cellular fuel metabolism and as attenuators of reactive oxygen species production through strong or mild uncoupling. The generic function and broad tissue distribution of the uncoupling protein family means that they are increasingly implicated in a range of pathophysiological processes including obesity, insulin resistance and diabetes mellitus, neurodegeneration, cardiovascular disease, immunity and cancer. The significant recent progress describing the turnover of novel uncoupling proteins, as well as current views on the physiological roles and regulation of UCPs, is outlined.

Figure 1. Mammalian UCP gene expression and activity is regulated at multiple steps

Stimuli such as cold and overfeeding activate sympathomimetic pathways that act on the UCP1 enhancer box (2.5 kb upstream), thereby increasing Ucp1 gene expression in BAT. These pathways also increase lipolysis resulting in fatty acids that stimulate UCP1 catalytic activity. Inhibition of lysosomal pathways that degrade UCP1 also contribute to optimising UCP1-mediated thermogenesis. UCP2 appears in various tissues. Its gene expression is regulated by various nutrients and cytokines/immunomodulators, which act via PPAR and SREBP at the transcription level. Translation efficiency is regulated by either the upstream ORF or pseudo-start codons in the 5′UTR, and this region appears to be responsive towards glutamine. UCP3 is targeted to skeletal muscle by coordination of PPAR and the MyoD element. In BAT, a 1.5 kb upstream element controls BAT-specific expression. PPAR elements may transmit information about changes in fatty acid metabolism to Ucp3 gene expression. The transcription factor ATF1 appears to regulate hypoxic-induced regulation of UCP3 while TREs mediate response to thyroid hormone. Translation efficiency has not been studied, but there are pseudo-start codons in the 5′UTR, putatively trapping ribosomes. UCP2 and UCP3 (but not UCP1) are rapidly turned over by the cytosolic proteasome.

Figure 2. Models of UCP2 degradation

In model A, UCP2 is ubiquitinated by an unidentified putative E3 ligase (A2) and unfolded from the mitochondrial inner membrane by processes that may be ATP- or Δψ-dependent. At the mitochondrial outer membrane, the proteasome, perhaps tethered by FKBP8, recognises polyubiquitinated UCP2 (A4) and participates in its extraction from mitochondria in an ATP-dependent fashion, whereby the protein is subsequently degraded by the peptidase activity of the proteasome core (A5). However, firstly it remains unknown whether UCP2 can be ubiquitinated whilst still residing inside mitochondria: there are no known intramitochondrial E3 ligases, and it is widely believed that mitochondrially associated E3 ligases reside in the outer membrane and ubiquitinate proteins on the cytosolic face of mitochondria. Secondly, the speculative nature of model A also extends to the formation of mitochondrial inner and outer membrane contact sites (A3). Since there is evidence that the proteasome may be required for direct removal of UCP2 from mitochondria [116], the contact site feature was modelled to describe how the cytosolic proteasome might gain access to UCP2 given the interposition of the mitochondrial outer membrane. An alternative model B to explain the data from [116] is that a mitochondrial process ejects UCP2 only as far out as the mitochondrial outer membrane (B2), whereupon it is ubiquitinated by cytosolic-facing outer membrane-associated E3 ligases (B3), then retrotranslocated by the proteasome (B4) before being degraded in the cytosol (B5).