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bioRxiv · 10.1101/2025.04.27.650829

The non-thermogenic function of opossum UCP1 is independent of its cytoplasmic binding network.

Roticiani, G.·Kreiter, J.·Pohl, E. E.
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Abstract

The primary function of uncoupling protein 1 (UCP1) is to mediate non-shivering thermogenesis in brown adipose tissue by facilitating proton transport across mitochondrial membranes. However, recent study has shown that UCP1 from the opossum (a marsupial) lacks thermogenic activity (Keipert et al., Science, 2024). This deficiency was attributed to two altered residues, K100 and Y289, within the cytosolic salt bridge network. Interestingly, the same residues are also present in UCP2 and UCP3 from murine species, both of which are known to transport protons in the presence of long-chain fatty acids (FAs). This raises questions about the validity of the proposed mechanism involving these residues in the loss of thermogenic function in opossum UCP1. In this study, we performed conductance measurements of planar lipid bilayers reconstituted with either recombinant mouse UCP1, or UCP1 mutant (Q100K/F289Y), or UCP2, or UCP3. Our data demonstrate that the conductance of the UCP1 double mutant, UCP2, and UCP3 is comparable to that of wild-type mouse UCP1 in the presence of palmitic or arachidonic acids. These findings suggest that the altered cytosolic residues (K100 and Y289) do not explain the lack of thermogenic function in opossum UCP1. Thus, the underlying molecular mechanism responsible for the absence of thermogenesis in opossum UCP1 remains unresolved, and further studies are warranted to elucidate the precise cause of this dysfunction. Given the emerging interest in UCP1 uncoupling as a potential therapeutic approach for treating obesity by increasing energy expenditure, understanding the molecular basis of UCP1s thermogenic dysfunction is of significant relevance.

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Roticiani, G., Kreiter, J., Pohl, E. E.. 2025-04-30. The non-thermogenic function of opossum UCP1 is independent of its cytoplasmic binding network.. https://doi.org/10.1101/2025.04.27.650829

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