*Review* **Uncoupling Proteins and Regulated Proton Leak in Mitochondria**

**Afshan Ardalan 1,†, Matthew D. Smith 2 and Masoud Jelokhani-Niaraki 1,\***


**Abstract:** Higher concentration of protons in the mitochondrial intermembrane space compared to the matrix results in an electrochemical potential causing the back flux of protons to the matrix. This proton transport can take place through ATP synthase complex (leading to formation of ATP) or can occur via proton transporters of the mitochondrial carrier superfamily and/or membrane lipids. Some mitochondrial proton transporters, such as uncoupling proteins (UCPs), transport protons as their general regulating function; while others are symporters or antiporters, which use the proton gradient as a driving force to co-transport other substrates across the mitochondrial inner membrane (such as phosphate carrier, a symporter; or aspartate/glutamate transporter, an antiporter). Passage (or leakage) of protons across the inner membrane to matrix from any route other than ATP synthase negatively impacts ATP synthesis. The focus of this review is on regulated proton transport by UCPs. Recent findings on the structure and function of UCPs, and the related research methodologies, are also critically reviewed. Due to structural similarity of members of the mitochondrial carrier superfamily, several of the known structural features are potentially expandable to all members. Overall, this report provides a brief, ye<sup>t</sup> comprehensive, overview of the current knowledge in the field.

**Citation:** Ardalan, A.; Smith, M.D.; Jelokhani-Niaraki, M. Uncoupling Proteins and Regulated Proton Leak in Mitochondria. *Int. J. Mol. Sci.* **2022**, *23*, 1528. https://doi.org/10.3390/ ijms23031528

Academic Editor: Giovanni Natile

Received: 24 December 2021 Accepted: 26 January 2022 Published: 28 January 2022

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**Keywords:** mitochondrial carriers; uncoupling proteins; ADP/ATP carrier; membrane protein structure and function; regulation and mechanism of proton transport; membrane protein oligomerization; ATP synthesis; biphasic proton transport model; alternating access mechanism; reactive oxygen species control
