**9. Conclusions**

Overall, proton leak plays a vital role in mitochondrial bioenergetics as well as ROS generation and oxidative stress. Direct and indirect evidence have shown increased rate of mitochondrial proton leak upon aging [96], Thus proton transporters (basal and regulated) can be considered as potential drug targets for therapy of numerous diseases and understanding the underlying mechanism of proton transport is extremely valuable.

In this report we reviewed the current developments regarding the structure and function of proton transporters with special focus on UCPs. UCPs have been linked to thermogenesis as well as several metabolic diseases such as diabetes, hypertension, obesity, and cancer, making them fascinating targets for drug development [36]. Despite their biological importance there is no agreemen<sup>t</sup> on their mechanism of activity or their functional structure. For example, there is evidence that UCPs can exist in the IMM as functional monomers, dimers, tetramers, or a mixture of all. Protons are transported from the internal channel of the monomer or monomeric subunits of the dimer or tetramer. Regardless of what has been observed in experimental models, oligomeric state of UCPs (and other MCF members) might be interchangeable and differ in response to environmental factors or stress (in cell and organism), which can be also observed in mitochondrial structure (morphology) and its dynamic lipid and protein composition. In studying and

interpreting dynamic processes in mitochondria or cell, it is essential to always consider the limitations applied to studying the model systems with current technologies when relating the results to a living, independent and ever-changing (non-rigid) system.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ijms23031528/s1.

**Author Contributions:** Conceptualization, A.A. and M.J.-N.; investigation, A.A.; writing—original draft preparation, A.A.; writing—review and editing, A.A., M.D.S. and M.J.-N.; supervision, M.J.-N. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery and Canada Foundation for Innovation (CFI) grants to M.J.-N. (05900 and 6786, respectively), and M.D.S. (NSERC Discovery 05437). A.A. was a recipient of the Ontario Trillium Scholarship for the duration of her doctoral studies at Wilfrid Laurier University.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors would like to acknowledge the technical contributions of Mikko Karttunen and Shahin Sowlati-Hashjin (both at Western University, Canada) in the computational component of this research, through SHARCNET (www.sharcnet.ca (last accessed on 23 December 2021)) and Compute Canada (www.computecanada.ca (last accessed on 23 December 2021)).

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
