Humans, like other mammals, are capable of adapting to a wide range of temperatures, including the colder temperatures of the Finnish winter. However, how exposure to cold temperatures alters physiological and metabolic circuitry remains unclear. Researchers from Harvard Medical School/Dana-Farber Cancer Institute conducted a study in which mice were placed under colder temperatures (ca. 4°C) and normal room temperatures (ca. 28°C) for around 8 days. This time allowed the mice to rewire their metabolic circuitry and adjust to the applied temperatures.
After a careful and calibrated experimental protocol, the respiratory supercomplexes of the mitochondrial electron transport chain were extracted from brown adipose tissues. These were examined with a high-resolution imaging technique, cryo-electron microscopy. They identified two main structural conformations, called type 1 and type 2 of the mitochondrial supercomplexes. Type 1 is found in both cold-adapted and thermoneutral samples. Type 2 is exclusively found in the cold-adapted sample, which also showed higher levels of catalytic activity. An intriguing difference between the two structures is the rotated arrangement of the CIII2 complex.
To further establish the molecular mechanism of cold-adapted catalytic enhancement, molecular dynamics simulations and quantum chemical calculations were performed by Amina Djurabekova and Oleksii Zdorevskyi, from the Computational Bioenergetics Group at the Department of Physics, led by Vivek Sharma. These large-scale simulations, consisting of ca. 2 million atomic models in realistic environments, were studied with molecular dynamics utilizing the top-level HPC resources of the Center for Scientific Computing, Finland.
The simulation data revealed differential dynamics of the rotated CIII2 complex in type 2 compared to type 1 conformation. CIII2 is found to be more dynamic despite having a higher number of protein-protein interactions with CI. This suggests that the observed mobility is in part due to the rotated conformation of CIII2 in type 2, which creates a larger gap for lipids and unique lipid-protein interactions. The closer proximity of selective CI and CIII2 subunits in type 2 and a shorter angle distribution of the membrane and peripheral arms of CI highlight molecular reasons behind higher levels of catalytic activity of the cold-adapted conformation.
In addition, quantum-chemistry approaches with molecular dynamics incorporated assisted in identifying potential favorable electron transfer routes in CI in the cold-adapted structure, compared to the thermoneutral case.
The study highlights the importance of an integrative approach combining physiology, biochemistry, structural biology, and computer simulations in solving challenging questions of mitochondrial biology.
Publication: Young-Cheul Shin, Pedro Latorre-Muro, Amina Djurabekova, Oleksii Zdorevskyi, Christopher F. Bennett, Nils Burger, Kangkang Song, Chen Xu, Joao A. Paulo, Steven P. Gygi, Vivek Sharma, Maofu Liao, Pere Puigserver. Structural basis of respiratory complex adaptation to cold temperatures. Cell (October 2024). https://doi.org/10.1016/j.cell.2024.09.029