Respiratory complex II acting as a homeostatic regulatory sensor

The succinate-ubiquinone oxidoreductase (SQR) complex connects two of the cell's most vital energy-producing metabolic processes: the tricarboxylic acid cycle and the electron transport chain. Hence, the SQR complex is essential in cell metabolism, and its malfunction leads to the progression of multiple metabolic disorders and other diseases, such as cancer. In the current study, we calculated the electron tunneling (ET) pathways between the different redox systems in the SQR complex, including the SQR ligands and the distant heme b redox center, using the broken-symmetry semi-empirical ZINDO method. Interestingly, we discovered a water channel running from the mitochondrial matrix, filling the space between Fe₃S₄ and heme b redox centers. To investigate the physiological function of the water channel, we performed extensive molecular dynamics (MD) simulations of the membrane-embedded SQR complex in small and large water boxes, representing regular (MD_A) and extended (MD_B) volume states, respectively. We found that under regular volume conditions (MD_A), the ET reaction is conducted through both the iron-sulfur cluster chain (i.e., pathway A) and through heme b (i.e., pathway B). Hence, the SQR complex encompasses an internal interferometer similar to the Mach-Zender interferometer, such that the tunneling electron experiences a self-interference effect through pathways A and B, enhancing the SQR complex's overall ET thermodynamics and favoring the forward ET direction of oxidizing succinate to fumarate and reducing ubiquinone to ubiquinol. On the other hand, we found that under extended volume conditions (MD_B), the internal water channel of the SQR complex "senses" the expansion in the mitochondrial volume, pushing the heme b and Fe₄S₃ redox centers apart and hence lowering the SQR equilibrium constant to almost unity. Therefore, the SQR complex could be driven to work in the reverse direction, catalyzing the production of ubiquinone molecules essential for the physiological function of respiratory complexes I and III and restoring the inner-mitochondrial membrane potential, which leads to restoring the function of the H-K anti-porter, pumping K⁺ outward from the matrix and restoring the regular mitochondrial volume.