Respiratory complex II acting as a homeostatic regulatory sensor

Area of Science:

• Biochemistry
• Molecular Biology
• Bioenergetics

Background:

• The succinate-ubiquinone oxidoreductase (SQR) complex is crucial for cellular energy production, linking the tricarboxylic acid cycle and electron transport chain.
• Dysfunction of the SQR complex is implicated in metabolic disorders and diseases like cancer.

Purpose of the Study:

• To investigate the electron tunneling (ET) pathways within the SQR complex.
• To explore the role of a newly discovered water channel in SQR function and its response to mitochondrial volume changes.

Main Methods:

• Calculated ET pathways using the broken-symmetry semi-empirical ZINDO method.
• Performed molecular dynamics (MD) simulations of the membrane-embedded SQR complex under varying volume conditions (MD_A for regular, MD_B for extended).

Main Results:

• Identified a water channel between the Fe3S4 and heme b redox centers.
• Under regular volume (MD_A), ET occurs via two pathways (iron-sulfur cluster chain and heme b), creating an interferometer effect that enhances forward ET.
• Under extended volume (MD_B), the water channel alters redox center spacing, reducing the SQR equilibrium constant and potentially reversing its function.

Conclusions:

• The SQR complex functions as an internal interferometer, optimizing electron transfer for succinate oxidation.
• The water channel plays a key role in sensing mitochondrial volume, regulating SQR activity and potentially restoring mitochondrial function and volume.
• These findings offer insights into metabolic regulation and potential therapeutic targets for related diseases.