Credit: CC0 Public Domain
Researchers from the Department of Physics at the University of Helsinki, Finland, and Jagiellonian University Krakow, Poland discovered that a subtle hydrogen-bonding rearrangement due to an exercise-intolerance-related mitochondrial disease mutation could disrupt the normal functioning of the respiratory complex III. Complex III is one key enzyme that contributes to the generation of energy (ATP) in cells.
The mitochondria in cells produce energy in the form ATP. The electron transport chain is a pathway that consists of five enzymes. They synthesize ATP through a complex movement of electrons, protons and electrons. Cytochrome bc1, or complex III, is the third enzyme in the chain. It catalyzes electron transfer reactions by proton pumping.
Multiple mitochondrial diseases can be caused by mutations in complex III. Patryk Kuleta performed spectroscopic experiments that showed clear differences between the mutant enzyme and the wild-type enzyme. Kuleta is a member of the Jagiellonian University research group, Krakow, Poland.
Jonathan Lasham, a doctoral candidate at the Department of Physics University of Helsinki, used classical molecular dynamics simulations as well as density functional theory calculations to study wild type and mutant enzymes. These computational results provided new insights into the experimental data and deeper mechanistic insight.
One point mutation that transforms amino acid glycine into serine stabilizes a stronger hydrocarbon bond to the complex III heme group. This alters the spin state and redox potential of heme which in turn affects complex III's wild-type electron transfer function.
"These combined experimental-computational results provide detailed molecular insights into how diseases may emerge by point mutations in mitochondrial enzymes and provide grounds for developing therapeutics of the future," summarizes Vivek Sharma, Academy Research Fellow and Sigrid Juslius Senior Researcher from the Department of Physics at the University of Helsinki.
PRACE and the Center for Scientific Computing (CSC) provided the computational resources necessary to produce these results. On the Mahti supercomputer at CSC, Finland, large-scale molecular dynamics simulations could be performed.
The PNAS published the results of the combined experimental and computational biophysics study.
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More information: Patryk Kuleta and colleagues, Hydrogen bonding rearrangement in the mitochondrial disease mutation of cytochrome BC1 perturbs the heme-bH redox pot and spin state, Proceedings of the National Academy of Sciences (2021). Information from the Journal: Proceedings of National Academy of Sciences Patryk Kuleta and colleagues, Hydrogen bonding rearrangement in cytochrome Bc1 by a mitochondrial mutation in cytochrome BC1 perturbs heme's bH redox pot and spin state, (2021). DOI: 10.1073/pnas.2026169118
