Molecular mechanism of proton pumping by complex I: A single enzyme study

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Mitochondria are the powerhouses of the cells in our body. Complex I is an enzyme complex that plays a crucial role in this process. It uses the energy obtained from chemical reactions to pump positively charged protons across a 5nm thin membrane. This process is not unlike the charging of a battery. Complex I does not always function under optimal conditions and is known to be source of radical oxygen species, which is believed to have important roles in aging. Furthermore, malfunction of complex I has important consequences for (human) health.We like to know how complex I pumps protons across the membrane. Many studies have already been performed in the past, but the pumping mechanism is still unclear and although hypotheses have been formulised, none of these have been experimentally proven. All studies in the past have looked at large ensembles of complex I and form a picture of how these complexes function on average. However, we think that a better understanding of the pumping mechanism can be obtained if we look at these complexes one by one. We have recently developed new experimental methods that are so sensitive they can detect proton pumping by single complexes. In this proposal we want to apply these experiments to study complex I. The results will give us a better understanding on how these complexes function in our mitochondria and what happens when they do not work optimally. The questions we aim to address are of fundamental, 'blue-sky' nature, but on the long term we hope that deeper understanding of the processes that generate energy in our body will help us to tackle diseases often related with aging, including Alzheimer's disease and cancer.