Mitochondria and the Electron Transport Chain
Mitochondria are organelles within eukaryotic cells, and are responsible for generating energy. This energy is in the form of ATP (adenosine triphosphate), which goes on to power many cellular functions and is necessary for life. ATP is specifically generated by the electron transport chain (ETC), a series of protein complexes. Mitochondria are a double-membraned organelle, meaning they have two membranes: an inner and an outer membrane. In human cells, the electron transport chain is located in the inner mitochondrial membrane.
There are a total of 5 protein complexes in the electron transport chain: complex I, complex II (succinate dehydrogenase), complex III (ubiquinol–cytochrome c oxidoreductase), complex IV (cytochrome c oxidase), and complex V (ATP synthase). During a series of reactions, electrons are moved from one protein complex to the next. Each time the electrons are transferred to a new protein complex, energy is released, and each movement helps to continue building an electrochemical gradient. Oxygen molecules (O2) are the final electron acceptor; at the end of the chain, oxygen will take the electrons and bind two of the protons to form water molecules (H2O). The electrochemical gradient is what will be used to generate ATP.
Mitochondrial Complex I
Mitochondrial complex I is the first protein complex, and is responsible for beginning the electron transport chain. It goes by multiple names, including NADH dehydrogenase and ubiquinone oxidoreductase. The specific role of mitochondrial complex I is to remove two electrons from the electron carrier molecule NADH. A proton is also removed from NADH, and the NADH becomes NAD+; mitochondrial complex I also serves the purpose of pumping these free protons across the inner mitochondrial membrane. The two electrons are then free to move through the remaining protein complexes. Mitochondrial complex I is the primary point for electrons to enter the electron transport chain, and it’s also a rate limiting step, meaning it largely controls how much energy can be produced.
Mitochondrial Complex I Deficiencies
Mitochondrial Complex I is critical to overall mitochondrial health. When functioning properly, the mitochondria supports processes in the entire cell, which contributes to tissue and organ health. Glucocerebrosidase (GCase) is an lysosomal enzyme that plays an important role in maintaining mitochondrial complex I integrity. In addition to residing within lysosomes, GCase can be found within the mitochondria, where it interacts with mitochondrial quality control proteins and promotes healthy mitochondrial complex I function.
GCase dysfunction has been linked to Parkinson’s disease; in fact, mutations to the GBA1 gene (which encodes GCase) is the most prominent genetic risk factor for Parkinson’s disease. Defective GCase leads to an increase in oxidative stress, which eventually damages mitochondrial DNA.
While treatments are limited, Gain has recently completed a phase 1 clinical trial for GT-02287, a small molecule GCase modulator. GT-02287 has been shown to repair and rehabilitate lysosomal and mitochondrial function. In preclinical models of PD, GT-02287 restored GCase enzymatic function, reduced ER stress, lysosomal and mitochondrial pathology.
