Through a series of assays, however, the researchers were able to ascertain that this complex was indeed running in reverse in cultured cells, largely due to accumulation of a molecule called ubiquinol, which the researchers observed to build up under low-oxygen conditions. "Fumarate is used as an electron acceptor in lower eukaryotes, but they use a totally different enzyme and electron carrier, and mammals are not known to possess either of these." "Although the SDH complex is known to catalyze some fumarate reduction, it was thought that it was thermodynamically impossible for this SDH complex to undergo a net reversal," Spinelli said. For the opposite to happen, the SDH complex would need to be running in reverse. Usually, the fumarate-succinate reaction runs the other direction in cells-a protein complex called the SDH complex takes away electrons from succinate, leaving fumarate. "This led us to think that maybe this accumulation of succinate that's occurring could actually be caused by fumarate being used as an electron acceptor, and that this reaction could explain the maintenance of mitochondrial functions in hypoxia," Spinelli said. When you add electrons to fumarate, it becomes succinate. When you add electrons to oxygen at the end of the electron transport chain, it picks up two protons and becomes water. When cells were deprived of oxygen, researchers noticed a high level of a molecule called succinate. The researchers began their investigation into how cells can maintain mitochondrial function without oxygen by using mass spectrometry to measure the quantities of molecules called metabolites that are produced through cellular respiration in both normal and low-oxygen conditions. The research, which was completed in the laboratory of former Whitehead Member David Sabatini, answers a long-standing mystery in the field of cellular metabolism, and could potentially inform research into diseases that cause low oxygen levels in tissues, including ischemia, diabetes and cancer. Their research shows that when cells are deprived of oxygen, another molecule called fumarate can step in and serve as a terminal electron acceptor to enable mitochondrial function in this environment. In a paper published December 2 in the journal Science, Whitehead Institute scientists and collaborators led by Spinelli have found the answer to these questions. "We wanted to understand, how does this work? How are mitochondria capable of maintaining these electron inputs when oxygen is not the terminal electron acceptor?" "This indicated that mitochondria could actually have partial function, even when oxygen is not the electron acceptor," said Whitehead Institute postdoctoral researcher Jessica Spinelli. In the past, however, scientists have noticed that cells are able to maintain some functions of the electron transport chain, even in the absence of oxygen. At the end of this chain, two electrons remain, which are typically passed off to oxygen, the "terminal electron acceptor." This completes the reaction and allows the process to continue with more electrons entering the electron transport chain.
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