The enzyme ATP synthase makes energy for cells within the human body. It was previously debated whether an ATP synthase dimer was required for channel activity and cell death via the mitochondrial permeability transition pore (mPTP), a channel that causes cell death in a variety of diseases, such as heart attack, stroke, chronic kidney and liver diseases, and neurodegenerative diseases.
But in the new report, released in December, “
“For this report, we decided to look at the whole ATP synthase, which is not an easy thing to do,” explained Jonas. “It took Nelli over a year to purify the ATP synthase correctly, to make sure it was intact and free from contaminants. Then, working with Fred Sigworth’s group in the Department of Physiology, she was able to obtain an image of the ATP synthase reconstituted into artificial lipid vesicles using a cryo-electron microscope and could see that there is extremely high probability that the mPTP channel activity, recorded with a patch clamp electrode placed on the vesicles, is found within the monomeric version of the ATP synthase.”
The team studies how modulation of the ATP synthase leak channel may ameliorate disease processes. Their hypothesis is that a relative decrease in channel activity may delay onset of neurodegenerative diseases and could also enhance normal brain development in individuals with neurodevelopmental disease. Going forward, Mnatsakanyan will use cryo-EM to learn more about the structure of the mPT pore, which she and Jonas have evidence resides within the c-subunit or membrane-bound portion of the ATP synthase monomer. Additionally, Mnatsakanyan will use cryo-EM to study morphological changes to mitochondria that may occur during metabolic alterations in neurons and other cells.
in Nature Communications.
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