Skip to Main Content

Cell Death Channel Found Within ATP Synthase Monomer, Study Finds

January 06, 2020
by Julie Parry

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, “A mitochondrial megachannel resides in monomeric F1FO ATP synthase,” the team led by lead author Nelli Mnatsakanyan, PhD, assistant professor of medicine (endocrinology) and Elizabeth Jonas, MD, professor of medicine (endocrinology) and neuroscience showed that mPTP activity can reside in a single ATP synthase enzyme, rather than a double version, as some groups had previously thought.

“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.

Read the complete article in Nature Communications.

The Section of Endocrinology & Metabolism works to improve the health of individuals with endocrine and metabolic diseases by advancing scientific knowledge; applying new information to patient care; and training the next generation of physicians and scientists to become leaders in the field. To learn more about their mission, visit Endocrinology & Metabolism.

Submitted by Julie Parry on January 06, 2020