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Monday, December 6, 2021

New drug prevents cell death

A new drug has been discovered that can prevent programmed cell death, also known as apoptosis. The drug could be a novel therapy for treating heart attack, stroke and neurodegenerative diseases, in which nerve cells are lost.

Jodi Nunnari, a professor of molecular and cellular biology at UC Davis, has been studying mitochondria, the part of the cell that generates energy. For several years, her lab has been studying how mitochondria divide and fuse.

She and a group of collaborators were interested in dissecting the mechanism of mitochondrial dynamics and certain proteins that can promote mitochondrial division.

We were becoming interested in exploring in more detail the physiological roles that dynamics play in cells, in addition to the more fundamental ones, Nunnari said.

It turns out that mitochondrial fusion and division play important roles in the regulation of apoptosis.

Apoptosis is the major way in which animal cells die, and the mitochondrial pathway of apoptosis is the most prominent pathway for this form of cell death in mammals, said Douglas Green, a collaborator and chair of the department of immunology St. Jude Children’s Research Hospital.

When mitochondrial apoptosis occurs, a group of proteins, called the Bcl-2 proteins, interact. The proteins are either pro-apoptotic or anti-apoptotic and determine whether the cell will die or survive. If the pro-apoptotic proteins beat out the anti-apoptotic proteins, then they are activated and transferredto the outer membrane of the mitochondria.

Once on the outer membrane of the mitochondria, the proteins make the membrane permeable, allowing material to pass through it. This event is called mitochondrial outer membrane permeabilization (MOMP) and causes the release of proteins such as cytochrome c, a cell death mediator, which activates other proteins that result in the cell’s death.

It’s only a matter of time until the cell’s completely cleared out of the body. It’s a very definitive process. There are a lot of activation cascades, but the key step is the permeabilization of the outer membrane and that’s what the drug blocks, Nunnari said.

In order to find the drug, the researchers screened 23,000 compounds that blocked mitochondrial division in yeast and reasoned that because the proteins that mediate division are highly conserved, it would work in mammalian systems.

I did a secondary screen, which was adding the drug to yeast cells and looking to see what happened to the mitochondrial morphology, said Ann Cassidy-Stone, a postdoctoral researcher in the Nunnari lab. If [the drug] was inhibiting mitochondrial division, there is a characteristic structure [formed in which] the mitochondria become net-like.

After the secondary screening, it was found that only one out of the 23,000 compounds was effective in inhibiting mitochondrial division, which the researchers named mdivi-1.

The researchers found that the drug mdivi-1 blocks the mitochondrial division dynamin in yeast and mammalian cells. The self-assembly of these proteins into spiral structures are thought to promote division.

According to the team’s paper in the February 2008 issue of the Developmental Cell, in cells, mdivi-1 retards apoptosis by inhibiting MOMP.

The delay in MOMP keeps proteins that mediate cell death from being released, thus avoiding cell death. Mdivi-1 interferes with dynamin assembly and may target a protein that is part of division machinery called Drp1.

The drug could prevent damage in heart attacks and strokes as cells deteriorate and die.

With what we have created, we can figure out the connection mechanistically between Drp1 and outer membrane permeabilization [to] reveal a novel therapeutic target for many different types of diseases. There are diseases that will benefit from inhibiting apoptosis such as stroke and myocardial infarction, said Nunnari. We’ve had some great collaborators, and I think that that’s key in science. It was really a team effort and a huge amount of a work.

YASSMIN ATEFI can be reached at science@californiaaggie.com.

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