Understanding how cleaning up bad mitochondria affects stem cell division

Most of us remember enough biology to recall that mitochondria are known as "the powerhouse of the cell." Even that audacious term may downplay the importance of mitochondria and what happens when mitochondria go bad.

Dysfunctional mitochondria lead to neurodegenerative diseases, congenital heart disease, strokes, and, of course, cancer. Essentially, at the root of every type of human malady lies worn out or failed mitochondria.

"I study a process called mitophagy, and mitophagy cleans up these damaged mitochondria," said Alicia Pickrell, an assistant professor in the School of Neuroscience, part of the Virginia Tech College of Science. What Pickrell studies goes beyond that: She's trying to find out how the molecules inside a cell communicate with each other. How does a cell know the mitophagy cleanup is going on so it can stop producing new neurons that may be compromised? How does it know when mitophagy is complete to start generating them again?

The work of Pickrell and her team could lead to treatments or preventative medicine for not just one chronic illness like heart disease, but "could give us information about many other diseases."

For this research, the U.S. National Institutes of Health recently awarded Pickrell a $1.9 million grant over five years. The funding is known as a MIRA grant, Maximizing Investigators' Research Award, aimed at providing investigators more flexibility to pursue a breakthrough discovery if their research turns up promising, unexpected findings that weren't in the proposal.

Rather than a grant that focuses on a hypothesis or idea, this grant focuses on a promising, early career-stage scientist that a committee of [her] peers thinks is going to make significant breakthroughs in the field. This speaks to Dr. Pickrell's reputation and the important contributions she has already made in just a few years as an independent faculty member. All of us in the School of Neuroscience are excited for and proud of Alicia."

Michael Fox, Director of the School of Neuroscience

Back to the high school biology class analogy: When the nucleus of a cell divides, the cell replicates its DNA to produce two identical daughter cells. Pickrell's research studies "interorganelle signalling," where the cell would warn the nucleus that there's a problem and it should stop dividing.

But what if the cell doesn't get the message to stop dividing?

"If I'm a cell and I don't get these signals that says, 'I'm cleaning up damaged mitochondria,' and I keep dividing," Pickrell said, "now I'm dividing and my bad mitochondria is inherited into these healthy daughter cells."

She compares this to the individual cells within a car battery: At first, the battery might continue to function even after a couple of the battery's cells go bad, but there's a threshold. With too many bad cells, the battery stops working. With too many bad mitochondria accumulating in neurons in the brain, a person is susceptible to Parkinson's or Alzheimer's disease.

Pickrell is trying to understand how cleaning up bad mitochondria affects stem cell division, which genes are involved, and how mitochondria and other organelles communicate inside the cell. How does the cell know that mitophagy is underway so the cell can stop dividing? How do organelles communicate with the cell to let it know the clean-up work is done and it's safe to start producing more cells again?

And there's a big complication to the mystery: The mitochondria are not touching the nucleus, so if there is not a physical connection how is the communication sent?

Pickrell and her research team have found one molecule, a kinase, which is a certain kind of protein, that can move back and forth inside the cell to transmit information, but Pickrell thinks there must be other ways.

"We think biology is smart, and cells are not going to rely on just one thing to keep themselves alive," she said.

Initially with the grant, her team is delving into neural stem cells, because they divide frequently and perform a lot of mitophagy to clean up the bad mitochondria.

"With cell division, you have to have a lot of energy to do that, so it's important to have a nice healthy pool of mitochondria," she said.