Finding The Roots Of Neurodegenerative Disease

Anyone who’s taken high school biology knows that mitochondria are the powerhouses of cells. While it’s true that these organelles are responsible for converting sugars into energy, they also have many less-appreciated jobs, including generating heat, storing and transporting calcium, and regulating cell growth and death. In recent decades, researchers have linked the breakdown of these functions to the development of certain cancers and heart disease.

When it comes to diseases like dementia, Parkinson’s, and ALS, however, Duke University cell biologist Chantell Evans thinks it’s time to look specifically at neurons. “Mitochondria are implicated in almost every neurodegenerative disease,” says Evans. By unraveling how neurons deal with malfunctioning mitochondria, her work could open up possibilities for treating many currently incurable conditions.

Evans’ work focuses on understanding a process called mitophagy—how cells deal with dead or malfunctioning mitochondria—in neurons. There are plenty of reasons to believe brain cells might manage their organelles in unique ways: For one, they don’t divide and replenish themselves, which means the 80 billion or so we’re issued at birth have to last a lifetime. Neurons are also extremely stretched out (the longest ones run from the bottom of the backbone to the tip of each big toe) which means each nucleus has to monitor and maintain its roughly two million mitochondria over a great distance.

Before Evans launched her investigation in 2016, research on epithelial cells—those that line the surface of the body and its organs—had identified two proteins, PINK1 and Parkin, that seem to be mutated in patients with Parkinson’s disease. But, confusingly, disabling those proteins in mice in the lab didn’t lead to the mouse equivalent of Parkinson’s. To Evans, that suggested that the story of neural mitophagy must be more complicated.

To find out how, she went back to basics. Her lab watched rodent brain cells in a dish as they processed dysfunctional mitochondria. Evans gradually cranked up the stress they experienced by removing essential nutrients from their growth medium. This, she argues, is more akin to what happens in an aging human body than the typical process, which uses potent chemicals to damage mitochondria.

Results she published in 2020 in the journal eLife found that disposing of damaged mitochondria takes significantly longer in neurons than it does in epithelial cells. “We think, because [this slowness] is specific to neurons, that it may put neurons in a more vulnerable state,” she explains. Evans has also helped identify additional proteins that are involved in the best-known repair pathway—and determined that that action takes place in the soma, or main body, of a neuron but not in its threadlike extensions, known as axons. That, she says, could mean there’s a separate pathway that’s maintaining the mitochondria in the axon. Now, she wants to identify and understand that one too.

Thoroughly documenting these mechanics will take time, but Evans says charting the system could lead to precious medicine. “If we understand what goes wrong,” she says, “We might be able to diagnose people earlier… and be more targeted in trying to develop better treatment options.”—M.G.

Publication: Elizabeth Murphy, et al., Mitochondrial Function, Biology, and Role in Disease, Circulation Research (2023). DOI: 10.1161/RES.0000000000000104

Original Story Source: University of Arizona