Unlike our organs, cell organelles such as mitochondria are not fixed in place, but when, where, how, and why organelles move remain unclear. Research publishing December 18 in the Cell Press journal Biophysical Journal shows that when beta cells—the pancreatic cells that produce insulin—are exposed to high levels of glucose, their mitochondria move toward the cell's periphery. This mitochondrial migration could play a role in regulating insulin secretion because beta cells' mitochondria are responsible for sensing glucose levels.
"Organelles are not static; they're always moving around, talking to each other," says corresponding author and biophysicist Shankar Mukherji of Washington University in Saint Louis. "Our findings highlight how the organization of the cell might be playing a big role in cell function, even in contexts that you might not expect."
Mitochondria produce ATP by breaking down glucose, which fuels cellular activities. Previous studies have shown that neurons actively position their mitochondria in axons and dendrites, which are far away from the cell's central body and require large amounts of energy to function. But neurons represent an extreme in terms of cell shape and size, and investigations in most other cell types have shown a seemingly random distribution of mitochondria. So the researchers were surprised to find that in pancreatic beta cells, mitochondria seem to respond to glucose availability by moving toward the cell's edge.
"Pancreatic beta cells are relatively simple and compact," says Mukherji. "They don't have a weird shape like a neuron does, so we were a bit surprised when we happened upon this pattern."
The researchers tagged the mitochondria of lab-cultured pancreatic cells with a fluorescent dye, exposed the cells to low and high levels of glucose (2.5 and 25 mM; a healthy blood glucose level is between 3.9 and 5.6 mM), and photographed them under the microscope. When they counted the number of mitochondria in different parts of the cell, they found that cells exposed to high glucose levels had a higher density of mitochondria around their edges.
To investigate the mechanism underpinning this pattern, the researchers used chemicals to disrupt different cellular functions. They found that inhibiting ATP production did not impact the distribution of mitochondria, indicating that mitochondrial movement does not hinge upon mitochondrial function. However, when they disrupted the cells' microtubules (proteins that form part of the cytoskeleton), fewer mitochondria moved toward the cells' peripheries, even in high-glucose conditions. Similarly, inhibiting cAMP, a signaling molecule that facilitates the movement along microtubules, also resulted in fewer peripherally located mitochondria despite high glucose availability.
By incorporating these findings into a computational model, the researchers showed that mitochondria redistribute themselves in response to glucose by binding to microtubules, allowing them to move more rapidly and intentionally than they otherwise would.
"When mitochondria bind to microtubules, they get a boost in their speed towards the edge, and we think that edge-directed transport is ultimately triggered by glucose," says Mukherji.
In beta cells, mitochondria are also involved in insulin secretion. Beta cells continually take up glucose from the bloodstream and convert it to ATP. When ATP levels within beta cells reach a certain threshold, it triggers an influx of calcium into the cell, which then triggers insulin secretion.
The researchers are now testing whether the glucose-induced change in mitochondrial movement is directly linked to insulin secretion. They also plan to develop methods to film mitochondrial movements in action.
"Mitochondria sit at this hub that connects glucose to insulin secretion," says Mukherji. "Showing that insulin secretion itself depends on where the mitochondria are in the cell will be essential for understanding how this is relevant to beta cells' physiological role, and for understanding where things could be breaking down in disease."
