Cells endure starvation conditions by rewiring their metabolic pathways. For example, in yeast, ribosomes are known to coat mitochondria. Exactly how this behavior promotes survival has remained unclear, even though it has interested scientists who believe that it could help us understand how cancer cells—always voracious—manage to thrive in difficult circumstances.
To look at the ribosome-mitochondria phenomenon more closely, scientists at the European Molecular Biology Laboratory (EMBL) and the University of Virginia (UV) used cryo-electron microscopy and cryo-electron tomography to uncover the molecular details of how Schizosaccharomyces pombe endure glucose deprivation.
The scientists, led by EMBL’s Simone Mattei, PhD, and UV’s Ahmad Jomaa, PhD, detailed their findings in Nature Communications, in an article titled, “Ribosomes hibernate on mitochondria during cellular stress.”
“Our study uncovers a previously unexplored adaptive mechanism operating within a eukaryotic system to ensure persistence,” the article’s authors wrote. “This mechanism exemplifies energy regulation under environmental stress through the recruitment of the protein synthesis machinery at the mitochondria and the suspension of biosynthetic activity. This response is underpinned by rearrangements at the organellar and molecular levels and contributes to the initiation of cell dormancy.”
Essentially, the scientists demonstrated that upon glucose depletion, yeast cells cease protein synthesis by resorting to the ribosome-mitochondria phenomenon. The scientists also elucidated the underlying mechanism: “[Hibernating] ribosomes tether to fragmented mitochondria and establish eukaryotic-specific, higher-order storage structures by assembling into oligomeric arrays on the mitochondrial surface.”
Ribosomes are the cell’s heavyweight molecular machinery that produces proteins. It turned out, however, that in hungry yeast cells, the ribosomes that crowd on the surface of the mitochondria don’t produce anything. They are hibernating.
“One way for a cell to survive stressful conditions until better days is to reduce its use of energy to a minimum,” explained Olivier Gemin, PhD, a postdoctoral fellow on the Mattei team and the lead author of the new study. “Producing proteins demands a lot of energy, which can be saved by blocking ribosomes.”
Why the hibernating ribosomes attach to the surface of mitochondria is a mystery.
“There could be different explanations,” Mattei said. “A starved cell will eventually start digesting itself, so the ribosomes might be coating the mitochondria to protect them. They might also attach to trigger a signaling cascade inside the mitochondria.”
Another possibility that Mattei is investigating relates to the fact that starving cells need a way to quickly start producing energy once food (in the form of glucose) is available again. Since mitochondria are the energy producers of the cell, having ribosomes nearby to produce necessary proteins might help this process along.
What made the scientists’ jaws drop was noticing that the ribosomes attach to the mitochondrial outer membrane in a way that contradicts what’s been known about them before.
“So far, ribosomes were known to interact with membranes only via their large subunit,” Mattei noted. “But in starved cells, we saw that they do this upside-down, via the small subunit!”
In their future studies, the team will investigate how and why the ribosomes attach in such an unusual way.
The struggles of the starved yeast cells have some similarities to those of cancer cells.
Believe it or not, being a cancer cell is really tough. When a tumor becomes aggressive, its cells grow so rapidly that their demand for nutrients and oxygen outpaces the supply. This means most cancer cells are constantly starving in a kind of hell they create for themselves.
Yet, they survive and even multiply.
“That’s why we need to understand the basics of adaptation to starvation and how these cells become dormant to stay alive and avoid death,” Jomaa said. “For that, we use yeast first, because we can manipulate it much more easily. Beyond this, we try to starve cultured cancer cells too, which is not easy, to figure out how they overcome starvation and can sometimes lead to cancer relapse.”
Understanding the principles of this adaptation could help us find ways to override it, making cancer cells vulnerable to starvation and thus more susceptible to treatment.