If you studied biology in high school, you may recall that mitochondria are the cell’s ‘power plants.’ They are small kidney bean-shaped structures that convert nutrients entering the cell into ATP the cell’s energy currency. Cells use this currency to perform basic functions, such as encoding memories in nerve cells and detoxifying toxic chemicals in liver cells. Energy alone isn’t enough for cells to survive, they also need raw materials to build new cellular components, ensuring that each new cell receives a full and equal allotment.
“There’s one question we set out to answer, and that is, ‘Why is it that an acute injury can lead to diabetes?’ We’ve come to the following conclusion: ‘It is related to the activation of a particular white blood cell,’ ” says Craig Thompson, MD, a member of Memorial Sloan Kettering Cancer Center’s Cancer Biology and Genetics Program and senior author of a report printed November 6, 2024, in Nature. “What exactly are mitochondria balancing between bad and good for all the cells in our body?” It’s supposed to be easy for cells to square their balance sheets under typical circumstances, he says.
Dr. Thompson says to have an appreciation for the dilemma a cell finds itself in, consider what happens when you cut yourself. “It starts to bleed, and then bleed out the nutrients that normally keep the tissue viable.” Now the cells are in a stressful situation. They need urgently ATP to spend on the healing process and they need immediate new supplies to repair the wounded tissue. ‘But how the cell decides between these competing demands hasn’t been clear,’ said Yongmin Kim, one of the authors of the study.
In a new paper, Dr. Thompson and his colleagues detailed how mitochondria resolve this vexing problem. Dramatic and dynamic physical and chemical transformation of mitochondria give rise to distinct subpopulations, each specialized for meeting one or another of the demands that compete.
Looking at which, enzymes the two different pathways have in common provided one clue to the mystery of how mitochondria can carry out two different functions simultaneously. They found only one: an enzyme called P5CS. “It’s like a linchpin protein, you need it to make the judgment to go down one pathway or the other,” explains Dr. Thompson.
The team looked in greater detail at what P5CS was doing in the stressed-out cells and discovered that individual P5CS enzymes had teamed up to form long filaments. However, curiously, the filaments appeared in only one subpopulation of mitochondria; mitochondria from the other group did not contain the filaments.
The P5CS filaments were present within the subpopulation of mitochondria in other ways. Usually, the inner membrane of mitochondria, which make ATP, forms complex folded structures, called cristae, visible in textbooks appearing with their mitochondria. In the mitochondria that were P5CS cristae were lacking.
Then probing a little further, I realized that each subpopulation had taken its different role to the extreme: One population had dedicated itself to just making ATP while another population had dedicated itself to making new cellular building blocks. This division of labor has an essential upshot–each subpopulation got better and better at what it did and helps explain why those original stressed-out cells were able to make enough ATP and enough building blocks to keep themselves alive and grow in stressful conditions.
Why is that relevant to cancer? As anyone who has worked with cancer knows, cancer cells are pretty resilient, actually, and they can live in stressful conditions that normally kill normal cells. A tissue extracted from prostate cancer and examined to understand if there is a connection between mitochondrial changes and cancer growth, this was observed by Dr. Thompson. Sure enough, the tumors, as before, had discrete subpopulations of mitochondria, but the normal tissue did not.
“Amongst pancreatic ductal adenocarcinoma, these mitochondrial changes appear to be driving how cancer progresses,” says Dr. Thompson. The team also hopes to understand exactly how these mitochondrial changes may help promote cancer progression. “They could be fueling how cancer cells acquire the ability to metastasize or spread,” he says.
Reference: Ryu KW, Fung TS, Baker DC, et al. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature. 2024;635(8039):746-754. doi:10.1038/s41586-024-08146-w
