Ryu KW, Fung TS, Baker DC, Saoi M, Park J, Febres-Aldana CA, Aly RG, Cui R, Sharma A, Fu Y, Jones OL. Cai X, Pasolli HA, Cross JR, Rudin CM, Thompson CB (2024) Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature 6: 1–9.

 

You see one; you’ve seen them all. That has been pretty much the view of mitochondria for some time. But maybe that isn’t the case after all. The laboratory of Craig Thompson reports that, under stress conditions, mitochondria assume different roles.  Dr. Thompson is the former president of Memorial Sloan Kettering Cancer Center and currently holds the Douglas A. Warner III Chair in the Cancer Biology and Genetics Program.

Dr. Thompson’s research team began their search with a careful rethinking of mitochondrial functions. While mitochondria have many key functions, they are best known for producing the energy that we all need from the food that we eat.  However, the Thompson lab was interested in the role of mitochondria in wound healing. Repairing tissue requires energy and also proteins, lipids, nucleic acids and other biomolecules. Thus, part of our food goes for the raw materials to synthesize new biomolecules to repair and/or maintain our tissues. They discovered that the amino acid proline is critical for wound healing and that the mitochondria are important for its synthesis.

With that discovery, they became curious about how the mitochondria balance their efforts to make energy and proline. As often happens in science, a few simple experiments conducted by changing the cell culture conditions left them with even more questions. The cells seemed to be able to both make energy and raw materials at the same time. How could that be?

To tackle that question, they exposed cells to 2 different sets of stresses. In one set cells were made to need more ATP, and in the other to need more proline. Surprisingly, when cells were deprived of proline, some of the mitochondria changed their morphology. They developed a series of filaments within the inner membrane that increase their ability to make proline and ornithine. When cells needed more ATP their mitochondria also separated into two distinct subpopulations. In fact, the two types of mitochondria could be differentiated by simple microscopy. The bonus finding was that an enzyme called pyroline-5-carboxylate synthase or P5CS was the key to how glutamate was used to yield the two types.

The separation of activities is closely related to the ability of mitochondria to fuse together and separate by fission. When the cell’s need for oxidative synthesis increases, P5CS is segregated into a subset of mitochondria that lack cristae and ATP synthase, the enzyme that makes ATP.

Thus, the mitochondria can easily rearrange themselves to focus on one process or the other. Interfering with the fission-fusion cycle inhibits their ability to specialize. This paper shows that mitochondrial fission and fusion are intimately involved in maintaining the balance between the need for energy and synthesis of biomolecules.

 

Reference

Ryu KW, Fung TS, Baker DC, Saoi M, Park J, Febres-Aldana CA, Aly RG, Cui R, Sharma A, Fu Y, Jones OL. Cai X, Pasolli HA, Cross JR, Rudin CM, Thompson CB (2024) Cellular ATP demand creates metabolically distinct subpopulations of mitochondria. Nature 6: 1–9.