If you took biochemistry classes, chances are good you remember memorizing the Krebs cycle, a well-known metabolic pathway in which sugars are converted through a series of steps to generate ATP, a crucial fuel that powers many cellular processes. The Krebs cycle, also known as the tricarboxylic acid (TCA) cycle, was discovered by Hans Krebs in 1937, and once the process was outlined, what we knew about it remained largely unchanged. But scientists have now found that there is an alternate version of the TCA cycle. The findings have been reported in Nature.
Researchers have known that cells use various parts of the TCA cycle to various degrees, which has suggested that cells have a variety of ways to meet their energy needs, said study leader Lydia Finley, a cell biologist at the Sloan Kettering Institute (SKI). "Now, with this latest research, we can say there is a complete alternative to the canonical TCA cycle, and we explain how it works."
Part of the alternate pathway happens in organelles called the mitochondria and another in the cytosol. The cycle uses carbon found in sugar molecules to produce crucial molecules such as lipids instead of ATP. In addition, when a cell opts to use this alternate TCA cycle, it may undergo a change in identity.
In this study, the researchers referred back to Krebs' original work after they discovered that the TCA cycle could be disrupted in different ways, without stopping it. Some of the scientists noted that different cells can skip over parts of the Krebs cycle. Other researchers used CRISPR gene-editing tools to knock out enzymes in the Krebs cycle, but the lack of one or another was not halting the pathway. The team found that the original work only looked at the TCA cycle in pigeon breast muscle cells.
"Nobody really talks about that," and the researchers wondered if different kinds of cells would distinctly prefer one or the other pathway, said SKI graduate student and first study author Paige Arnold.
The researchers found that the cell preferred one version of the pathway when they were cultured as stem cells, and then switched to the other once they became cells called myotubes. Additional work confirmed that cell fate has an impact on which biochemical pathway the cell opts to utilize.
The Krebs cycle is great for producing energy. "But if you want to grow, ATP is actually not the limiting reagent. You actually need to retain those carbons to make new biomass," and that is where the alternate pathway becomes important, said Finley. Carbon can be picked up from the cytosol and used to build, instead of burning it for fuel.
This work may also be relevant to cancer cells, whose hallmark is unchecked growth. More research will be needed to study how this pathway works in vivo. The study authors cautioned that these experiments were done using cells growing in culture, and not in animal models.
It's worth noting that Nature rejected the original Krebs paper.