Author response: The fate of pyruvate dictates cell growth by modulating cellular redox potential
Year: 2025
Type: peer-review
Abstract: Cells require nutrients to produce energy and build vital biomolecules, such as nucleic acids, proteins, lipids and carbohydrates to support organ functions. An imbalance of nutrients can significantly affect cell growth and behavior, which has been seen in diseases like cancer, diabetes and heart failure. Pyruvate is a key product of sugar metabolism. It can enter cell components called mitochondria to fuel energy production or be converted into lactate and other molecules to support the production of essential molecules (called biosynthesis) and maintain redox balance (i.e., the right proportion of electron carriers). The mitochondrial pyruvate carrier (MPC) controls how much pyruvate enters the mitochondria, and changes in its activity have been linked to abnormal cell growth and impaired heart function. Most of our understanding of this balance comes from studies of dividing cells, but it is less clear how pyruvate affects cells that no longer divide, such as liver cells or hepatocytes in the liver. To determine whether pyruvate metabolism directly influences biosynthetic capacity and growth of cells, Toshniwal et al. studied the fat body of fruit fly larvae, a metabolic organ analogous to the mammalian liver. The results showed that pyruvate metabolism affects cell size through changes in the redox balance of a cell. In genetically modified cells that overexpressed MPC, more pyruvate entered the mitochondria. This restricted the growth of cells and limited protein synthesis in the fat body cells of fruit fly larvae. Restricted cell growth was also observed in spheroids derived from human liver cancer cells and in primary rat hepatocytes. Further experiments revealed that the restricted cell growth was not the result of engaging the normal growth signaling pathways. Instead, it was due to changes in the way cells use pyruvate in the mitochondria. Rather than using it for energy production, the cells redirected it toward gluconeogenesis, producing and releasing glucose. This shift was caused by a more reduced redox state in the cell (more precisely, an imbalance in NADH/NAD+ levels). Because of this redox shift, the cells made fewer amino acids, and with fewer building blocks for proteins, the cells could not make as much protein, limiting their growth and size. These results demonstrate how specialized cells, such as hepatocytes, employ distinct metabolic adaptations to meet the organismal demands under varying nutritional conditions. The fate of pyruvate could profoundly influence the redox state and gluconeogenic capacity of the mammalian liver. Understanding these mechanisms may eventually benefit patients with metabolic disorders, such as diabetes. Until then, further studies are needed to translate these findings from model systems to human physiology and to evaluate the safety and efficacy of targeting these pathways in living organisms.
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4417364361
Cites:
Cited by:
Related to: