Cells must use nutrient resources as efficiently as possible to ensure survival. This involves an intricate balance between the synthesis and degradation of cellular components, the latter of which can be used to release metabolites of unnecessary components during periods of stress. Autophagy is a key intracellular degradation pathway that is triggered under such conditions. Autophagy captures and transports cellular material to a special compartment called the vacuole (or lysosome in animal cells), where it breaks down to produce basic metabolites such as amino acids, which are the building blocks of proteins. These metabolites can be returned to the cytoplasm for reuse by the cell.
How exactly are these autophagy-derived metabolites used? While scientists have found this recycling to be important, it is not known where the metabolites are needed in the cell.
To address this question, researchers from the Tokyo Institute of Technology (Tokyo Tech), Japan, and Monash University, Australia, including 2016 Nobel Laureate in Physiology or Medicine, Dr. Yoshinori Ohsumi, set out to identify how they are used. metabolites derived from autophagy. by cells. Their findings have been published in Communications from nature.
Dr. Alexander I. May, lead author of the article, explains: “We wanted to better understand the physiology of autophagy, which is a long-standing question in the field of autophagy research. We transferred mutant yeast cells, which are incapable of autophagy, from a glucose medium to an ethanol medium, forcing these cells to adapt to respiratory growth in a way that is very easy to observe. This change in respiration requires a large increase in mitochondrial function and, therefore, therefore, it involves the remodeling of most of the metabolic machinery of the cell. We found that yeast with defects in autophagy took longer to adapt to respiratory growth than normal yeast cells, and we worked backwards from this observation to find out why. “
The team then looked in more detail at the cells undergoing the fermentation transition, when yeast cells break down glucose into ethanol in the cytosol for energy, upon respiration, during which other carbohydrates are used to produce energy in mitochondria. They found that this transition triggers autophagy, suggesting that cells need to recycle metabolites to adapt to respiration.
What metabolites derived from autophagy help facilitate respiratory growth? To find out, the group first looked for nutrients that could be recycled by autophagy to support growth, adding metabolites individually to autophagy-defective mutant cultures and testing whether each metabolite could help cells adapt to respiration and thus support normal growth. It turned out that the amino acid serine is capable of rescuing the delayed adaptation of mutant cells from autophagy to respiratory growth.
Next, the authors asked how serine helps cells begin to breathe. Serine feeds on an important mitochondrial metabolic pathway called one-carbon metabolism. This pathway plays a central role in the initiation of protein synthesis in the mitochondria. Although few, these proteins are absolutely critical for mitochondrial respiration. Dr. May and his colleagues showed that key markers of mitochondrial one-carbon metabolism were altered in mutant autophagy cells, and that the addition of serine to these cells restored one-carbon metabolism and mitochondrial protein synthesis.
Explaining the results of this study, Dr. May says: “In yeast that adapts to respiratory growth, autophagy plays a central role in supplying serine to mitochondria, which otherwise experience a critical serine deficit. In addition, serine is used in numerous cellular pathways to mitochondrial respiration, suggesting that there is competition between these pathways. At a more conceptual level, our findings indicate that autophagy provides key adaptive pathways with sufficient precursors, allowing for more efficient deployment of cellular resources during their adaptation to environmental fluctuations. This is critical when the concentration of important metabolites is reduced during periods of stress such as the glycolytic to respiratory transition, when competition between cellular pathways for limited resources acts as a bottleneck in growth “
In addition to promoting our fundamental understanding of autophagy, this study establishes a still unknown link between autophagy and one-carbon metabolism, which is known to play an important role in cancer cell metabolism. The results may provide medical researchers developing therapeutic strategies with a new tool to attack cancer cells.
Materials provided by Tokyo Institute of Technology. Note: content can be edited for style and length.