Mitochondria are the small organelles that generate the energy our bodies need to grow, move, and stay healthy. As mitochondria have to constantly adjust their function to meet the cell's energy demands, the process of energy production is highly adaptable and is known to be adjusted by the nutrients available to the cell at a given moment. However, until now, it has been unclear how nutrients influence this adaptation.
Now, a research team led by Professor Dr Thorsten Hoppe from the Institute for Genetics and the CECAD Cluster of Excellence on Aging Research at the University of Cologne identified a novel pathway through which the amino acid leucine enhances mitochondrial function. The new findings demonstrate how leucine stabilizes key mitochondrial proteins and boosts energy production. They have been published under the title "Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration" in Nature Cell Biology.
Leucine is an essential amino acid, meaning it must be obtained through the diet. It is an important building block for protein synthesis and can be found in protein-rich foods such as dairy, meat, and legumes, such as beans and lentils. The researchers now found that leucine prevents the degradation of specific proteins present on the surface of mitochondria. These proteins support energy production by importing other metabolic molecules into the mitochondria. By preserving these proteins, leucine enables mitochondria to function more efficiently, ultimately boosting the cell's energy production.
"We were thrilled to discover that a cell's nutrient status, especially its leucine levels, directly impacts energy production," said Dr Qiaochu Li, first author of the study. "This mechanism enables cells to swiftly adapt to increased energy demands during periods of nutrient abundance."
The team also discovered that this regulation is mediated by SEL1L, a protein involved in cellular quality control. SEL1L typically identifies damaged or misfolded proteins for degradation. Leucine appears to downregulate SEL1L, thus reducing the degradation of mitochondrial proteins and consequently enhancing mitochondrial performance. "Modulating leucine and SEL1L levels could be a strategy to boost energy production," Li added. "However, it is important to proceed with caution. SEL1L also plays a crucial role in preventing the accumulation of damaged proteins, which is essential for long-term cellular health."
Indeed, while exploring the broader implications of their findings using the model organism Caenorhabditis elegans, the team observed that defects in the breakdown of leucine can negatively affect mitochondrial function and lead to fertility problems. Using human lung cancer cells, they also observed that certain cancer cell mutations that affect leucine metabolism enhance cancer cell survival, an important factor to consider in future cancer therapies.
These new findings provide important new evidence that the nutrients in our diet not only fuel the body, but also actively shape how energy is produced at the cellular level. By revealing how leucine influences mitochondrial metabolism, this study identifies potential new therapeutic targets for diseases associated with impaired energy production, such as cancer and metabolic disorders.
This research was supported by Germany's Excellence Strategy in the framework of CECAD as well as by various Collaborative Research Centres funded by the German Research Foundation (DFG). Additional support was provided by the European Research Council through the ERC Advanced Grant "Cellular Strategies of Protein Quality Control-Degradation" (CellularPQCD), and the Alexander von Humboldt Foundation.
