A University of Cologne team reports in Nature Cell Biology that the essential amino acid leucine enhances cellular energy production by preserving key outer‑mitochondrial‑membrane proteins through the quality‑control factor SEL1L, linking diet to organelle function and hinting at implications for metabolic disease and cancer.
Mitochondria must continually adjust to shifting energy demands, a process influenced by nutrients. A team led by Professor Dr. Thorsten Hoppe at the University of Cologne’s Institute for Genetics and the CECAD Cluster of Excellence on Aging Research has identified a nutrient‑responsive pathway that helps mitochondria meet those demands. According to the study, leucine stabilizes proteins on the outer mitochondrial membrane that are critical for respiration, thereby improving cellular energy output. (ScienceDaily; University of Cologne press office.) (sciencedaily.com)
The paper, “Leucine inhibits degradation of outer mitochondrial membrane proteins to adapt mitochondrial respiration,” reports that leucine reduces activity of SEL1L, a component of the cell’s protein‑quality‑control system, limiting degradation of these outer‑membrane proteins and supporting mitochondrial performance. Nature Cell Biology further details a leucine–GCN2–SEL1L axis that links amino‑acid sensing to mitochondrial proteostasis. (Nature Cell Biology.) (nature.com)
“We were thrilled to discover that a cell’s nutrient status, especially its leucine levels, directly impacts energy production,” said Dr. Qiaochu Li, the study’s first author. “This mechanism enables cells to swiftly adapt to increased energy demands during periods of nutrient abundance.” Li added a cautionary note: “Modulating leucine and SEL1L levels could be a strategy to boost energy production. 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.” (ScienceDaily; University of Cologne.) (sciencedaily.com)
The authors tested the mechanism in multiple systems. In Caenorhabditis elegans, defects in leucine catabolism impaired mitochondrial function and were linked to fertility problems. In human lung cancer cells, elevated intracellular branched‑chain amino acids reduced ubiquitylation of outer‑membrane proteins and increased resistance to inhibition of mitochondrial protein import, a finding the authors say could inform future cancer research. (Nature Cell Biology; University of Cologne.) (nature.com)
Leucine is an essential amino acid obtained from protein‑rich foods such as dairy, meat and legumes. While the work points to potential therapeutic targets, the researchers note that SEL1L is also vital for preventing the buildup of damaged proteins, underscoring the need for caution in any intervention. (ScienceDaily; University of Cologne.) (sciencedaily.com)
Funding came through Germany’s Excellence Strategy within CECAD, Collaborative Research Centres of the German Research Foundation (DFG), the European Research Council (ERC Advanced Grant “CellularPQCD”), and the Alexander von Humboldt Foundation. The study was published online on October 31, 2025, in Nature Cell Biology (DOI: 10.1038/s41556-025-01799-3). (ScienceDaily; University of Cologne; Nature Cell Biology.) (sciencedaily.com)
