Research A single-amino-acid cleavage controls global mitochondrial complex integrity

Mitochondrial proteins need to be precisely processed after their import into mitochondria, but how these maturation steps contribute to mitochondrial function in human cells has remained unclear. In this study, researchers from the Vögtle lab together with Marcin Luzarowski, head of the Core Facility for Mass Spectrometry and Proteomics at Heidelberg University, and collaboration partners at the University of Freiburg investigated the role of the mitochondrial protease ICP55, which removes just a single amino acid from newly imported proteins. Using advanced proteomic approaches, the team identified more than 100 human ICP55 substrates and uncovered previously unknown cleavage specificities of the protease. 

Surprisingly, loss of this seemingly minor processing step had widespread consequences for mitochondrial organization. Without ICP55, proteins carrying just one additional amino acid were less efficiently maintained within large protein assemblies, resulting in destabilization of respiratory chain complexes, the mitochondrial HSP60 folding machinery and numerous other protein complexes. The findings reveal that the removal of a single amino acid can have proteome-wide consequences for mitochondrial protein complex integrity and identify precise N-terminal protein processing as an important layer of mitochondrial quality control.