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Importing of peroxiredoxins to distinct mitochondrial compartments: impacts on physiology and pathology

Grant number: 17/09443-3
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): September 01, 2017
Effective date (End): August 31, 2020
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Luis Eduardo Soares Netto
Grantee:Fernando Gomes
Home Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID


Human mitochondria contain approximately 1500 different proteins, most of which (99%) are synthesized on cytosolic ribosomes, and subsequently imported to their functional destination in the mitochondrial subcompartments by specific targeting signals. Presequence is a sorting signal in the form of an N-terminal extension that directs the import of nearly all mitochondrial matrix proteins and a considerable fraction of inner membrane proteins, being cleaved off by the mitochondrial processing peptidase (MPP) after the import. Additionally, for a specific group of proteins, the octapeptidyl aminopeptidase 1 (Oct1) protease recognizes and cleaves an octapeptide localized in the N-terminal after initial processing by MPP. Physiological relevance of cleavage by Oct1 remains poorly characterized but appears to be involved in neurodegenerative diseases such as Friedreich's ataxia. Recently, we have shown that mitochondria peroxiredoxins (Prxs) from human beings (Prx3) and from yeast (Prx1) are cleaved by yeast Oct1. Furthermore, we showed that yeast Prx1 presents double location: in the matrix and intermembrane space, being transported through processes mediated by Oct1 and IMP complex, respectively. Prxs are thiol-dependent peroxidases that catalyze the reduction of a wide range of peroxides, including H2O2. In mammals, Prx3 and Prx5 are sorted to the mitochondrion, performing a significant role in peroxides metabolism. However, their distributions to the distinct mitochondrial subcompartments are still poorly characterized. The objective of this project is the investigation of the mechanisms of the import of Prxs into distinct mitochondrial compartments in different biological systems. The proposed translational approach involving different models (yeast, mouse, C. elegans and human cells) may have impacts on physiology and pathology, given the importance of Prxs in the metabolism of peroxides. It should be noted that little is known about the action of proteases like Oct1 and the IMP complex in the process of importing proteins into the various mitochondrial compartments.