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

• Grant number: 17/09443-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2017
• End date: January 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Luis Eduardo Soares Netto
• Grantee: Fernando Gomes
• Host 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

Abstract

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.

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

GOMES, FERNANDO; TURANO, HELENA; RAMOS, ANGELICA; NETTO, LUIS E. S.. Assessment of Submitochondrial Protein Localization in Budding Yeast Saccharomyces cerevisiae. JOVE-JOURNAL OF VISUALIZED EXPERIMENTS, n. 173, JUL 2021. (17/09443-3, 13/07937-8, 17/23839-7)

CONDELES, ANDRE LUIS; GOMES, FERNANDO; DE OLIVEIRA, MARCOS ANTONIO; SOARES NETTO, LUIS EDUARDO; TOLEDO JUNIOR, JOSE CARLOS. Thiol Peroxidases as Major Regulators of Intracellular Levels of Peroxynitrite in Live Saccharomyces cerevisiae Cells. ANTIOXIDANTS, v. 9, n. 5, MAY 2020. (13/07937-8, 17/09443-3)

PAULELA, JANAINA A.; GOMES, FERNANDO; CAMANDONA, VITTORIA DE LIMA; ALEGRIA, THIAGO G. P.; NETTO, LUIS E. S.; BLEICHER, LUCAS; BARROS, MARIO H.; FERREIRA-JUNIOR, JOSE RIBAMAR. Coq3p relevant residues for protein activity and stability. FEMS Yeast Research, v. 21, n. 7, p. 16-pg., 2021-11-01. (17/09443-3, 13/00586-5, 13/07937-8)

DEMASI, MARILENE; AUGUSTO, OHARA; BECHARA, ETELVINO J. H.; BICEV, RENATA N.; CERQUEIRA, FERNANDA M.; DA CUNHA, FERNANDA M.; DENICOLA, ANA; GOMES, FERNANDO; MIYAMOTO, SAYURI; NETTO, LUIS E. S.; et al. Oxidative Modification of Proteins: From Damage to Catalysis, Signaling, and Beyond. Antioxidants & Redox Signaling, v. N/A, p. 65-pg., 2021-04-26. (17/09443-3, 17/22501-2, 13/07937-8, 16/11724-8)