Molecular mechanisms underlying the suborganellar distribution of mammalian mitochondrial peroxiredoxins: impacts on physiology and pathology

• Grant number: 22/08446-7
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2023
• End date: March 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Agreement: National Research Foundation of Korea (NRF)
• Principal Investigator: Luis Eduardo Soares Netto
• Grantee: Luis Eduardo Soares Netto
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated scholarship(s): 23/01812-0 - Dissecting the molecular mechanisms underlying the mitochondrial import of mammalian peroxiredoxin 3 (Prdx3), BP.TT

Abstract

Mitochondria are not only the powerhouses of the cell, but also play central roles in biological processes such as aging, cancer and neurodegenerative diseases. H2O2 is a byproduct of oxidative phosphorylation that is now also recognized to mediate signaling pathways underlying physiology and pathology. Therefore, the comprehension of the mechanisms that degrade H2O2 generated inside the distinct mitochondrial compartments is highly relevant. Peroxiredoxins (Prxs) is by far the most relevant system responsible for H2O2 decomposition because these enzymes are abundant and highly reactive towards this oxidant. Surprisingly, the knowledge related to the localization of Prx on the four mitochondrial subcompartments (outer membrane, intermembrane space (IMS), inner membrane and matrix) is scarce. Therefore, this collaborative research proposal intends to elucidate the regulatory mechanisms of import, maturation and turnover of mitochondrial Prxs in different tissues of mice and in human cell cultures, taking advantage of the complementary skills of the Brazilian and South Korean groups that by different approaches have studied the localization of Prxs in mitochondria. This proposal contains four specific aims: 1) Determine the submitochondrial localization of PrxIII and PrxV; 2) Investigate the molecular mechanisms that control the submitochondrial distribution of PrxIII, PrxIV and PrxV; 3) Investigate the biological relevance of mitochondrial peroxiredoxin cleavage by MIP protease; 4) Investigate the effects of pathological conditions on the mitochondrial import of Prxs III and V, using animal models with liver diseases and cancers at the central nervous system. As this proposal deals on fundamental aspects of cell biology, we expect that high impact publications will be generated and that the knowledge may have impact on human health. (AU)

Scientific publications

(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; HADDAD, LUCIANA A.; NETTO, LUIS. E. S.. Human mitochondrial peroxiredoxin Prdx3 is dually localized in the intermembrane space and matrix subcompartments. REDOX BIOLOGY, v. 78, p. 13-pg., 2024-11-25. (22/08446-7, 23/01812-0, 17/09443-3, 13/07937-8, 17/23839-7)