Mitochondrial formyl peptides as signaling molecules in cardiac Ischemia-reperfusion injury

• Grant number: 19/25049-9
• Support Opportunities: Regular Research Grants
• Duration: May 01, 2020 - April 30, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Julio Cesar Batista Ferreira
• Grantee: Julio Cesar Batista Ferreira
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Mitochondria are key organelles involved in ATP production and regulation of several signaling cascades that ultimately affect cell death and survival. Mitochondrial dysfunction plays a critical role in the development and progression of cardiovascular diseases, such as myocardial infarction. Therefore, mitochondria have become an attractive therapeutic target for the treatment of cardiovascular diseases. Recently, mitochondrial-derived peptides (MDP) have emerged as a new class of communication conveyed by the mitochondrion to regulate cellular processes. Thus, we believe that exploratory studies to identify bioactive mitochondrial peptides and characterize their role in different pathophysiological conditions are crucial for the development of new therapies. Moreover, considering that protein synthesis in mitochondria starts with N-formyl methionine, such as in prokaryotes, we believe that damaged mitochondria can communicate with the organism at different levels (paracrine and autocrine actions) in a bacteria-like pathway, by releasing formyl peptides produced during maturation or degradation of mitochondrial-encoded proteins. Recent studies from our group and others have demonstrated that mitochondria are key players in the establishment and propagation of damage triggered by ischemia/reperfusion injury (IR). In addition, in a pilot study we observed disruption of mitochondrial proteostasis and consequent accumulation of peptides in mitochondrial fraction of rat hearts submitted to IR ex vivo. Next, we performed a mass spectrometry-based peptidomic screen and identified an N-formyl peptide in IR samples, derived from a mitochondrial-encoded protein. We then synthesized this formyl peptide and tested its biological effect on myoblast cell line, and observed an important role of this synthetic peptide in preventing cell death induced by hypoxia/reoxygenation (HR) in vitro. These preliminary results support our hypothesis that mitochondrial formyl peptides might act as signaling molecules in the process of ischemia/reperfusion injury and bring a new approach for the development of novel therapies against ischemic heart disease. Thus, in the present study we intend to understand the role of mitochondrial formyl peptides as signaling molecules in the process of cardiac ischemia/reperfusion injury. This study is interesting and valuable since a better understanding of the role mitochondrial formyl peptides may contribute for future therapies acting on key mechanisms involved in the pathophysiology of cardiac diseases. Finally, our proposal is deeply supported by outstanding international scientists such as Emer Suavinho Ferro (ICB-USP); Daria Mochly-Rosen (Stanford U., USA), Che-Hong Chen (Stanford U., USA), Alexander Van der Bliek (UCLA, USA), Antje Ebert (U. Gottingen, Alemanha) e Nir Qvit (Bar-llan U., Israel). (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)

PARADA, CAROLINA A.; DE OLIVEIRA, IVAN PIRES; GEWEHR, MAYARA C. F.; MACHADO-NETO, JOAO AGOSTINHO; LIMA, KELI; EICHLER, ROSANGELA A. S.; LOPES, LUCIA R.; BECHARA, LUIZ R. G.; FERREIRA, JULIO C. B.; FESTUCCIA, WILLIAM T.; et al. ffect of FKBP12-Derived Intracellular Peptides on Rapamycin-Induced FKBP-FRB Interaction and Autophag. ELL, v. 11, n. 3, FEB 2022. (19/25049-9, 13/07937-8, 19/27149-0, 17/02201-4, 16/04000-3, 19/07332-5, 19/23864-7)

GARCIA, ADRIANA A.; KOPERNIKU, ANA; FERREIRA, JULIO C. B.; MOCHLY-ROSEN, DARIA. Treatment strategies for glucose-6-phosphate dehydrogenase deficiency: past and future perspectives. TRENDS IN PHARMACOLOGICAL SCIENCES, v. 42, n. 10, p. 829-844, OCT 2021. (15/22814-5, 13/07937-8, 18/18627-3, 19/25049-9)

CAMPOS, JULIANE C.; CHEN, CHE-HONG; FERREIRA, JULIO C. B.. Comment on: ``Aldehyde dehydrogenases contribute to skeletal muscle homeostasis in healthy, aging, and Duchenne muscular dystrophy patients{''} by Etienne et al.. JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE, JUL 2020. (15/22814-5, 17/16540-5, 19/25049-9, 19/18444-9)