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Mitochondrial retrograde signaling profile during ischemia-reperfusion injury

Grant number: 14/24145-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): February 01, 2015
Effective date (End): December 31, 2015
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Ruda Prestes e Albuquerque
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Ischemic diseases represent the first cause of mortality and morbidity worldwide. The process known as Ischemia-Reperfusion (I/R) causes irreparable damage at the afflicted organs (i.e. heart, brain and kidney) as a result of the great variation of the tissue's oxygen tension. The reperfusion of ischemic tissue (low oxygen tension) results in an abrupt oxygen income (high oxygen tension), resulting in a metabolic breakdown, characterized by mitochondrial dysfunction and elevated free radicals burst. Nowadays tissue's reperfusion is described as a necessary evil because it is indispensable for the short term maintenance of life (after an ischemic insult), but it generates a metabolic dysfunction picture that will reduce the long term life expectation. Therefore, the full comprehension of the cell signaling events involved with the establishment and propagation of the metabolic dysfunction induced by the ischemia-Reperfusion is essential for the development of novel therapeutic strategies that might be applied at the treatment of myocardium infarction, stroke, renal ischemia and organ transplant. The current proposal intend to characterize the mitochondrial retrograde signaling profile during Ischemia-Reperfusion injury. Mitochondrial retrograde signaling pathway, also known as Mitochondrial Unfolded Protein Response, is a mitochondria- nucleus feedback process capable of maintaining the organelle's protein quality control over stress conditions that affect mitochondrial proteostase. During stress, small mitochondrial peptides are transported to the cytoplasm and activate specific proteins that migrate to the nucleus and induce the expression of mitochondrial chaperones, proteases and membrane transporters that will reestablish the optimal functioning of the organelle thru metabolic remodeling. We hypothesize that Ischemia-Reperfusion down regulates mitochondrial retrograde signaling, supporting the metabolic dysfunction picture. We emphasize that there is no data about this subject in the literature. In order to test our hypothesis MEF (mouse embryonic fibroblasts) cells will be submitted to the Ischemia-Reperfusion process and the retrograde signaling mitochondrial metabolism, inner membrane potential, peroxide production and cell viability will be measured. Finally our finding will be validated in a cardiac ischemia-reperfusion ex-vivo model using Wistar rats. The decision of initially characterize the mitochondrial unfolded protein response in the cellular level was taken because of the ease of hyper-expressing and silencing genes of interest, performing proofs of concept in this system (future step of this project, depending on our findings over the retrograde signaling pathway). The experiments with more complex systems (isolated rat's heart) were also planned in order to show the possible relevance of the mitochondrial retrograde signaling as a future therapeutic target over treatment of ischemic diseases.