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Mitochondrial Ca2+/Na+ exchange in cardiac protection against ischemia/reperfusion induced by caloric restriction

Grant number: 23/00024-9
Support Opportunities:Research Grants - Visiting Researcher Grant - Brazil
Duration: August 01, 2023 - October 15, 2023
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Alicia Juliana Kowaltowski
Grantee:Alicia Juliana Kowaltowski
Visiting researcher: Heberty di Tarso Fernandes Facundo
Visiting researcher institution: Universidade Federal do Cariri (UFCA), Brazil
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:20/06970-5 - Mitochondrial ion transporters as sensors and regulators in energy metabolism, AP.TEM

Abstract

Cardiovascular diseases are important causes of mortality and morbidity. Cardiac infarction (also called cardiac ischemia) could be better managed clinically with a better understanding of stress-related mechanisms involved in cardiac ischemia. Several cardiac protection strategies have mitochondria as a target, including cardiac preconditioning and calorie restriction. Indeed, ischemic damage induces mitochondrial dysfunction. Additionally, drugs that protect mitochondria induce direct protection against cardiac infarction. The ischemic event leads (among other effects) to a loss of mitochondrial Ca2+ homeostasis. Mitochondria actively internalize Ca2+, but its excess under pathological conditions can induce mitochondrial damage. Excess Ca2+ is removed from the mitochondrial matrix by a Ca2+/Na+ exchanger (NCLX). The central hypothesis of this proposal is that NCLX may be involved in the pathological mechanisms of ischemia and protection induced by caloric restriction against ischemic damage. This hypothesis will be tested by pharmacological manipulations (using the NCLX inhibitor CGP-37157) and silencing of the gene encoding NCLX, using RNA interference. We will test the hypothesis that interventions that decrease NCLX activity (or levels) during caloric restriction reverse the protection of cardiac function and contraction in ischemia/reperfusion. We will investigate how pharmacological inhibition (or reduction in levels) of NCLX interferes with cell viability, mitochondrial calcium accumulation, and opening of the mitochondrial permeability transition pore during ischemia/reperfusion in caloric restriction models. We will test how the presence or absence of active NCLX can influence mitochondrial function (respiration, ATP generation, membrane potential, production of reactive oxygen species, among others) in cardiac tissue subjected to ischemia/reperfusion conditions in the presence of (or not) of caloric restriction. The results of this project may generate new therapies and uncover new approaches to treat heart diseases. (AU)

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