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Role of mitochondrial unfolded protein response (UPRmt) in doxorubicin-induced cardiomyopathy: applying comparative metabolomics to identify metabolic signatures

Grant number: 19/07221-9
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): September 01, 2019
Effective date (End): August 31, 2020
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Julio Cesar Batista Ferreira
Grantee:Luiz Henrique Marchesi Bozi
Supervisor abroad: Edward T Chouchani
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Local de pesquisa : Harvard University, Boston, United States  
Associated to the scholarship:16/09611-0 - Doxorubicin-induced cardiotoxicity: role of mitochondrial retrograde signaling activated by protein imbalance, BP.PD

Abstract

Doxorubicin is an anthracycline widely used to treat different types of cancer including leukemia, lymphomas and breast cancer. However, it has high risk of cardiotoxicity since it accumulates and negatively affects cardiac mitochondrial proteostasis and bioenergetics. Disruption of mitochondrial proteostasis triggers a conserved signaling pathway termed mitochondrial unfolded protein response (UPRmt), responsible for re-establishing mitochondrial homeostasis and bioenergetics. Here we plan to study the role of UPRmt in doxorubicin-induced cardiomyopathy. Our preliminary data demonstrate that doxorubicin induces a transient and beneficial activation of UPRmt in muscle from C. elegans. However, in the long-term, UPRmt responsiveness to doxorubicin is lost, which is followed by impaired mitochondrial bioenergetics and reduced contractility properties. Therefore, suggesting that reduced UPRmt responsiveness might contribute to doxorubicin-induced cardiomyopathy In fact, a genetic model of dysfunctional UPRmt in C. elegans displays premature impaired mitochondrial bioenergetics and muscle dysfunction upon doxorubicin treatment. As a proof of concept, C. elegans with constitutively active UPRmt are resistant to doxorubicin toxicity. Similar results were found in hearts from mice exposed to doxorubicin, where injection of a single dose of doxorubicin activates UPRmt, which is followed by the re-establishment of both mitochondrial and cardiac function. However, chronic administration of doxorubicin is associated with UPRmt inhibition, mitochondrial dysfunction and heart failure. Genetic disruption of UPRmt exacerbates toxicity of doxorubicin in isolated cardiomyocytes. Collectively, our findings suggest that doxorubicin induces an acute compensatory activation of UPRmt that is lost in the long-term; therefore contributing to cardiac dusfinction. However, the molecular mechanisms behind UPRmt activation remain unclear. Considering the potential of UPRmt as a novel therapeutic target for the treatment of doxorubicin-induced cardiomyopathy, we decide to apply comparative metabolomics to identify metabolic pathways responsible for UPRmt-mediated resistance to doxorubicin.The current research proposal is a joint effort between the labs of Dr. Julio Ferreira (USP) and Dr. Edward Chouchani (Harvard). Dr. Chouchani´s lab focuses on unraveling mechanisms of the metabolic dysfunction that drives cardiovascular diseases. His lab applies mass spectrometry and biochemical approaches to identify mitochondrial metabolic signatures that control the protective and pathological signaling cascades initiated by this organelle. Therefore, this international cooperation will allow us to investigate the metabolic pathways responsible for UPRmt-mediated resistance to during doxorubicin-induced cardiotoxicity.

News published in Agência FAPESP Newsletter about the scholarship:
Molecule that regulates muscle adaptation to exercise is discovered 
Articles published in other media outlets (56 total):
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Jornal de Piracicaba: Cientistas identificam molécula que regula adaptação de músculos ao exercício físico (22/Sep/2020)
UOL: Descoberta molécula que regula a adaptação dos músculos ao exercício físico (17/Sep/2020)
Portal São José dos Campos: Pesquisadores de Harvard e da USP descobrem molécula que regula a adaptação dos músculos ao exercício físico (25/Feb/2021)
Santé blog (França): Muscle : Le succinate, la petite molécule qui l’adapte à l’exercice (15/Dec/2020)
Ltmuye.com (China): Cell论文详解!揭示锻炼期间肌肉细胞释放琥珀酸促进肌肉重塑机制论文 (08/Dec/2020)
Bioon.com (China): Cell论文详解!揭示锻炼期间肌肉细胞释放琥珀酸促进肌肉重塑机制 (07/Dec/2020)
Qihuangjy.com (China): Cell论文详解!揭示锻炼期间肌肉细胞释放琥珀酸促进肌肉重塑机制 (07/Dec/2020)
Notizie Scientifiche (Itália): Scoperta molecola che rinforza i muscoli a seguito dell’attività fisica (03/Dec/2020)
The Science Times (EUA): What’s Making Muscles Adapt To Exercise? (03/Dec/2020)
Metamag (França): Découverte d’une molécule qui renforce les muscles après une activité physique (03/Dec/2020)
Unica Radio (Itália): Il Succinato rinforza i muscoli a seguito dell’attività fisica (03/Dec/2020)
Tin Mới Giới (Vietnã): Ði?u gì làm cho co b?p thích nghi v?i vi?c t?p th? d?c? (03/Dec/2020)
Lab Manager (Canadá): Scientists Discover Molecule That Regulates Muscle Adaptation to Exercise (02/Dec/2020)
Knowledia (França): Researchers describe cellular mediator that makes muscle adaptation to exercise possible (02/Dec/2020)
Nuevo Periodico (EUA): Se descubre la molécula que regula la adaptación muscular al ejercicio (02/Dec/2020)
Globe Health News: Researchers describe cellular mediator that makes muscle adaptation to exercise possible (02/Dec/2020)
Technology Times (Paquistão): Molecule That Regulates Muscle Tissue To Exercise (02/Dec/2020)
Baladiyetelmahalla: Researchers describe cellular mediator that makes muscle adaptation to exercise possible (02/Dec/2020)
Phys.Org (Reino Unido): Molecule that regulates muscle adaptation to exercise is discovered (01/Dec/2020)
News Medical (Austrália): Researchers describe cellular mediator that makes muscle adaptation to exercise possible (01/Dec/2020)
Science Codex: Molecule that regulates muscle adaptation to exercise is discovered (01/Dec/2020)
Scienmag Science Magazine (Reino Unido): Molecule that regulates muscle adaptation to exercise is discovered (01/Dec/2020)
7thSpace: Molecule that regulates muscle adaptation to exercise is discovered (01/Dec/2020)
Burada Biliyorum (Turquia): Molecule that regulates muscle adaptation to exercise is discovered (01/Dec/2020)
QNewsHub (Índia): Molecule that regulates muscle adaptation to exercise is discovered (01/Dec/2020)
Pure Health News (EUA): Molecule that regulates muscle adaptation to exercise is discovered (01/Dec/2020)
Alpha Tech: Molecule that regulates muscle adaptation to train is found (01/Dec/2020)
Florida News Times (EUA): Molecules have been discovered that regulate muscle adaptation to exercise (01/Dec/2020)
Duna Press : SP: Pesquisadores da USP descobrem como o músculo se regenera após o exercício (06/Oct/2020)
Acontece Botucatu : Pesquisadores da USP descobrem como o músculo se regenera após o exercício (04/Oct/2020)
Portal da Cidade (Registro, SP): Pesquisadores da USP descobrem como o músculo se regenera após o exercício (04/Oct/2020)
Portal do Governo do Estado de São Paulo: Pesquisadores da USP descobrem como o músculo se regenera após o exercício (03/Oct/2020)
Notícias Botucatu: Pesquisadores da USP descobrem como o músculo se regenera após o exercício (03/Oct/2020)
Mix Vale: Pesquisadores da USP descobrem como o músculo se regenera após o exercício (03/Oct/2020)
Rápido no Ar: Pesquisadores da USP descobrem como o músculo se regenera após o exercício (03/Oct/2020)
Cidade Azul Notícias: Pesquisadores da USP descobrem como o músculo se regenera após o exercício (03/Oct/2020)
Secretaria da Educação do Estado de São Paulo: Cientistas identificam molécula que regula adaptação de músculos ao exercício físico (25/Sep/2020)
Diário da Saúde: Como seus músculos sabem que você está se exercitando? (22/Sep/2020)
Biblioteca FMUSP: Descoberta molécula que regula a adaptação dos músculos ao exercício físico (21/Sep/2020)
Beto Ribeiro Repórter: Cientistas identificam molécula que regula adaptação de músculos ao exercício físico (21/Sep/2020)
Portal da Cidade (Registro, SP): Cientistas identificam molécula que regula adaptação de músculos ao exercício (21/Sep/2020)
Região Noroeste : Molécula regula adaptação de músculos ao exercício físico (20/Sep/2020)
Notícias Botucatu: Cientistas identificam molécula que regula adaptação de músculos ao exercício físico (20/Sep/2020)
Folha Nobre: Cientistas identificam molécula que regula adaptação de músculos ao exercício físico (20/Sep/2020)
Portal do Governo do Estado de São Paulo: Cientistas identificam molécula que regula adaptação de músculos ao exercício físico (19/Sep/2020)
Sistema Costa Norte de Comunicação: Identificada molécula que regula adaptação de músculos a exercícios (19/Sep/2020)
Correio Independente: Cientistas identificam molécula que regula adaptação de músculos ao exercício físico (19/Sep/2020)
Top Stories Brazil: Identificada molécula que regula adaptação de músculos a exercícios (19/Sep/2020)
ABC - Academia Brasileira de Ciências : Descoberta molécula que regula a adaptação dos músculos ao exercício físico (18/Sep/2020)
MSN: Revelada molécula que regula adaptação de músculos a exercício físico (18/Sep/2020)
Revista Amazônia: Descoberta molécula que regula a adaptação dos músculos ao exercício físico (18/Sep/2020)
Planeta online: Revelada molécula que regula adaptação de músculos a exercício físico - Planeta (18/Sep/2020)
LabNetwork: Descoberta molécula que regula a adaptação dos músculos ao exercício físico (18/Sep/2020)
Portal da Enfermagem: Descoberta molécula que regula a adaptação dos músculos ao exercício físico (18/Sep/2020)
Revista Go Outside online: Descoberta molécula que regula a adaptação dos músculos ao exercício físico (18/Sep/2020)
Tito Volei Jequié: Descoberta molécula que regula a adaptação dos músculos ao exercício físico (17/Sep/2020)