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

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.