Elucidating the remodelling of mitochondrial Ca2+ signalling during the progression of metabolic HFpEF to guide therapy
Heart failure with preserved ejection fraction (HFpEF) has become a major socio-economic burden, arising mostly from metabolic origin in front of the worldwide rising prevalence of type 2 diabetes (T2D) and obesity. Yet, effective therapy is lacking, partly due to the limited knowledge on the molecular determinants, notably in patients. Therefore, a better understanding of the molecular mechanisms involved in the development of HFpEF is urgently required. Mitochondria play a central role in the regulation of cardiac energy metabolism, notably through the modulation of mitochondrial Ca2+ content. The mitochondrial Ca2+ uniporter (mtCU) represents here the key structure which controls Ca2+ entry inside the mitochondrial matrix. Partner teams showed a reduced sarcoplasmic reticulum-mitochondria (SR-mito) Ca2+ coupling in a mouse model of early metabolic HFpEF; and a structural SR-mito Ca2+ uncoupling together with a mtCU gene remodeling in T2D patients evolving to HFpEF. Partners have developed innovative strategies to study the SR-mito Ca2+ coupling and the mtCU interactome. Based on this evidence, the TIMELY project aims at examining the molecular interplay between mitochondrial metabolism, sarcoplasmic reticulum-mitochondria Ca2+ signaling and the alteration of the mtCU during metabolic HFpEF. Our originality is to bring together experts in different fields from preclinical and human studies, to systems genetics and biocomputing through advanced technologies in microscopy, in order to make substantial progress towards treating metabolic HFpEF. Omics characterization of pre-clinical models of metabolic HFpEF, and human cardiac biopsies, will specify the molecular determinants of HFpEF in order to guide future therapy aiming at repurposing existing modifiers of mitochondrial Ca2+ signaling. We expect our collaborative work to identify the molecular determinants of the alteration of mitochondrial Ca2+ signaling in metabolic HFpEF, to propose novel therapeutic strategie
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Imported from OpenAIRE Germany | Grant ANR-25-CE14-3635.
Open sourceOverview
Grant agreement ANR-25-CE14-3635 | TIMELY
Open sourceHeart failure with preserved ejection fraction (HFpEF) has become a major socio-economic burden, arising mostly from metabolic origin in front of the worldwide rising prevalence of type 2 diabetes (T2D) and obesity. Yet, effective therapy is lacking, partly due to the limited knowledge on the molecular determinants, notably in patients. Therefore, a better understanding of the molecular mechanisms involved in the development of HFpEF is urgently required. Mitochondria play a central role in the regulation of cardiac energy metabolism, notably through the modulation of mitochondrial Ca2+ content. The mitochondrial Ca2+ uniporter (mtCU) represents here the key structure which controls Ca2+ entry inside the mitochondrial matrix. Partner teams showed a reduced sarcoplasmic reticulum-mitochondria (SR-mito) Ca2+ coupling in a mouse model of early metabolic HFpEF; and a structural SR-mito Ca2+ uncoupling together with a mtCU gene remodeling in T2D patients evolving to HFpEF. Partners have developed innovative strategies to study the SR-mito Ca2+ coupling and the mtCU interactome. Based on this evidence, the TIMELY project aims at examining the molecular interplay between mitochondrial metabolism, sarcoplasmic reticulum-mitochondria Ca2+ signaling and the alteration of the mtCU during metabolic HFpEF. Our originality is to bring together experts in different fields from preclinical and human studies, to systems genetics and biocomputing through advanced technologies in microscopy, in order to make substantial progress towards treating metabolic HFpEF. Omics characterization of pre-clinical models of metabolic HFpEF, and human cardiac biopsies, will specify the molecular determinants of HFpEF in order to guide future therapy aiming at repurposing existing modifiers of mitochondrial Ca2+ signaling. We expect our collaborative work to identify the molecular determinants of the alteration of mitochondrial Ca2+ signaling in metabolic HFpEF, to propose novel therapeutic strategie