ElucidaTing the remodelling of mItochondrial Ca2+ signalling during the progression of MEtaboLic HFpEF to guide therapY

• Applicant: Professorin Fabiana Perocchi, Ph.D.
• Subject Area: Anatomy and Physiology ; Cell Biology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568914951

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 and obesity. Yet, effective therapy is lacking, partly due to the limited knowledge on the molecular determinants. Therefore, a better understanding of the molecular mechanisms involved in the development of HFpEF is urgently required. Alteration of sarcoplasmic reticulum-mitochondria Ca2+ coupling and mitochondrial metabolism has been demonstrated in animal models of HFpEF. Mitochondria play a central role in the regulation of the cardiac energy metabolism, notably through the modulation of the mitochondrial Ca2+ content. The mitochondrial Ca2+ uniporter (mtCU) represents here the key structure which controls Ca2+ entry inside the mitochondrial matrix. 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 the timecourse of 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 early and severe 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+ and metabolism signaling. We expect our collaborative work to identify the molecular determinants of the alteration of mitochondrial Ca2+ signaling in the pathogenesis of metabolic HFpEF, in order to propose novel therapeutic strategies.

• DFG Programme: Research Grants
• International Connection: France, USA
• Cooperation Partners: Professor Dr. Gyorgy Hajnoczky, Ph.D.; Professorin Dr. Melanie Paillard, Ph.D.; Professorin Dr. Hélène Thibault, Ph.D.