Project Details
Projekt
The LETM1-TMBIM5 Axis: A Regulatory Network Linking Mitochondrial Ion Homeostasis to Cardiac Stress Adaptation and Proteostasis
Subject Area
Cardiology, Angiology
Term
since 2026
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 576557360
Mitochondrial dysfunction is a central driver of heart failure, yet the molecular mechanisms regulating mitochondrial homeostasis under cardiac stress remain incompletely understood. LETM1 (Leucine Zipper and EF-Hand Containing Transmembrane Protein 1), a highly conserved inner mitochondrial membrane protein, functions as a K⁺/H⁺ and Ca²⁺/H⁺ exchanger and is essential for mitochondrial biogenesis. Despite its association with Wolf-Hirschhorn syndrome, which features congenital heart defects, LETM1's role in cardiac physiology has never been systematically investigated. Our preliminary data reveal that LETM1 is markedly upregulated in ischemic cardiomyopathy and that cardiomyocyte-specific deletion of Letm1 causes embryonic lethality, demonstrating its essential role in heart development. Both gain and loss of LETM1 function severely impair mitochondrial oxidative phosphorylation and trigger caspase-dependent apoptosis. Remarkably, adult-onset conditional deletion of Letm1 initially causes cardiac dysfunction but recovers over time, coinciding with upregulation of TMBIM5, a mitochondrial Ca²⁺/H⁺ exchanger that directly interacts with LETM1 and the m-AAA protease AFG3L2. This recovery suggests that TMBIM5 can functionally compensate for LETM1 loss through overlapping roles in mitochondrial ion homeostasis and proteostasis. This project will provide the first comprehensive analysis of the LETM1-TMBIM5 regulatory axis in cardiac pathophysiology, defining how this network coordinates mitochondrial ion transport with protein quality control mechanisms. By elucidating these interactions, we aim to identify novel therapeutic targets for ischemic heart disease and mitochondrial cardiomyopathies.
DFG Programme
Research Grants
