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@ARTICLE{Deshpande:304091,
      author       = {A. Deshpande and L. Weirauch and T. K. Baral and M. Steier
                      and A. Borlepawar and M. Kumari and L. S. Kilian and K.
                      Richter$^*$ and E. Hammer and D. Frank and C. Schmidt and N.
                      Frey and A. Y. Rangrez},
      title        = {{E}levated levels of {L}etm1 drives mitochondrial
                      dysfunction and cardiomyocyte stress-mediated apoptosis in
                      cultured cardiomyocytes.},
      journal      = {Cell communication and signaling},
      volume       = {23},
      number       = {1},
      issn         = {1478-811X},
      address      = {London},
      publisher    = {Biomed Central},
      reportid     = {DKFZ-2025-01759},
      pages        = {378},
      year         = {2025},
      abstract     = {Cardiac ischemia, a predominant cause of heart failure, is
                      marked by profound mitochondrial dysfunction, dysregulated
                      ion homeostasis, and maladaptive cellular remodeling, all of
                      which compromise cardiac performance. The mitochondrial
                      inner membrane protein Leucine zipper-EF-hand containing
                      Transmembrane Protein 1 (Letm1), implicated in
                      Wolf-Hirschhorn Syndrome, is essential for mitochondrial
                      function. Although genetic alterations in Letm1 are linked
                      to cardiomyopathies, its specific contributions to cardiac
                      pathophysiology, particularly in the context of ischemic
                      heart disease, remain poorly defined. This study aims to
                      elucidate the role of Letm1 in ischemic cardiac pathology
                      and its mechanistic impact on cardiomyocyte function.Letm1
                      expression was assessed in human and murine models of heart
                      failure due to ischemic cardiomyopathy (ICM) and cardiac
                      hypertrophy. Letm1 was overexpressed in neonatal rat
                      ventricular cardiomyocytes, adult mouse cardiomyocytes, and
                      human induced pluripotent stem cell (iPSC)-derived
                      cardiomyocytes to study mitochondrial function (Seahorse
                      assays), structural and molecular remodeling (fluorescence
                      microscopy, transmission electron microscopy (TEM), qPCR,
                      immunoblotting), transcriptomic/proteomic profiles, calcium
                      handling and electrophysiology (patch-clamp), autophagic
                      flux (Bafilomycin A1, LC3-RFP-GFP), and cell survival.Letm1
                      was markedly upregulated in ICM in both human and murine
                      hearts, but unchanged in hypertrophic heart failure.
                      Overexpression of Letm1 in cardiomyocytes resulted in
                      profound mitochondrial dysfunction, including downregulation
                      of oxidative phosphorylation (OXPHOS) genes, impaired
                      membrane potential, reduced ATP output, increased proton
                      leak, and elevated ROS levels. A metabolic shift toward
                      glycolysis was observed, accompanied by reduced fatty acid
                      oxidation. Electron microscopy revealed mitochondrial
                      fragmentation, mitophagic vesicles, and sarcomeric disarray.
                      Transcriptomic and proteomic analyses highlighted
                      dysregulation of genes linked to mitochondrial organization,
                      ion transport, and autophagy. Electrophysiologically, Letm1
                      reduced L-type Ca2+ current density and significantly
                      shortened action potential duration, leading to impaired
                      contractility. Letm1 overexpression activated upstream
                      autophagy regulators (AMPK, ULK1) and enhanced LC3-II and
                      p62 accumulation, but autophagic flux was impaired, as
                      confirmed by LC3-RFP-GFP reporter and exacerbated by
                      Bafilomycin A1 treatment. This dysregulated autophagy was
                      coupled with mitochondrial stress, increased apoptosis
                      (cleaved caspases), and reduced cardiomyocyte viability.This
                      study indicates that Letm1 upregulation drives mitochondrial
                      dysfunction, electrophysiology alterations, and activation
                      of autophagy and apoptosis, culminating in cardiomyocyte
                      injury in ischemic cardiomyopathy. By disrupting OXPHOS,
                      calcium handling, and cell survival pathways, Letm1
                      contributes to ischemic remodeling and cardiac dysfunction.
                      Targeting Letm1 presents a promising therapeutic strategy to
                      alleviate ischemic damage and preserve cardiac function.},
      keywords     = {Myocytes, Cardiac: metabolism / Myocytes, Cardiac:
                      pathology / Animals / Humans / Apoptosis / Mice / Rats /
                      Mitochondria: metabolism / Mitochondria: pathology / Cells,
                      Cultured / Membrane Proteins: metabolism / Membrane
                      Proteins: genetics / Autophagy / Calcium-Binding Proteins:
                      metabolism / Calcium-Binding Proteins: genetics / Induced
                      Pluripotent Stem Cells: metabolism / Male / Arrhythmias
                      (Other) / Cardiomyocytes (Other) / Hypertrophy (Other) /
                      Letm1 (Other) / Mitochondrial metabolism (Other) / LETM1
                      protein, human (NLM Chemicals) / Membrane Proteins (NLM
                      Chemicals) / Calcium-Binding Proteins (NLM Chemicals)},
      cin          = {W230},
      ddc          = {570},
      cid          = {I:(DE-He78)W230-20160331},
      pnm          = {319H - Addenda (POF4-319H)},
      pid          = {G:(DE-HGF)POF4-319H},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40849623},
      doi          = {10.1186/s12964-025-02378-7},
      url          = {https://inrepo02.dkfz.de/record/304091},
}