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Dysregulation of FLVCR1-dependent mitochondrial calcium handling in neural stem cells causes congenital hydrocephalus.

ABSTRACT: Congenital hydrocephalus (CH), occurring in approximately 1/1000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH-genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH Here we identify FLVCR1 (Feline Leukemia Virus Subgroup C Receptor 1) as a novel gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the heme exporter FLVCR1a interacts with IP3R3-VDAC, a complex located on mitochondrial-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1 in mouse neural stem cells (NSCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NSC calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Fiorella Andrea Solari

LAB HEAD: Albert Sickmann

PROVIDER: PXD047897 | Pride | 2024-08-09

REPOSITORIES: Pride

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Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus.

Bertino Francesca F Mukherjee Dibyanti D Bonora Massimo M Bagowski Christoph C Nardelli Jeannette J Metani Livia L Zanin Venturini Diletta Isabella DI Chianese Diego D Santander Nicolas N Salaroglio Iris Chiara IC Hentschel Andreas A Quarta Elisa E Genova Tullio T McKinney Arpana Arjun AA Allocco Anna Lucia AL Fiorito Veronica V Petrillo Sara S Ammirata Giorgia G De Giorgio Francesco F Dennis Evan E Allington Garrett G Maier Felicitas F Shoukier Moneef M Gloning Karl-Philipp KP Munaron Luca L Mussano Federico F Salsano Ettore E Pareyson Davide D di Rocco Maja M Altruda Fiorella F Panagiotakos Georgia G Kahle Kristopher T KT Gressens Pierre P Riganti Chiara C Pinton Paolo P PP Roos Andreas A Arnold Thomas T Tolosano Emanuela E Chiabrando Deborah D

Cell reports. Medicine 20240701 7

Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that t ...[more]

PMID: 39019006

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Project description:Intracellular calcium (Ca2+) overload is known to play a critical role in the development of cardiac dysfunction. Despite the remarkable improvement in managing the progression of heart disease, developing effective therapies for heart failure (HF) remains a challenge. A better understanding of molecular mechanisms that maintain proper Ca2+ levels and contractility in the injured heart could be of therapeutic value. Here, we report that the transcription factor Zinc finger E-box-binding homeobox2 (ZEB2) is induced by Hypoxia-inducible factor 1-alpha (HIF1a) in hypoxic cardiomyocytes and regulates a network of genes involved in Ca2+-handling and contractility during ischemic heart disease. Gain- and loss-of-function studies in genetic mouse models revealed ZEB2 in cardiomyocytes to be necessary and sufficient to protect the heart against ischemia-induced diastolic dysfunction and structural remodeling. Moreover, RNA sequencing (RNA-seq) of ZEB2-overexpressing (Zeb2 cTg) hearts post-injury implicated ZEB2 in regulating numerous Ca2+-handling and contractility-related genes. Mechanistically, ZEB2 overexpression increased the phosphorylation of phospholamban (PLN) at both serine-16 and threonine-17, implying enhanced activity of sarcoplasmic reticulum Ca2+-ATPase (SERCA2a), thereby augmenting SR Ca2+ uptake and contractility. Furthermore, we observed a decrease in the activity of Ca2+-dependent calcineurin/NFAT signaling in Zeb2 cTg hearts, which is the main driver of pathological cardiac remodeling. On a post-transcriptional level, we showed that ZEB2 expression can be regulated by the cardiomyocyte-specific microRNA-208a (miR-208a). Blocking the function of miR-208a with antimiR-208a increased ZEB2 expression in the heart and effectively protected from the development of pathological cardiac hypertrophy. Together, we present ZEB2 as a central regulator of contractility and Ca2+-handling components in the mammalian heart. Further mechanistic understanding of the role of ZEB2 in regulating Ca2+ homeostasis in cardiomyocytes is an essential step towards the development of improved therapies for HF.

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