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

Francesca Bertino; Dibyanti Mukherjee; Massimo Bonora; Christoph Bagowski; Jeannette Nardelli; Livia Metani; Diletta Isabella Zanin Venturini; Diego Chianese; Nicolas Santander; Iris Chiara Salaroglio; Andreas Hentschel; Elisa Quarta; Tullio Genova; Arpana Arjun McKinney; Anna Lucia Allocco; Veronica Fiorito; Sara Petrillo; Giorgia Ammirata; Francesco De Giorgio; Evan Dennis; Garrett Allington; Felicitas Maier; Moneef Shoukier; Karl Philipp Gloning; Luca Munaron; Federico Mussano; Ettore Salsano; Davide Pareyson; Maja di Rocco; Fiorella Altruda; Georgia Panagiotakos; Kristopher T. Kahle; Pierre Gressens; Chiara Riganti; Paolo P. Pinton; Andreas Roos; Thomas Arnold; Emanuela Tolosano; Deborah Chiabrando

doi:10.1016/j.xcrm.2024.101647

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

Francesca Bertino
, Dibyanti Mukherjee
, Massimo Bonora
, Christoph Bagowski
, Jeannette Nardelli
, Livia Metani
, Diletta Isabella Zanin Venturini
, Diego Chianese
, Nicolas Santander
, Iris Chiara Salaroglio
, Andreas Hentschel
, Elisa Quarta
, Tullio Genova
, Arpana Arjun McKinney
, Anna Lucia Allocco
, Veronica Fiorito
, Sara Petrillo
, Giorgia Ammirata
, Francesco De Giorgio
, Evan Dennis

Garrett Allington, Felicitas Maier, Moneef Shoukier, Karl Philipp Gloning, Luca Munaron, Federico Mussano, Ettore Salsano, Davide Pareyson, Maja di Rocco, Fiorella Altruda, Georgia Panagiotakos, Kristopher T. Kahle, Pierre Gressens, Chiara Riganti, Paolo P. Pinton, Andreas Roos, Thomas Arnold, Emanuela Tolosano, Deborah Chiabrando

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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 the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

Original language	English
Article number	101647
Journal	Cell Reports Medicine
Volume	5
Issue number	7
DOIs	https://doi.org/10.1016/j.xcrm.2024.101647
State	Published - 16 Jul 2024

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Bertino, F., Mukherjee, D., Bonora, M., Bagowski, C., Nardelli, J., Metani, L., Zanin Venturini, D. I., Chianese, D., Santander, N., Salaroglio, I. C., Hentschel, A., Quarta, E., Genova, T., McKinney, A. A., Allocco, A. L., Fiorito, V., Petrillo, S., Ammirata, G., De Giorgio, F., ... Chiabrando, D. (2024). Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus. Cell Reports Medicine, 5(7), Article 101647. https://doi.org/10.1016/j.xcrm.2024.101647

@article{cf3c90389af84859a8a886a95122298b,

title = "Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus",

abstract = "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 the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.",

author = "Francesca Bertino and Dibyanti Mukherjee and Massimo Bonora and Christoph Bagowski and Jeannette Nardelli and Livia Metani and \{Zanin Venturini\}, \{Diletta Isabella\} and Diego Chianese and Nicolas Santander and Salaroglio, \{Iris Chiara\} and Andreas Hentschel and Elisa Quarta and Tullio Genova and McKinney, \{Arpana Arjun\} and Allocco, \{Anna Lucia\} and Veronica Fiorito and Sara Petrillo and Giorgia Ammirata and \{De Giorgio\}, Francesco and Evan Dennis and Garrett Allington and Felicitas Maier and Moneef Shoukier and Gloning, \{Karl Philipp\} and Luca Munaron and Federico Mussano and Ettore Salsano and Davide Pareyson and \{di Rocco\}, Maja and Fiorella Altruda and Georgia Panagiotakos and Kahle, \{Kristopher T.\} and Pierre Gressens and Chiara Riganti and Pinton, \{Paolo P.\} and Andreas Roos and Thomas Arnold and Emanuela Tolosano and Deborah Chiabrando",

note = "Publisher Copyright: {\textcopyright} 2024 The Author(s)",

year = "2024",

month = jul,

day = "16",

doi = "10.1016/j.xcrm.2024.101647",

language = "English",

volume = "5",

journal = "Cell Reports Medicine",

issn = "2666-3791",

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Bertino, F, Mukherjee, D, Bonora, M, Bagowski, C, Nardelli, J, Metani, L, Zanin Venturini, DI, Chianese, D, Santander, N, Salaroglio, IC, Hentschel, A, Quarta, E, Genova, T, McKinney, AA, Allocco, AL, Fiorito, V, Petrillo, S, Ammirata, G, De Giorgio, F, Dennis, E, Allington, G, Maier, F, Shoukier, M, Gloning, KP, Munaron, L, Mussano, F, Salsano, E, Pareyson, D, di Rocco, M, Altruda, F, Panagiotakos, G, Kahle, KT, Gressens, P, Riganti, C, Pinton, PP, Roos, A, Arnold, T, Tolosano, E & Chiabrando, D 2024, 'Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus', Cell Reports Medicine, vol. 5, no. 7, 101647. https://doi.org/10.1016/j.xcrm.2024.101647

TY - JOUR

T1 - Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus

AU - Bertino, Francesca

AU - Mukherjee, Dibyanti

AU - Bonora, Massimo

AU - Bagowski, Christoph

AU - Nardelli, Jeannette

AU - Metani, Livia

AU - Zanin Venturini, Diletta Isabella

AU - Chianese, Diego

AU - Santander, Nicolas

AU - Salaroglio, Iris Chiara

AU - Hentschel, Andreas

AU - Quarta, Elisa

AU - Genova, Tullio

AU - McKinney, Arpana Arjun

AU - Allocco, Anna Lucia

AU - Fiorito, Veronica

AU - Petrillo, Sara

AU - Ammirata, Giorgia

AU - De Giorgio, Francesco

AU - Dennis, Evan

AU - Allington, Garrett

AU - Maier, Felicitas

AU - Shoukier, Moneef

AU - Gloning, Karl Philipp

AU - Munaron, Luca

AU - Mussano, Federico

AU - Salsano, Ettore

AU - Pareyson, Davide

AU - di Rocco, Maja

AU - Altruda, Fiorella

AU - Panagiotakos, Georgia

AU - Kahle, Kristopher T.

AU - Gressens, Pierre

AU - Riganti, Chiara

AU - Pinton, Paolo P.

AU - Roos, Andreas

AU - Arnold, Thomas

AU - Tolosano, Emanuela

AU - Chiabrando, Deborah

PY - 2024/7/16

Y1 - 2024/7/16

N2 - 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 the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

AB - 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 the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

UR - https://www.scopus.com/pages/publications/85198244442

U2 - 10.1016/j.xcrm.2024.101647

DO - 10.1016/j.xcrm.2024.101647

M3 - Article

AN - SCOPUS:85198244442

SN - 2666-3791

VL - 5

JO - Cell Reports Medicine

JF - Cell Reports Medicine

IS - 7

M1 - 101647

ER -

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

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