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Delgado De La Herran, H.C. ; Vecellio Reane, D. ; Cheng, Y. ; Katona, M.* ; Hosp, F.* ; Greotti, E.* ; Wettmarshausen, J. ; Patron, M.* ; Mohr, H. ; Prudente de Mello, N. ; Chudenkova, M. ; Gorza, M. ; Walia, S.R. ; Feng, M. ; Leimpek, A. ; Mielenz, D.* ; Pellegata, N.S. ; Langer, T.* ; Hajnoczky, G.* ; Mann, M.* ; Murgia, M.* ; Perocchi, F.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

EMBO J., DOI: 10.1038/s44318-024-00219-w (2024)
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The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Calcium Signaling ; Mitochondria ; Mitochondrial Calcium Uniporter ; Organelle ; Proteomics; Ca2+; Protein; Micu1; Mcu; Identification; Cells; Oscillations; Mechanisms; Cytoscape; Membrane
Language english
Publication Year 2024
HGF-reported in Year 2024
ISSN (print) / ISBN 0261-4189
e-ISSN 1460-2075
Journal EMBO Journal, The
Publisher Wiley
Publishing Place Heidelberg, Germany
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Obesity (IDO)
Institute of Diabetes and Cancer (IDC)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502295-001
G-502200-001
G-502590-001
Grants NIH
Bavarian Molecular Biosystems Research Network
Bavarian Ministry of Sciences, Research
German Research Foundation (DFG)
European Union
Initiative and Network Fund of the Helmholtz Association
Munich Center for Systems Neurology (SyNergy)
DOI 10.1038/s44318-024-00219-w
WOS ID 001322037700002
Scopus ID 85203599731
PubMed ID 39261663
Erfassungsdatum 2024-10-23
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