Abstract
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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | EMBO Journal |
| Vol/bind | 43 |
| Udgave nummer | 21 |
| Sider (fra-til) | 5288–5326 |
| Antal sider | 39 |
| ISSN | 0261-4189 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:The authors thank Tullio Pozzan for his substantial contribution to this study, both in the design of the experiments and interpretation of the results, until his passing in October 2022. The authors thank Marcus Conrad, Toshitaka Nakamura, Suresh Joseph and David Weaver for critical reading of the paper and helpful discussions; Tim K\u00F6nig and Daniela M. Arduino for experimental advice. FP, HCD, SW, NPD, MF, YC, and MC were supported by the Munich Center for Systems Neurology (SyNergy EXC 2145; Project ID 390857198) and the ExNet-0041-Phase2-3 (\u2018SyNergy-HMGU\u2019) through the Initiative and Network Fund of the Helmholtz Association. DVR was supported by the European Union funding program Horizon Europe (HORIZON-MSCA-2021-PF Project ID 101065790). JW, AL, and MG were supported by the German Research Foundation (DFG) under the Emmy Noether Programme (PE 2053/1-1) and the Bavarian Ministry of Sciences, Research and the Arts in the framework of the Bavarian Molecular Biosystems Research Network (D2\u2013F5121.2\u201310c/4822) MK and GH were supported by an NIH grant (RO1-HL142271) to GH The authors acknowledge Euro-BioImaging ( www.eurobioimaging.eu ) for providing access to imaging technologies and services via the ALM Node (Padua, Italy).
Publisher Copyright:
© The Author(s) 2024.