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MICU3 is a tissue-specific enhancer of mitochondrial calcium uptake

Cell Death & Differentiationvolume 26pages179195 (2019) | Download Citation

Abstract

The versatility and universality of Ca2+ as intracellular messenger is guaranteed by the compartmentalization of changes in [Ca2+]. In this context, mitochondrial Ca2+ plays a central role, by regulating both specific organelle functions and global cellular events. This versatility is also guaranteed by a cell type-specific Ca2+ signaling toolkit controlling specific cellular functions. Accordingly, mitochondrial Ca2+ uptake is mediated by a multimolecular structure, the MCU complex, which differs among various tissues. Its activity is indeed controlled by different components that cooperate to modulate specific channeling properties. We here investigate the role of MICU3, an EF-hand containing protein expressed at high levels, especially in brain. We show that MICU3 forms a disulfide bond-mediated dimer with MICU1, but not with MICU2, and it acts as enhancer of MCU-dependent mitochondrial Ca2+ uptake. Silencing of MICU3 in primary cortical neurons impairs Ca2+ signals elicited by synaptic activity, thus suggesting a specific role in regulating neuronal function.

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Acknowledgements

This work was supported by grants from the University of Padova (SID 2016 to DDS), the Italian Ministries of Health (Ricerca Finalizzata to R.R.), and of Education, University and Research (FIRB to RR), the European Union (ERC mitoCalcium, no. 294777), NIH (Grant #1P01AG025532-01A1), the Italian Association for Cancer Research (AIRC IG18633 to RR) and Telethon-Italy (GGP16029 to RR). M.P. is supported by an EMBO long-term fellowships (ALTF649-2015; LTFCOFUND2013; and GA-2013-609409). JE holds a post-doctoral fellowship from Junta de Extremadura (jointly financed by the European Regional Development Fund, ERDF, ref. PO14011)

Author Contributions

: MP, VG and JE performed the experiments and analyzed the data. MP, VG, DDS and RR designed the research. DDS and RR wrote the manuscript.

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Author notes

    • Maria Patron

    Present address: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine (CMMC), University of Cologne, Cologne, Germany

    • Veronica Granatiero

    Present address: Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, 401 East 61st Street, New York, NY, 10065, United States

  1. These authors contributed equally: Maria Patron, Veronica Granatiero.

Affiliations

  1. Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58B, 35131, Padova, Italy

    • Maria Patron
    • , Veronica Granatiero
    • , Javier Espino
    • , Rosario Rizzuto
    •  & Diego De Stefani
  2. Max Planck Institute for Biology and Aging, Cologne, Germany

    • Maria Patron

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Rosario Rizzuto or Diego De Stefani.

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https://doi.org/10.1038/s41418-018-0113-8

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