MICU1 regulation of mitochondrial Ca2+ uptake dictates survival and tissue regeneration
Open accessAbstract
Mitochondrial Ca 2+ uptake through the recently discovered Mitochondrial Calcium Uniporter (MCU) is controlled by its gatekeeper Mitochondrial Calcium Uptake 1 (MICU1). However, the physiological and pathological role of MICU1 remains unclear. Here we show that MICU1 is vital for adaptation to postnatal life and for tissue repair after injury. MICU1 knockout is perinatally lethal in mice without causing gross anatomical defects. We used liver regeneration after partial hepatectomy as a physiological stress response model. Upon MICU1 loss, early priming is unaffected, but the pro-inflammatory phase does not resolve and liver regeneration fails, with impaired cell cycle entry and extensive necrosis. Ca 2+ overload-induced mitochondrial permeability transition pore (PTP) opening is accelerated in MICU1-deficient hepatocytes. PTP inhibition prevents necrosis and rescues regeneration. Thus, our study identifies an unanticipated dependence of liver regeneration on MICU1 and highlights the importance of regulating MCU under stress conditions when the risk of Ca 2+ overload is elevated.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Perturbing activity of IMM Ca2+ uniporter (MCU, SMDT1, MICU1, MICU2) affects mouse survival and liver regeneration after partial hepatectomy by promoting mitochondrial Ca2+ overload and MPT-driven necrosis.
“Thus, perturbing the activity of the IMM Ca2+ uniporter, consisting of mitochondrial calcium uniporter (MCU), single-pass membrane protein with aspartate-rich tail 1 (SMDT1; also known as EMRE), mitochondrial calcium uptake 1 (MICU1) and MICU2, reportedly affects mouse survival and liver regeneration after partial hepatectomy by promoting mitochondrial Ca2+ overload and MPT-driven necrosis [417].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [417]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Experimental pathology of the liver
Higgins, G. (1931) · Medical Entomology and Zoology · Cited by 4,057 · see citing works
Higgins, G. (1931) · Cited by 2,444 · see citing works
Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter
Baughman, J. M., Perocchi, F., Girgis, H. S., Plovanich, M. E., Belcher-Timme, C. A., Sancak, Y., Bao, X., Strittmatter, L., Goldberger, O., Bogorad, R., et al. (2011) · Nature · doi:10.1038/nature10234 · Cited by 1,926 · see citing works
Mitochondria as sensors and regulators of calcium signalling
Rizzuto, R., De Stefani, D., Raffaello, A., & Mammucari, C. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3412 · Cited by 1,781 · see citing works
Mechanisms by which mitochondria transport calcium
Gunter, T. E., & Pfeiffer, D. R. (1990) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1990.258.5.c755 · Cited by 1,640 · see citing works
Liver regeneration: from myth to mechanism
Taub, R. (2004) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm1489 · Cited by 1,567 · see citing works
A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter
Stefani, D. D., Raffaello, A., Teardo, E., Szabò, I., & Rizzuto, R. (2011) · Nature · doi:10.1038/nature10230 · Cited by 1,431 · see citing works
The mitochondrial calcium uniporter is a highly selective ion channel
Kirichok, Y., Krapivinsky, G., & Clapham, D. E. (2004) · Nature · doi:10.1038/nature02246 · Cited by 1,409 · see citing works
Michalopoulos, G. K. (2007) · Journal of Cellular Physiology · doi:10.1002/jcp.21172 · Cited by 1,384 · see citing works
Decoding of cytosolic calcium oscillations in the mitochondria
Hajnóczky, G., Gaspers, L. D., Seitz, M. B., & Thomas, A. P. (1995) · Cell · doi:10.1016/0092-8674(95)90430-1 · Cited by 1,110 · see citing works
Self-citationMICU1 encodes a mitochondrial EF hand protein required for Ca2+ uptake
Perocchi, F., Gohil, V. M., Girgis, H. S., Bao, X. R., McCombs, J. E., Palmer, A. E., & Mootha, V. K. (2010) · Nature · doi:10.1038/nature09358 · Cited by 881 · see citing works
Liver Regeneration after Partial Hepatectomy
Michalopoulos, G. K. (2010) · The American Journal of Pathology · doi:10.2353/ajpath.2010.090675 · Cited by 713 · see citing works
Mallilankaraman, K. B., Doonan, P. J., Cárdenas, C., Chandramoorthy, H. C. K., Müller, M., Miller, R., Hoffman, N. E., Gandhirajan, R. K., Molgó, J., Birnbaum, M. J., et al. (2012) · Cell · doi:10.1016/j.cell.2012.10.011 · Cited by 661 · see citing works
Pan, X., Liu, J., Nguyen, T. T. M., Liu, C., Sun, J., Teng, Y., Fergusson, M. M., Rovira, I. I., Allen, M. D., Springer, D., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2868 · Cited by 645 · see citing works
A reproducible and well-tolerated method for 2/3 partial hepatectomy in mice
Mitchell, C., & Willenbring, H. (2008) · Nature Protocols · doi:10.1038/nprot.2008.80 · Cited by 577 · see citing works
Patrón, M., Checchetto, V., Raffaello, A., Teardo, E., Reane, D. V., Mantoan, M., Granatiero, V., Szabó, I., Stefani, D. D., & Rizzuto, R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.01.013 · Cited by 517 · see citing works
MICU1 Controls Both the Threshold and Cooperative Activation of the Mitochondrial Ca2+ Uniporter
Csordás, G., Golenár, T., Seifert, E. L., Kamer, K. J., Sancak, Y., Perocchi, F., Moffat, C., Weaver, D., de la Fuente, S., Bogorad, R. L., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.04.020 · Cited by 491 · see citing works
Self-citationPlovanich, M., Bogorad, R. L., Sancak, Y., Kamer, K. J., Strittmatter, L., Li, A. A., Girgis, H. S., Kuchimanchi, S., Groot, J. D., Speciner, L., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0055785 · Cited by 463 · see citing works
Norris, A. W., Chen, L., Fisher, S. J., Szanto, I., Ristow, M., Jozsi, A. C., Hirshman, M. F., Rosen, E. D., Goodyear, L. J., Gonzalez, F. J., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci17305 · Cited by 417 · see citing works
Mitochondria: The Hub of Cellular Ca2+Signaling
Szabadkai, G., & Duchen, M. R. (2008) · Physiology · doi:10.1152/physiol.00046.2007 · Cited by 403 · see citing works
Luongo, T. S., Lambert, J. P., Yuan, A., Zhang, X., Gross, P., Song, J., Shanmughapriya, S., Gao, E., Jain, M., Houser, S. R., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.017 · Cited by 384 · see citing works
Logan, C. V., Szabadkai, G., Sharpe, J. A., Parry, D. A., Torelli, S., Childs, A., Kriek, M., Phadke, R., Johnson, C. A., Roberts, N. Y., et al. (2013) · Nature Genetics · doi:10.1038/ng.2851 · Cited by 369 · see citing works
Kwong, J. Q., Lu, X., Correll, R. N., Schwanekamp, J. A., Vagnozzi, R. J., Sargent, M. A., York, A. J., Zhang, J. J., Bers, D. M., & Molkentin, J. D. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.06.002 · Cited by 360 · see citing works
Waldmeier, P. C., Feldtrauer, J.-J., Qian, T., & Lemasters, J. J. (2002) · Molecular Pharmacology · doi:10.1124/mol.62.1.22 · Cited by 288 · see citing works
Kristal, B. S., & Dubinsky, J. M. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69020524.x · Cited by 229 · see citing works
MICU1 and MICU2 play nonredundant roles in the regulation of the mitochondrial calcium uniporter
Kamer, K. J., & Mootha, V. K. (2014) · EMBO Reports · doi:10.1002/embr.201337946 · Cited by 218 · see citing works
Mitochondrial calcium function and dysfunction in the central nervous system
Nicholls, D. G. (2009) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2009.03.010 · Cited by 213 · see citing works
Structure and function of the mitochondrial calcium uniporter complex
Stefani, D. D., Patrón, M., & Rizzuto, R. (2015) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.04.008 · Cited by 206 · see citing works
Selzner, N., Selzner, M., Odermatt, B., Tian, Y., van Rooijen, N., & Clavien, P. (2003) · Gastroenterology · doi:10.1053/gast.2003.50098 · Cited by 201 · see citing works
MCU encodes the pore conducting mitochondrial calcium currents
Chaudhuri, D., Sancak, Y., Mootha, V. K., & Clapham, D. E. (2013) · eLife · doi:10.7554/elife.00704 · Cited by 181 · see citing works
Atlas of the developing mouse brain at E 17.5, P0, and P6
Paxinos, G., Halliday, G. M., WATSON, C. R. R., Koutcherov, Y., & Wang, H. (2007) · Elsevier eBooks · Cited by 143 · see citing works
Prostaglandins are required for CREB activation and cellular proliferation during liver regeneration
Rudnick, D. A., Perlmutter, D. H., & Muglia, L. J. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.151217998 · Cited by 136 · see citing works
Structural and mechanistic insights into MICU1 regulation of mitochondrial calcium uptake
Wang, L., Yang, X., Li, S., et al. (2014) · The EMBO Journal · doi:10.1002/embj.201386523 · Cited by 125 · see citing works
The elusive importance of being a mitochondrial Ca2+ uniporter
Pendin, D., Greotti, E., & Pozzan, T. (2014) · Cell Calcium · doi:10.1016/j.ceca.2014.02.008 · Cited by 94 · see citing works
Crumm, S. E., Cofán, M., Juskeviciute, E., & Hoek, J. B. (2008) · Hepatology · doi:10.1002/hep.22421 · Cited by 73 · see citing works
Self-citationFurchtgott, L., Chow, C. C., & Periwal, V. (2009) · Biophysical Journal · doi:10.1016/j.bpj.2009.01.061 · Cited by 70 · see citing works
Involvement of the innate immune system in liver regeneration and injury
Fausto, N. (2006) · Journal of Hepatology · doi:10.1016/j.jhep.2006.06.009 · Cited by 60 · see citing works
Mitochondrial calcium regulates rat liver regeneration through the modulation of apoptosis
Guerra, M. T., Fonseca, E. A., Melo, F. M., Andrade, V. A., Aguiar, C. J., de Andrade, L. M., Pinheiro, A. C. N., Casteluber, M. C. D. F., Resende, R. R., Pinto, M. C. X., et al. (2011) · Hepatology · doi:10.1002/hep.24367 · Cited by 58 · see citing works
Chou, C., Lai, S.-L., Chen, C., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066268 · Cited by 44 · see citing works
Cytosolic calcium regulates liver regeneration in the rat†
Lagoudakis, L., Garcin, I., Julien, B., et al. (2010) · Hepatology · doi:10.1002/hep.23673 · Cited by 39 · see citing works
Calcium Signalling and Liver Regeneration
Garcin, I., & Tordjmann, T. (2012) · International Journal of Hepatology · doi:10.1155/2012/630670 · Cited by 29 · see citing works
Pathology of the Developing Mouse
(2015) · CRC Press eBooks · doi:10.1201/b18160 · Cited by 27 · see citing works
MICU1 Serves as a Ca2+-Controlled Gatekeeper for the Mitochondrial Ca2+ Uniporter
Csordás, G., Golenár, T., Seifert, E. L., et al. (2012) · Biophysical Journal · doi:10.1016/j.bpj.2011.11.889 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
The mitochondrial Na+/Ca2+ exchanger is essential for Ca2+ homeostasis and viability
Luongo, T. S., Lambert, J. P., Gross, P., Nwokedi, M., Lombardi, A. A., Shanmughapriya, S., Carpenter, A. C., Kolmetzky, D., Gao, E., van Berlo, J. H., et al. (2017) · Nature · doi:10.1038/nature22082 · Cited by 396 · see citing works
Rottenberg, H., & Hoek, J. B. (2017) · Aging Cell · doi:10.1111/acel.12650 · Cited by 275 · see citing works
Self-citationThe roles of mitochondria in global and local intracellular calcium signalling
Cartes-Saavedra, B., Ghosh, A., & Hajnóczky, G. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00820-1 · Cited by 126 · see citing works
Self-citationThe Mitochondrial Ca2+ Uptake and the Fine-Tuning of Aerobic Metabolism
Gherardi, G., Monticelli, H., Rizzuto, R., & Mammucari, C. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.554904 · Cited by 109 · see citing works
- Authors
- Antony, A. N., Paillard, M., Moffat, C., Juskeviciute, E., Correnti, J., Bolon, B., Rubin, E., Csordás, G., Seifert, E. L., Hoek, J. B., & Hajnóczky, G.
- Affiliations
- Thomas Jefferson University (US)
- The Ohio State University (US)
- Corresponding author
- Seifert, Erin L.
- Hoek, Jan B.
- Hajnóczky, György
- Venue
- Nature Communications
- Published
- 2016-03-09
- Volume
- 7
- Issue
- 1
- Pages
- 10955-10955
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4786880
- OpenAlex
- W2294335173
- Cited by
- 206
- References
- 43
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 15 · 2023: 17 · 2022: 13 · 2021: 23 · 2020: 31 · 2019: 16 · 2018: 23 · 2017: 28 · 2016: 12
- FWCI
- 13.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Medicine Forum (submittedVersion, cc-by)
- HAL (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Heart Association
- Ohio State University (P30CA016058)
- University of South Carolina
- National Institutes of Health (NIM811, RO1 GM102724, CA016058)
- National Institute on Alcohol Abuse and Alcoholism (T32AA007463, R01 AA01887, R01AA018873)
- National Cancer Institute (CA016058, P30CA016058)
- National Institute of General Medical Sciences (R01GM102724)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- MICU1, mitochondrial calcium uptake, mitochondrial calcium uniporter, liver regeneration, partial hepatectomy, mitochondrial permeability transition pore, calcium overload, liver necrosis, tissue regeneration, postnatal adaptation, cell cycle entry
- MeSH terms
- Mitochondrial Permeability Transition Pore, Animals, Calcium, Calcium-Binding Proteins, Cell Survival, Female, Humans, Liver, Liver Regeneration, Male, Mice, Inbred C57BL, Mitochondria, Mice, Knockout, Hepatocytes, Mitochondrial Membrane Transport Proteins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
