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The dynamics of mitochondrial Ca2+ fluxes Fuente Pérez, Sergio De La Montenegro, Pablo Fonteriz García, Rosalba Inés Moreno Díaz-Calderón, Alfredo Domínguez Lobatón, María Carmen Montero Zoccola, María Teresa Álvarez Martín, Javier Producción Científica MICU1 (Ca2+ uptake protein 1, mitochondrial) is an important regulator of the MCU (Ca2+ uniporter protein, mitochondrial) that has been shown recently to act as a gatekeeper of the MCU at low [Ca2+]c (cytosolic [Ca2+]). In the present study we have investigated in detail the dynamics of MCU activity after shRNA-knockdown of MICU1 and we have found several new interesting properties. In MICU1-knockdown cells, the rate of mitochondrial Ca2+ uptake was largely increased at a low [Ca2+]c (<2 μM), but it was decreased at a high [Ca2+]c (>4 μM). In the 2-4 μM range a mixed behaviour was observed, where mitochondrial Ca2+ uptake started earlier in the MICU1-silenced cells, but at a lower rate than in the controls. The sensitivity of Ca2+ uptake to Ruthenium Red and Ru360 was similar at both high and low [Ca2+]c, indicating that the same Ca2+ pathway was operating in both cases. The increased Ca2+-uptake rate observed at a [Ca2+]c below 2 μM was transient and became inhibited during Ca2+ entry. Development of this inhibition was slow, requiring 5 min for completion, and was hardly reversible. Therefore MICU1 acts both as a MCU gatekeeper at low [Ca2+]c and as a cofactor necessary to reach the maximum Ca2+-uptake rate at high [Ca2+]c. Moreover, in the absence of MICU1, the MCU becomes sensitive to a slow-developing inhibition that requires prolonged increases in [Ca2+]c in the low micromolar range. 2024-04-15T09:13:59Z 2024-04-15T09:13:59Z 2014 info:eu-repo/semantics/article Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2010, vol. 1797, n. 10, p. 1727-1735 1879-2650 https://uvadoc.uva.es/handle/10324/67171 10.1016/j.bbabio.2010.06.008 1727 10 1735 Biochimica et Biophysica Acta (BBA) - Bioenergetics 1797 eng info:eu-repo/semantics/openAccess © 2010 Elsevier Elsevier SI