Slow activation of fast mitochondrial Ca(2+) uptake by cytosolic Ca(2+)
| Autor: | Tullio Pozzan, Emy Basso, Giulia Rigotto, Andrés Ernesto Zucchetti |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Programmed cell death Cell Mitochondrion Bioenergetics Inbred C57BL Biochemistry Mitochondrial Membrane Transport Proteins 03 medical and health sciences Mice Cytosol calcium transport Organelle medicine Animals Humans Uniporter Molecular Biology Cation Transport Proteins Chemistry protein complex Calcium channel Calcium-Binding Proteins Biological Transport Cell Biology uniporter Cell biology Mitochondria Mice Inbred C57BL MCU MICU1 MICU2 calcium channel calcium overload channel activation mitochondria Calcium Calcium Channels HEK293 Cells HeLa Cells Liver 030104 developmental biology medicine.anatomical_structure Mitochondrial matrix |
| Popis: | Mitochondrial Ca(2+) uptake through the mitochondrial Ca(2+) uniporter (MCU) is a tightly controlled process that sustains cell functions mainly by fine-tuning oxidative metabolism to cellular needs. The kinetics of Ca(2+) fluxes across the mitochondrial membranes have been studied both in vitro and in vivo for many years, and the discovery of the molecular components of the MCU has further clarified that this Ca(2+) uptake mechanism is based on a complex system subject to elaborate layers of controls. Alterations in the speed or capacity of the in-and-out pathways can have detrimental consequences for both the organelle and the cell, impairing cellular metabolism and ultimately causing cell death. Here, we report that pretreatment of deenergized mitochondria with low-micromolar Ca(2+) concentrations for a few minutes markedly increases the speed of mitochondrial Ca(2+) uptake upon re-addition of an oxidizable substrate. We found that this phenomenon is sensitive to alterations in the level of the MCU modulator proteins mitochondrial calcium uptake 1 (MICU1) and 2 (MICU2), and is accompanied by changes in the association of MICU1–MICU2 complexes with MCU. This increased Ca(2+) uptake capacity, occurring under conditions mimicking those during ischemia/reperfusion in vivo, could lead to a massive amount of Ca(2+) entering the mitochondrial matrix even at relatively low levels of cytosolic Ca(2+). We conclude that the phenomenon uncovered here represents a potential threat of mitochondrial Ca(2+) overload to the cell. |
| Databáze: | OpenAIRE |
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