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MICS1 is the Ca2+ /H+ antiporter of mammalian mitochondria

Austin, S.; Mekis, R.; Mohammed, S. E. M.; Scalise, M.; Pfeiffer, C.; Galluccio, M.; Borovec, T.; Parapatics, K.; Vitko, D.; Dinhopl, N.; Bennett, K. L.; Nowikovsky, K.

2021-11-12 biochemistry
10.1101/2021.11.11.468204 bioRxiv
Show abstract

Mitochondrial Ca2+ ions are crucial regulators of bioenergetics, cell death pathways and cytosolic Ca2+ homeostasis. Mitochondrial Ca2+ content strictly depends on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+/H+ exchanger (CHE). Originally identified as the mitochondrial K+/H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identified MICS1, the only mitochondrial member of the TMBIM family. Applying cell-based and cell-free biochemical assays, here we demonstrate that MICS1 is responsible for the Na+- and permeability transition pore-independent mitochondrial Ca2+ release and identify MICS1 as the long-sought mitochondrial CHE. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.

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