RT Journal Article
SR Electronic
T1 MICS1 is the Ca<sup>2+</sup>/H<sup>+</sup> antiporter of mammalian mitochondria
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.11.11.468204
DO 10.1101/2021.11.11.468204
A1 Shane Austin
A1 Ronald Mekis
A1 Sami E. M. Mohammed
A1 Mariafrancesca Scalise
A1 Christina Pfeiffer
A1 Michele Galluccio
A1 Tamara Borovec
A1 Katja Parapatics
A1 Dijana Vitko
A1 Nora Dinhopl
A1 Keiryn L. Bennett
A1 Cesare Indiveri
A1 Karin Nowikovsky
YR 2021
UL http://biorxiv.org/content/early/2021/11/12/2021.11.11.468204.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.