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

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.

The mystery of mitochondrial plasticity: TMBIM5 integrates metabolic state and proteostasis

“…In summary, Patron et al (2022) identified a novel mechanism of proteome remodeling in mitochondria, one that is intertwined with the proton gradient and with Ca 2+ cycling and, therefore, with the bioenergetics status of mitochondria. Of note, the Ca 2+ /H + antiporter function of TMBIM5 was confirmed by a recent preprint (Austin et al , 2021) but was partially contradicted in a current study by Zhang et al (2022). Disagreements on the channel activity aside, the latter publication carries intriguing phenotypic data of a mouse TMBIM5 mutant that shows skeletal myopathy and increased perinatal mortality.…”

Post-translational modifications and protein quality control of mitochondrial channels and transporters

“…LETM1-KD H9c2 cells altered Ca 2+ efflux, indicating LETM1-HCX mediated Ca 2+ efflux ( Natarajan et al, 2020 ) whereas another finding showed that LETM1 mediated mitochondrial Ca 2+ regulation is facilitated by a LETM1-KHE activity, modulating the activity of the mitochondrial Na + /H + exchanger (mNHE) eventually affecting NCLX-mediated Ca 2+ efflux ( Austin et al, 2017 ). A recent study demonstrates that MICS1 is the long-sought mitochondrial CHE and interacts with LETM1, modulating its activity ( Austin et al, 2021 ). Irrespective of its individuality, LETM1 has been implicated in interaction with signaling proteins such as MRPL36, BCS1L and CTMP to modulate protein import and assembly in IMM, mitochondrial morphology and metabolism ( Park et al, 2014 ; Li et al, 2019 ).…”

Goldilocks calcium and the mitochondrial respiratory chain: too much, too little, just right

“…The membrane potential generated by the electron transport chain (ETC), with a negative matrix charge, provides the electrochemical force necessary for positively charged ions, such as Ca 2+ , to enter. Ca 2+ efflux from the mitochondrial matrix occurs through the Na + /Ca 2+ exchanger (NCLX) (11), located in the inner mitochondrial membrane (IMM), and by a Ca 2+ /H + exchanger, which may have been recently identified (12,13).…”