CMT 2A: Mitofusin 2 regulates STIM1 migration from the Ca2+ store to the plasma

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J Biol Chem. 2011 Jan 10.

Mitofusin 2 regulates STIM1 migration from the Ca2+ store to the plasma membrane

in cells with depolarised mitochondria.

Singaravelu K, C, Bakowski D, s de Brito O, Ng SW, Di Capite J,

T, Scorrano L, Parekh AB.

Oxford University, United Kingdom

Abstract

Store-operated Ca2+ channels in the plasma membrane (PM) are activated by the

depletion of Ca2+ from the endoplasmic reticulum (ER) and constitute a

widespread and highly conserved Ca2+ influx pathway. After store emptying, the

ER Ca2+ sensor STIM1 forms multimers, which then migrate to ER-PM junctions

where they activate the CRAC channel Orai1. Movement of an intracellular protein

to such specialised sites where it gates an ion channel is without precedence

but the fundamental question of how STIM1 migrates remains unresolved.

Here, we show that trafficking of STIM1 to ER-PM junctions and subsequent CRAC

channel activity is impaired following mitochondrial depolarisation. We identify

the dynamin-related mitochondrial protein mitofusin 2, mutations of which causes

the inherited neurodegenerative disease Charcot-Marie-Tooth IIa in humans, as an

important component of this mechanism.

Our results reveal a molecular mechanism whereby a mitochondrial fusion protein

regulates protein trafficking across the endoplasmic reticulum and reveals a

homeostatic mechanism whereby mitochondrial depolarisation can inhibit

store-operated Ca2+ entry, thereby reducing cellular Ca2+ overload.