MICU1 Motifs Define Mitochondrial Calcium Uniporter Binding and Activity

Nicholas E Hoffman,Harish C Chandramoorthy,Santhanam Shamugapriya,Xueqian Zhang,Sudarsan Rajan,Karthik Mallilankaraman,Rajesh Kumar Gandhirajan,Ronald J Vagnozzi,Lucas M Ferrer,Krishnalatha Sreekrishnanilayam,Kalimuthusamy Natarajaseenivasan,Sandhya Vallem,Thomas Force,Eric T Choi,Joseph Y Cheung,Muniswamy Madesh

doi:10.1016/j.celrep.2013.11.026

Nicholas E Hoffman, Harish C Chandramoorthy + Show 14 more

Open Access

https://doi.org/10.1016/j.celrep.2013.11.026

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Journal: Cell Reports	Publication Date: Dec 1, 2013
Citations: 125	License type: cc-by

Affiliation: Temple University, King Khalid University

Abstract

Resting mitochondrial matrix Ca(2+) is maintained through a mitochondrial calcium uptake 1 (MICU1)-established threshold inhibition of mitochondrial calcium uniporter (MCU) activity. It is not known how MICU1 interacts with MCU to establish this Ca(2+) threshold for mitochondrial Ca(2+) uptake and MCU activity. Here, we show that MICU1 localizes to the mitochondrial matrix side of the inner mitochondrial membrane and MICU1/MCU binding is determined by a MICU1 N-terminal polybasic domain and two interacting coiled-coil domains of MCU. Further investigation reveals that MICU1 forms homo-oligomers, and this oligomerization is independent of the polybasic region. However, the polybasic region confers MICU1 oligomeric binding to MCU and controls mitochondrial Ca(2+) current (IMCU). Moreover, MICU1 EF hands regulate MCU channel activity, but do not determine MCU binding. Loss of MICU1 promotes MCU activation leading to oxidative burden and a halt to cell migration. These studies establish a molecular mechanism for MICU1 control of MCU-mediated mitochondrial Ca(2+) accumulation, and dysregulation of this mechanism probably enhances vascular dysfunction.

Highlights

Receptor-mediated cytosolic Ca2+ flooding is rapidly cleared by endoplasmic reticulum refilling, plasma membrane efflux and mitochondrial Ca2+ uptake (Berridge et al, 2003; Soboloff et al, 2012)
We show that MICU1 interacts with Mitochondrial Ca2+ Uniporter (MCU) in the mitochondrial matrix and MICU1/ MCU binding is determined by a MICU1 N-terminal polybasic domain and two coiled-coil MCU domains
The MCU pore subunit is located in the inner mitochondrial membrane (IMM), and its regulator, MICU1, must be present either in the intermembrane space or the matrix side of the mitochondrial inner membrane

Summary

Introduction

Receptor-mediated cytosolic Ca2+ flooding is rapidly cleared by endoplasmic reticulum refilling, plasma membrane efflux and mitochondrial Ca2+ uptake (Berridge et al, 2003; Soboloff et al, 2012). In most eukaryotic non-excitable and excitable cells, carriers, exchangers and channels regulate mitochondrial Ca2+ uptake during the resting and active states (Drago et al, 2011; Duchen et al, 2008; Nicholls, 2005; Rizzuto et al, 2012; SantoDomingo and Demaurex, 2010; Williams et al, 2013). Mitochondrial Ca2+ uptake stimulates bioenergetics through activation of Ca2+ sensitive dehydrogenases and modulates ATP synthesis (Babcock et al, 1997; Balaban, 2009; Denton and McCormack, 1980; Duchen et al, 2008; Hajnoczky et al, 1995; Hansford, 1994; McCormack et al, 1990). Pathophysiological dysregulation of mitochondrial Ca2+ uptake has been linked to organ damage via chronic oxidative burden, autophagy, and cellular dysfunction (Baines et al, 2005; Cardenas et al, 2010; Clapham, 2007; Joiner et al, 2012; Lemasters et al, 2009; Mallilankaraman et al, 2012b)

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