Article

MICU1 encodes a mitochondrial EF hand protein required for Ca uptake

Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nature (Impact Factor: 42.35). 09/2010; 467(7313):291-6. DOI: 10.1038/nature09358
Source: PubMed

ABSTRACT Mitochondrial calcium uptake has a central role in cell physiology by stimulating ATP production, shaping cytosolic calcium transients and regulating cell death. The biophysical properties of mitochondrial calcium uptake have been studied in detail, but the underlying proteins remain elusive. Here we use an integrative strategy to predict human genes involved in mitochondrial calcium entry based on clues from comparative physiology, evolutionary genomics and organelle proteomics. RNA interference against 13 top candidates highlighted one gene, CBARA1, that we call hereafter mitochondrial calcium uptake 1 (MICU1). Silencing MICU1 does not disrupt mitochondrial respiration or membrane potential but abolishes mitochondrial calcium entry in intact and permeabilized cells, and attenuates the metabolic coupling between cytosolic calcium transients and activation of matrix dehydrogenases. MICU1 is associated with the mitochondrial inner membrane and has two canonical EF hands that are essential for its activity, indicating a role in calcium sensing. MICU1 represents the founding member of a set of proteins required for high-capacity mitochondrial calcium uptake. Its discovery may lead to the complete molecular characterization of mitochondrial calcium uptake pathways, and offers genetic strategies for understanding their contribution to normal physiology and disease.

Download full-text

Full-text

Available from: Vishal M Gohil, Jul 28, 2015
0 Followers
 · 
144 Views
  • Source
    • "Instead, internal free calcium is taken up by the ER and mitochondria (Eisner et al., 2013; Hajnoczky et al., 2014). Mitochondrial calcium uptake is mediated by calcium transporters (in particular by the mitochondrial calcium uniporter mCU and by uncoupling proteins, UCPs (Perocchi et al., 2010; Baughman et al., 2011; De Stefani et al., 2011; Drago et al., 2011; Waldeck-Weiermair et al., 2011; Mallilankaraman et al., 2012 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dopamine (DA) releasing midbrain neurons are essential for multiple brain functions, such as voluntary movement, working memory, emotion and cognition. DA midbrain neurons within the substantia nigra (SN) and the ventral tegmental area (VTA) exhibit a variety of distinct axonal projections and cellular properties, and are differentially affected in diseases like schizophrenia, attention deficit hyperactivity disorder, and Parkinson's disease (PD). Apart from having diverse functions in health and disease states, DA midbrain neurons display distinct electrical activity patterns, crucial for DA release. These activity patterns are generated and modulated by specific sets of ion channels. Recently, two ion channels have been identified, not only contributing to these activity patterns and to functional properties of DA midbrain neurons, but also seem to render SN DA neurons particularly vulnerable to degeneration in PD and its animal models: L-type calcium channels (LTCCs) and ATP-sensitive potassium channels (K-ATPs). In this review, we focus on the emerging physiological and pathophysiological roles of these two ion channels (and their complex interplay with other ion channels), particularly in highly vulnerable SN DA neurons, as selective degeneration of these neurons causes the major motor symptoms of PD.
    Neuroscience 10/2014; 284. DOI:10.1016/j.neuroscience.2014.10.037 · 3.33 Impact Factor
  • Source
    • "Furthermore , as discussed in more detail below, Patron et al. [43] have recently suggested that MICU1 is a direct activator of MCU. Originally shown to be strongly associated with the inner mitochondrial membrane [33], MICU1 is predicted to have a transmembrane domain and it is relatively resistant to carbonate extraction [41], suggesting that it might be an integral membrane protein. "
    Biochemical and Biophysical Research Communications 04/2014; 449(4). DOI:10.1016/j.bbrc.2014.04.146 · 2.28 Impact Factor
  • Source
    • "Mitochondrial Ca 2+ uptake 1 ( MICU1 ) is a mitochondrial protein containing two canonical Ca 2+ - sensing EF - hands ( Perocchi et al . 2010 ) and interacts with the MCU ( Baughman et al . 2011 ; Mallilankaraman et al . 2012b ) . Si - lencing of MICU1 strikingly reduced mitochondrial Ca 2+ uptake in one study ( Perocchi et al . 2010 ) , whereas others reported a constitutively increased mitochondrial Ca 2+ con - centration under resting conditions but no effect on mitochon - drial Ca 2+ uptake by the MCU ( Mallilankaraman et al . 2012b ) . MICU1 appears to function as a gatekeeper for MCU - mediated mitochondrial Ca 2+ uptake and limits mitochondrial Ca 2+ uptake o"
    [Show abstract] [Hide abstract]
    ABSTRACT: Cerebral ischemia is a key pathophysiological feature of various brain insults. Inadequate oxygen supply can manifest regionally in stroke or as a result of traumatic brain injury or globally following cardiac arrest, all leading to irreversible brain damage. Mitochondrial function is essential for neuronal survival, since neurons critically depend on ATP synthesis generated by mitochondrial oxidative phosphorylation. Mitochondrial activity depends on Ca(2+) and is fueled either by Ca(2+) from the extracellular space when triggered by neuronal activity or by Ca(2+) released from the endoplasmic reticulum (ER) and taken up through specialized contact sites between the ER and mitochondria known as mitochondrial-associated ER membranes. The coordination of these Ca(2+) pools is required to synchronize mitochondrial respiration rates and ATP synthesis to physiological demands. In this review, we discuss the role of the proteins involved in mitochondrial Ca(2+) homeostasis in models of ischemia. The proteins include those important for the Ca(2+)-dependent motility of mitochondria and for Ca(2+) transfer from the ER to mitochondria, the tethering proteins that bring the two organelles together, inositol 1,4,5-triphosphate receptors that enable Ca(2+) release from the ER, voltage-dependent anion channels that allow Ca(2+) entry through the highly permeable outer mitochondrial membrane and the mitochondrial Ca(2+) uniporter together with its regulatory proteins that permit Ca(2+) entry into the mitochondrial matrix. Finally, we address those proteins important for the extrusion of Ca(2+) from the mitochondria such as the mitochondrial Na(+)/Ca(2+) exchanger or, if the mitochondrial Ca(2+) concentration exceeds a certain threshold, the mitochondrial permeability transition pore.
    Cell and Tissue Research 04/2014; 357(2). DOI:10.1007/s00441-014-1807-y · 3.33 Impact Factor
Show more