title: Pathological consequences of MICU1 mutations on mitochondrial calcium signalling and bioenergetics.
abstract: Loss of function mutations of the protein MICU1, a regulator of mitochondrial Ca2+uptake, cause a neuronal and muscular disorder characterised by impaired cognition, muscle weakness and an extrapyramidal motor disorder. We have shown previously that MICU1 mutations cause increased resting mitochondrial Ca2+concentration ([Ca2+]m). We now explore the functional consequences of MICU1 mutations in patient derived fibroblasts in order to clarify the underlying pathophysiology of this disorder. We propose that deregulation of mitochondrial Ca2+uptake through loss of MICU1 raises resting [Ca2+]m, initiating a futile Ca2+cycle, whereby continuous mitochondrial Ca2+influx is balanced by Ca2+efflux through the sodium calcium exchanger (NLCXm). Thus, inhibition of NCLXmby CGP-37157 caused rapid mitochondrial Ca2+accumulation in patient but not control cells. We suggest that increased NCLX activity will increase sodium/proton exchange, potentially undermining oxidative phosphorylation, although this is balanced by dephosphorylation and activation of pyruvate dehydrogenase (PDH) in response to the increased [Ca2+]m. Consistent with this model, while ATP content in patient derived or control fibroblasts was not different, ATP increased significantly in response to CGP-37157 in the patient but not the control cells. In addition, EMRE expression levels were altered in MICU1 patient cells compared to the controls. The MICU1 mutations were associated with mitochondrial fragmentation which we show is related to altered DRP1 phosphorylation. Thus, MICU1 serves as a signal-noise discriminator in mitochondrial calcium signalling, limiting the energetic costs of mitochondrial Ca2+signalling which may undermine oxidative phosphorylation, especially in tissues with highly dynamic energetic demands. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Gauri
authors.initials: G
authors.lastname: Bhosale
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Jenny A
authors.initials: JA
authors.lastname: Sharpe
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Amanda
authors.initials: A
authors.lastname: Koh
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Antonina
authors.initials: A
authors.lastname: Kouli
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom; Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Szabadkai
authors.affiliation: Department of Cell and Developmental Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom. Electronic address: m.duchen@ucl.ac.uk.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Duchen
mesh_terms: D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics*; D027682:Cation Transport Proteins / Q000235:genetics*; D002478:Cells, Cultured; D004734:Energy Metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation
chemical_list: D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C116241:MICU1 protein, human; D033681:Mitochondrial Membrane Transport Proteins
keywords: Calcium; MICU1; Mitochondria; PDH