Logan 2015 Abstract MiPschool London 2015

From Bioblast
Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signalling.


Sharpe JA, Logan CV, Szabadkai G, Parry DA, Torelli S, Childs AM, Kriek M, Phadke R, Johnson CA, Roberts NY, Bonthron DT, Pysden KA, Whyte T, Munteanu I, Foley AR, Wheway G, Szymanska K, Natarajan S, Abdelhamed ZA, Morgan JE, Roper H, Santen GWE, Niks EH, van der Pol WL, Lindhout D, Raffaello A, De Stefani D, den Dunnen JT, Sun Y, Ginjaar I, Sewry CA, Hurles M, Rizzuto R, UK10K Consortium, Duchen MR, Muntoni F, Sheridan E (2015)

Event: MiPschool London 2015

Mitochondria play a key role in cellular calcium homeostasis. Mitochondrial calcium uptake through the Mitochondrial Calcium Uniporter (MCU) links cytosolic calcium signals to the regulation of oxidative phosphorylation, which matches energy supply with demand (e.g. during muscle contraction).

We have identified the first human disease caused by a primary defect in mitochondrial calcium handling. Individuals with mutations in Mitochondrial Calcium Uptake 1 (MICU1), a regulator of the MCU, have a novel disease phenotype characterised by proximal myopathy, learning difficulties and a progressive extrapyramidal movement disorder. Fibroblasts from skin biopsies from affected subjects were cultured and live cell fluorescence imaging used to probe mitochondrial function, morphology or calcium signalling, which was also explored using luminescence measurements of aequorin targeted to mitochondrial matrix. Respiration was measured using high resolution respirometry with the Oroboros Oxygraph 2k.

While mitochondrial membrane potential and mitochondrial respiration were normal, a significant number of MICU1-deficient cells displayed severely fragmented and calcium-loaded mitochondria at rest. Rates of agonist-induced mitochondrial calcium uptake were increased in patient derived fibroblasts while cytosolic calcium responses were reduced. Viral expression of MICU1 rescued this phenotype. Dynamic measurements of agonist stimulated cytosolic and mitochondrial calcium signals revealed that MICU1 deficiency causes a loss of physiological co-operative sigmoid regulation of mitochondrial calcium uptake.

These data reveal the role of MICU1 as a signal-noise discriminator for mitochondrial calcium handling. The loss of MICU1 is associated with excessive mitochondrial calcium loading even at resting cytosolic calcium concentrations. This in turn leads to mitochondrial stress and ultimately to disease affecting the CNS and muscle.

β€’ O2k-Network Lab: UK London Duchen MR

Labels: MiParea: Patients 

Organism: Human  Tissue;cell: Endothelial;epithelial;mesothelial cell, Fibroblast 

Regulation: Calcium 

HRR: Oxygraph-2k 


1-Leeds Inst Biomed Clinical Sc, Leeds, UK

2-Dept Cell Developm Biol, UCL, London, UK

3-Dept Biomed Sc, Univ Padua, Italy

4-UCL Inst Child Health, Dubowitz Neuromuscular Centre MRC Centre Neuromuscular Diseases, London, UK

5-Dept Paediatric Neurology, Leeds General Infirmary, UK

6-Center Human Clinical Genetics, Leiden Univ Med Center, The Netherlands

7-UCL Inst Neurol, MRC Centre Neuromuscular Dis, London, UK

8-Dept Paediatrics, Birmingham Heartlands Hospital, UK

9-Dept Neurology, Leiden Univ Medical Center, The Netherlands

10-Dept Neurol Neurosurgery, Univ Med Center Utrecht, The Netherlands

11-Dept Medical Genetics, Univ Med Center Utrecht, The Netherlands

12-Wolfson Centre Inherited Neuromuscular Dis, Oswestry, UK

13-Wellcome Trust Sanger Inst, Cambridge, UK

14-A full list of members and affiliations appear in the Supplementary of doi:10.1038/ng.2851.

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