Molecular Cell
Volume 64, Issue 4, 17 November 2016, Pages 760-773
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Article
A MICU1 Splice Variant Confers High Sensitivity to the Mitochondrial Ca2+ Uptake Machinery of Skeletal Muscle

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Highlights

  • Skeletal muscle mitochondria express a unique MCU complex conserved in vertebrates

  • The complex prevalently contains the alternative splice isoform of MICU1, MICU1.1

  • MICU1.1-MICU2 heterodimers diminish the Ca2+ activation threshold of MCU

  • In skeletal muscle, MICU1.1 is required to amplify ATP supply for contraction

Summary

Skeletal muscle is a dynamic organ, characterized by an incredible ability to rapidly increase its rate of energy consumption to sustain activity. Muscle mitochondria provide most of the ATP required for contraction via oxidative phosphorylation. Here we found that skeletal muscle mitochondria express a unique MCU complex containing an alternative splice isoform of MICU1, MICU1.1, characterized by the addition of a micro-exon that is sufficient to greatly modify the properties of the MCU. Indeed, MICU1.1 binds Ca2+ one order of magnitude more efficiently than MICU1 and, when heterodimerized with MICU2, activates MCU current at lower Ca2+ concentrations than MICU1-MICU2 heterodimers. In skeletal muscle in vivo, MICU1.1 is required for sustained mitochondrial Ca2+ uptake and ATP production. These results highlight a novel mechanism of the molecular plasticity of the MCU Ca2+ uptake machinery that allows skeletal muscle mitochondria to be highly responsive to sarcoplasmic [Ca2+] responses.

Keywords

mitochondrial calcium uptake
alternative splicing
skeletal muscle
mitochondria
mitochondrial calcium homeostasis
mitochondrial calcium uniporter

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