A MICU1 Splice Variant Confers High Sensitivity to the Mitochondrial Ca2+Uptake Machinery of Skeletal Muscle.
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.
Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy.
Denis
D
Vecellio Reane
Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy.
Francesca
F
Vallese
Department of Biology, University of Padua, 35122 Padua, Italy.
Vanessa
V
Checchetto
Laboratory of Protein Chemistry, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35122 Padua, Italy.
Laura
L
Acquasaliente
Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy.
Gaia
G
Butera
Laboratory of Protein Chemistry, Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35122 Padua, Italy.
Vincenzo
V
De Filippis
Department of Biology, University of Padua, 35122 Padua, Italy.
Ildikò
I
Szabò
Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy.
Giuseppe
G
Zanotti
Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy; CNR Institute of Neuroscience, National Council of Research, 35122 Padua, Italy. Electronic address: rosario.rizzuto@unipd.it.
Rosario
R
Rizzuto
Department of Biomedical Sciences, University of Padua, 35122 Padua, Italy. Electronic address: anna.raffaello@unipd.it.
Anna
A
Raffaello
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D017136:Ion Transport; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism*; D033681:Mitochondrial Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D060172:Morpholinos / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D009928:Organ Specificity; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D002135:Calcium-Binding Proteins; C000610715:MICU1 protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D060172:Morpholinos; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D002118:Calcium
alternative splicing; mitochondria; mitochondrial calcium homeostasis; mitochondrial calcium uniporter; mitochondrial calcium uptake; skeletal muscle