Vecellio 2015 Abstract MiPschool London 2015

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Identification and characterization of a novel MICU1 splicing variant.

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Vecellio D, Raffaello A, Vitulo N, Pegoraro E, Rizzuto R (2015)

Event: MiPschool London 2015

The ability of mitochondria to uptake calcium plays a fundamental role in the regulation of several biological processes [1]. In the last three years, the molecular identification of the pore-forming subunit, MCU [3], MCUb and EMRE, and its regulatory subunits, MICU1, MICU2 and MCUR1, pictures the mitochondrial Ca2+ uptake channel as one of the most sophisticated ion channel described so far. For many decades, it has been known that the uniporter exhibits tissue specific properties whose molecular basis remains to be elucidated [2].

We identified an alternative splicing isoform (hereafter named asMICU1) of the positive MCU modulator MICU1, characterized by the addition of a micro-exon coding for 4 conserved amino acids (QWFE). Interestingly, while MICU1 shows a ubiquitous expression, asMICU1 shows a peculiar tissues distribution, being highly expressed in tissues which display the greatest levels of mitochondrial calcium uptake, skeletal muscle and brain. asMICU1, when overexpressed in HeLa cells, causes a major increase in mitochondrial calcium uptake upon histamine stimulation compared to conventional MICU1, without affecting the cytosolic values. Furthermore, MICU2 overexpression in cells expressing asMICU1 is unable to block the increase in mitochondrial calcium uptake induced by asMICU1. Despite that, asMICU1 is able to form heterodimers with MICU2 and, at resting calcium levels, the heterodimer asMICU1-MICU2 is able to act as gatekeeper of the channel as well as MICU1-MICU2 heterodimer [4].

Keywords: MCU


Labels:


Tissue;cell: Skeletal muscle, Nervous system, HeLa 


Regulation: Calcium 




Abstract continued

In conclusion, we characterized a transcript variant of MICU1, asMICU1, whose expression is restricted to tissues with the highest levels of mitochondrial calcium uptake and shows a higher ability to activate MCU compared to conventional MICU1. Importantly, asMICU1 seems to exert a peculiar function when bound to MICU2.

Affiliations

1-Dept Biomed Sc, Univ degli Studi di Padova, Italy - denis.vecellioreane@studenti.unipd.it

2-Dept Biology, Univ degli Studi di Padova

3-Dept Neuroscience, Univ degli Studi di Padova

4-Neuroscience Inst, National Research Council, Padova

References

  1. Rizzuto R, De Stefani D, Raffaello A, Mammucari C (2012) Mitochondria as sensors and regulators of calcium signalling. Nat Rev Mol Cell Biol 13:566-78.
  2. Fieni F, Lee SB, Jan YN, Kirichok Y (2012) Activity of the mitochondrial calcium uniporter varies greatly between tissues. Nat Commun 3:1317.
  3. De Stefani D, Raffaello A, Teardo E, Szabò I, Rizzuto R (2011) A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476:336-40.
  4. Patron M, Checchetto V, Raffaello A, Teardo E, Vecellio Reane D, Mantoan M, Granatiero V, Szabò I, De Stefani D, Rizzuto R (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 53:726-37.