Journal
EMBO JOURNAL
Volume 32, Issue 17, Pages 2362-2376Publisher
WILEY
DOI: 10.1038/emboj.2013.157
Keywords
calcium homeostasis; channel; mitochondria; uniporter
Categories
Funding
- Italian Ministries of Health (Ricerca Finalizzata)
- Education, University and Research (PRIN, FIRB)
- European Union (ERC mitoCalcium) [294777, 223576]
- NIA [2P01AG025532-06A1]
- Cariparo and Cariplo Foundations (Padua)
- Italian Association for Cancer Research (AIRC)
- Telethon-Italy [GPP1005A, GGP11082]
Ask authors/readers for more resources
Mitochondrial calcium uniporter (MCU) channel is responsible for Ruthenium Red-sensitive mitochondrial calcium uptake. Here, we demonstrate MCU oligomerization by immunoprecipitation and Forster resonance energy transfer (FRET) and characterize a novel protein (MCUb) with two predicted transmembrane domains, 50% sequence similarity and a different expression profile from MCU. Based on computational modelling, MCUb includes critical amino-acid substitutions in the pore region and indeed MCUb does not form a calcium-permeable channel in planar lipid bilayers. In HeLa cells, MCUb is inserted into the oligomer and exerts a dominant-negative effect, reducing the [Ca2+](mt) increases evoked by agonist stimulation. Accordingly, in vitro co-expression of MCUb with MCU drastically reduces the probability of observing channel activity in planar lipid bilayer experiments. These data unveil the structural complexity of MCU and demonstrate a novel regulatory mechanism, based on the inclusion of dominant-negative subunits in a multimeric channel, that underlies the fine control of the physiologically and pathologically relevant process of mitochondrial calcium homeostasis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available