Proteolytic control of the mitochondrial calcium uniporter complex
Name
Proteolytic control of the mitochondrial calcium uniporter complex
Size
1.26 MB
Format
Unknown
Checksum (MD5)
c89a51c9fa387ecd77b4bf47f48abf6e
Author(s)
Tsai, Chen-Wei
Wu, Yujiao
Pao, Ping-Chieh
Phillips, Charles B.
Williams, Carole
Miller, Christopher
Ranaghan, Matthew
Tsai, Ming-Feng
Date Issued
April 2017
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Tsai, Chen-Wei et al. “Proteolytic Control of the Mitochondrial Calcium Uniporter Complex.” Proceedings of the National Academy of Sciences 114, 17 (April 2017): 4388–4393 © 2017 National Academy of Sciences
Version
Final published version
Abstract
The mitochondrial calcium uniporter is a Ca²⁺-activated Ca²⁺ channel complex mediating mitochondrial Ca²⁺ uptake, a process crucial for Ca²⁺ signaling, bioenergetics, and cell death. The uniporter is composed of the pore-forming MCU protein, the gatekeeping MICU1 and MICU2 subunits, and EMRE, a single-passmembrane protein that links MCU and MICU1 together. As a bridging subunit required for channel function, EMRE could paradoxically inhibit uniporter complex formation if expressed in excess. Here, we show that mitochondrial mAAA proteases AFG3L2 and SPG7 rapidly degrade unassembled EMRE using the energy of ATP hydrolysis. Once EMRE is incorporated into the complex, its turnover is inhibited > 15-fold. Protease-resistant EMRE mutants produce uniporter subcomplexes that induce constitutive Ca²⁺ leakage into mitochondria, a condition linked to debilitating neuromuscular disorders in humans. The results highlight the dynamic nature of uniporter subunit assembly, which must be tightly regulated to ensure proper mitochondrial responses to intracellular Ca²⁺ signals.
MIT Department
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Picower Institute for Learning and Memory
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1073/pnas.1702938114
